二氧化氮与缺血性脑中风和血管性痴呆的相关性及其分子机制研究
|
摘要
NO2作为NOx的主要成分,是目前世界各国尤其是发达地区的主要大气污染物,和TSP、PM10、SO2等一同被列为各国大气环境质量监测和控制的重要对象。室外大气NO2主要来源于煤炭燃烧和汽车尾气排放,室内NO2主要来源于燃煤灶、燃气灶使用和抽烟等,许多职业场所包括用乙炔吹管焊接、电镀、会属清洗、采矿、染料制造、油漆以及公共场所如车库、渡轮和滑雪场中也可接触到高浓度N02。室外交通拥挤路段N02浓度一般不超过0.2ppm,室内则可高达2ppm,在职业暴露场所甚至会达到4ppm。因此,N02所引发的健康问题成为了国际共同关注的焦点话题。文献提示,NO2由口鼻进入体内时可通过腐蚀和刺激作用损害呼吸道深部细支气管及肺泡,故而,人们对NO2污染诱导呼吸系统损伤进而诱发相关疾病的效应给予了大量的关注,却忽视了它对其它组织系统的影响。
近年来,关于NO2诱导各类疾病病死率上升的流行病学数据大量涌现,特别是有学者指出,NO2会影响心脑血管系统和神经功能,并提示肺和支气管不是NO2毒性作用的唯一靶器官。因此在第一部分实验中,我们首先对正常大鼠进行了不同浓度(O、5、10和20mg/m3)NO2的吸入染毒处理,进而从氧化应激、炎性反应和细胞凋亡等多个角度考察了NO2对心脑组织的毒性作用。其中,组织病理损伤采用常规HE染色技术,而细胞凋亡则通过TUNEL标记法进行定量检测；抗氧化酶Cu/Zn-SOD、Mn-SOD和GPx的活性及NO和氧化产物MDA含量检测采用试剂盒法,PCO含量检测采用DNPH比色法；炎性因子TNF-α和IL-1β水平检测采用Elisa试剂盒法；即早和凋亡相关基因mRNA的表达检测采用实时定量RT-PCR技术。结果,在心肌组织中发现,NO2吸入可引起心肌组织的轻度病理学损伤,表现为心肌纤维排列紊乱,间隙变宽,心肌细胞收缩,染色质崩解团块,细胞核肿胀或收缩,并伴随浓度依赖性的炎性浸润。NO2吸入可促进或抑制抗氧化物酶的活性,促进氧化产物的形成；上调炎性因子TNF-α和IL-1p的表达与活性；上调凋亡相关基因p53的表达及bax与bcl-2的比值,导致细胞凋亡数目增加。与此同时,在大脑组织中检测到了与心肌组织中相类似的毒性损伤表现,包括组织病理损伤、细胞凋亡数量增加、抗氧化系统失调(Cu/Zn-SOD、Mn-SOD、GPx和NO活性及PCO含量)、即早基因(c-fos、c-jun)和凋亡基因(p53、bax和bcl-2)表达改变等多个方面。以上研究充分说明NO2吸入暴露可引起心肌和大脑毒性损伤,这可能会导致心脑血.管系统和神经系统疾病易感性的增加。
缺血性中风是当今社会导致人类死亡的第二大疾病,也是世界上致残性最强的疾病,其发病率极高,每年影响大约0.2%的人群的生命健康。在中国,缺血性中风每年以约9%的速度在增长。在美国,缺血性中风趋于年轻化,近十年5-44岁之间人群该病的发病率增长了近3倍之多。令人担忧的是,到目前为止,关于诱导缺血性中风发生的致病因子还未被完全揭示,也尚未找到对该疾病病死率进行控制的有效措施。近十年来,越来越多的流行病学调查报道,户外大气污染与中风的病死率相关,其效应污染物主要包括NO2、SO2、O3、CO和PM10等。不仅如此,更有学者发现N02可影响缺血性中风的发展结局,导致患者的早期死亡。然而,流行病学结果受样本量、调查范围和评定方法等方面的局限,且混杂因素较多,使得其结果可靠性较低,无法给出定性而统一的结论,更不能阐明相关分子机制。因此,在上一部分内容的基础上,我们重点探讨了N02与缺血性中风发生发展的相关性。血液流变学指标的检测采用宏润达YDA-IV全自动血液流变仪和旋转粘度仪进行测定；缺血性中风模型制备采用可逆性大脑中动脉闭塞(MCAO)线栓法；神经功能检测采用症状评分法；缺血局灶采用TTC染色法；组织病理和细胞凋亡分别采用HE和TUNEL法。结果发现,N02长期低浓度(5mg/m3)吸入可引起健康大鼠血液黏度,红细胞聚集指数、电泳指数和刚性指数等指标的上升,这一现象类似于缺血性中风患者的血液流变学特征。与此同时,我们建立了大鼠缺血中风模型并对其进行相同浓度的N02暴露,为期一周,结果发现,N02可时间依赖性地抑制MCAO大鼠神经结构和功能的恢复,加重MCAO引起的组织病理损伤和细胞凋亡。通过以上研究,我们证实了N02暴露诱导缺血性中风发生发展的效应。
内皮和炎性反应是缺血性中风发生发展过程中的两大主要病理机制。为了进一步阐明N02暴露诱导缺血性中风发生发展的具体分子机制,我们对Wistar大鼠进行了不同浓度N02的吸入染毒处理并考察了中风相关内皮和炎症因子的表达情况,结果发现,N02吸入可诱导大脑皮层内皮收缩因子ET-1、诱生型一氧化氮合酶iNOS、环氧化酶COX-2和细胞间黏附分子ICAM-1等因子mRNA和蛋白的表达而抑制内皮型一氧化氮合酶eNOS和脑型一氧化氮合酶nNOS的表达。在此基础上,我们又考察和比对了MCAO中风模型大鼠N02暴露前后大脑皮层以上因子的表达变化情况,结果发现MCAO处理同样引起了大鼠大脑皮层的内皮功能失调和炎症反应,而N02暴露会进一步加剧该损伤过程。本部分内容中中风相关因子mRNA和蛋白的表达分别采用了RT-PCR和Western blot技术,研究结果提示N02吸入通过内皮和炎性机制诱导了缺血性中风的发生发展,即：一方面打破内皮收缩因子的拮抗平衡,引起脑部血流减少,进而造成缺血损伤；另一方面诱导I1-1p、TNF-α的释放和iNOS、COX-2、ICAM-1的过表达,促进血液中炎性细胞的黏附和浸润,进而引起血液凝固,促进血栓形成,最终影响脑部血液供应,造成神经元凋亡和坏死。为了验证以上结果,我们又对健康大鼠进行了长时间的暴露染毒,发现eNOS、COX-2和ICAM-1在长期暴露后表达趋势与短期暴露结果相吻合,提示其可作为指示N02诱导缺血性中风效应发生的生物标记。
血管性痴呆是指因各种脑血管疾病,尤其是脑缺血等引起的脑功能障碍而造成的获得性智能障碍综合征,是缺血性中风的主要并发症或后遗症。我们的研究发现,N02吸入暴露引起了中风模型大鼠神经功能恢复的推迟,在一定程度上提示N02可能会增加血管性痴呆发生的风险。然而,到目前为止,该效应还未被阐明,相关分子机制则更不清楚。由于突触可塑性是大脑进行正常功能活动的分子细胞学机制和神经系统生长发育、神经损伤修复以及学习记忆的神经生物学基础,因此在本研究中将突触可塑性变化作为切入点来研究N02增加血管性痴呆患病风险的效应及其可能的分子机制。电镜观察结果显示,5mg/m3的N02吸入暴露不仅会加重缺血性中风模型大鼠大脑海马区神经元和突触的超微结构损伤,同时会诱导健康大鼠的神经元损伤效应。与此同时的Western Blot实验证明,N02吸入抑制了中风模型大鼠突触结构可塑性标记分子SYP和PSD-95的表达,以及突触功能可塑性LTP过程中关键调控因子蛋白的表达。与此相反,在健康大鼠中N02吸入却诱导了以上绝大部分蛋白的表达上调,并呈现出一定的浓度依赖性。以上结果提示,NO2吸入暴露会通过诱导健康大鼠的神经兴奋性毒性和降低中风模型大鼠的突触可塑性增加血管性痴呆发生的风险。
本课题实验结果揭示了N02对心脏和大脑组织的损伤效应,其分子机制与NO2对组织细胞的氧化作用有关,通过刺激炎症反应最终导致细胞的大量死亡,为肺以外其它组织中N02的毒性效应研究提供了一定的实验依据；阐明了N02与缺血性中风发生发展的相关性及其分子机制,建立了进行检测和危险度评价的生物标记；探讨了NO2与血管性痴呆发生发展的相关性及其突触机制,为污染事件发生时的临床治疗提供理论依据。
As important as TSP, PM10and SO2, NO2, the major component of nitrogen oxides (NOx), also represents an important urban pollutant in most developed cities of the world. People are widely exposed to NO2discharged from multiple sources including automobile exhaust, fossil fuel burning industries, gas cooking stoves, tobacco smoking and some others in occupational environment. Peak levels of up to0.2parts per million (ppm) are encountered in the outdoors, particularly along kerbsides in downtown areas with heavy motor vehicular traffic. Indoors NO2concentrations are often greater than those found outdoors, with peak levels exceeding2ppm in homes with unvented sources of combustion. In garages, ferries, skating ice rinks and kitchens with gas cookers, it can even reach up to4ppm. Herein, NO2-related health risks have become the global focal point. Due to the inhalation route of exposure, respiratory damage effect of NO2was always considered to be a key concern either in epidemiological or laboratory studies, while other effects were always ignored.
Recently, some epidemiological literatures linked NO2pollution with increasing risk of cardiovascular diseases and neurological disorders, which implied that lung is not the only target of NO2. To explore the toxicological effects of NO2on the heart and brain, a role for oxidative stress, inflammatory responses and cell apoptosis in the both tissues of rats treated with different concentrations of NO2(0,5,10and20mg/m3) was investigated. The pathological change was observed by Hematoxylin and eosin (HE) staining, and the number of apoptotic cells was quantified by TUNEL method; The activity or contents of Cu/Zn-SOD, Mn-SOD, GPx, MDA and NO were measured with test kits, while PCO were measured by DNPH assay; the levels of TNF-a and Ⅱ-1β were examined by ELISA; the mRNA expression of oncogenes and apoptosis-related genes were examined through real-time RT-PCR analysis. For the heart, mild pathology occurred after7-d exposure (6h/d); marked oxidative stresses were induced as reduction/induction of antioxidants (Cu/Zn-SOD, Mn-SOD and GPx) activity and increasing formation of MDA and PCO; mRNA and protein biomarkers of inflammation (TNF-α and IL-1β) were up-regulated, and p53mRNA expression, bax/bcl-2ratio and the mean number of TUNEL-positive myocytes were increased as well. For the brain, observable adverse effects were induced encompassing mild brain pathology, increased neuronal apoptosis, altered antioxidants (Cu/Zn-SOD, Mn-SOD, GPx and NO) activity and increasing formation of PCO after7-day exposure (6h/day); NO2inhalation also induced augment of oncogenes (c-fos, c-jun) levels, and deregulation of apoptosis-related genes (p53, bax and bcl-2) expression. With all above data, the present report provided essential information for the characterization of the cardiotoxic and neurotoxic hazard of NO2, which is required in response to the general concern about the vulnerability of the cardiovascular and neurological system to it.
Ischemic stroke is the second leading cause of death and the most frequent disease leading to disability in the world, with a high incidence affecting up to0.2%of the population every year. In China, the rate of ischemic stroke increased by almost9%every year. In USA, stroke rates in five to44-year-olds rose by about a third within10years. Worryingly, the risk factors for ischemic stroke have not been fully clarified, and the effective means to control its morbidity and mortality have not been found. In the last decade, an increasing body of epidemiologic literatures has provided compelling evidence to link outdoor air pollution to stroke mortality, with positive associations being observed for NO2, sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO) and particulate matter (PM). Moreover, it was reported that NO2could also influence the outcome of stroke patients. These effects, however, are not conclusive given the limited number of studies, their small size and their methodological constraints, which also leads to some contrary results. Moreover, relative molecular mechanisms cannot be elucidated by epidemiologic studies. Here the correlativity between NO2and ischemic stroke was determined. The hemorheological parameters were measured using YDA-IV blood viscosity apparatus; the rat model of ischemic stroke was set up using MCAO method; the behavioral deficits were measured through symptom scoring; the infarct volume were measured by TTC method; the pathological change and quantification of apoptosis cell number were measured by HE and TUNEL methods respectively. First, we found that blood viscosity, red blood cell (RBC) aggregation-, electrophoresis-and rigidity-index in healthy rats were increased after exposure to5mg/m3NO2for one-and three-month, which were very similar with the clinical phenomenon observed from ischemic stroke patients. Then, we set up stroke rat model and exposed them to NO2at the same concentration for one week, and found that NO2exposure time-dependently delayed neurological structure and function recovery of MCAO (middle cerebral artery occlusion) rat, and worsened pathological injuries and apoptosis induced by MCAO operation. Trough these studies, we confirmed the relevance of NO2exposure and ischemic stroke.
Endothelial and inflammatory responses are two common cellular pathomechanisms involved in ischemic brain damage. To elucidate the detailed mechanisms of ischemic stroke induced by NO2inhalation, we treated Wistar rats with NO2at various concentrations and determined the messenger RNA (mRNA) and protein expression of endothelin-1(ET-1), nitric oxide synthases (NOSs), cyclooxygenase-2(COX-2), and intercellular adhesion molecule1(ICAM-1) in the cortex, all of which are the endothelial and inflammatory biomarkers in stroke. The results showed that NO2elevated the levels of ET-1, iNOS, COX-2and ICAM-1mRNA and protein but inhibited the expression of eNOS and nNOS in a concentration-dependent manner. Then, we set up stroke rat model and exposed them to the lowest dose (5mg/m3) of NO2for one week, and found that endothelial injuries and inflammation were induced in cortex by MCAO treatment and exacerbated by followed NO2inhalation. The related mRNA and protein expression were examined via real-time RT-PCR technique as well as Western blotting method. In the present study, the upregulation of ET-1expression in rat cortex suggests the reduction of cerebral blood and a tendency to ischemic injuries via endothelial dysfunction following NO2inhalation. NO2inhalation-induced excessive expression of iNOS, COX-2and ICAM-1, as well as release of Ⅱ-1β and TNF-a could promote blood-borne inflammatory cell adherence and infiltration. Consequently, leukocytes exacerbated brain injury by physically obstructing capillaries and reducing blood flow during reperfusion and/or by migrating into the brain parenchyma and releasing cytotoxic products. Our data implicates the occurrence and development of ischemic injuries in rat brains via endothelial and inflammatory mechanisms after NO2exposure. Expression of eNOS, COX-2and ICAM-1protein after sub-chronic NO2exposure showed the same response as that observed after one-week exposure at higher concentrations, providing evidence that endothelial nitric oxide synthase (eNOS), cyclooxygenase-2(COX-2) and intercellular adhesion molecule1(ICAM-1) can be potential indicators for NO2-induced ischemic stroke.
As above reported, NO2could delay the recovery of nerve function after stroke, which implied a possible risk of vascular dementia (VaD) with NO2inhalation, which is often a common cognitive complication resulting from stroke. However, the effect and detailed mechanisms have not been fully elucidated. In the present study, synaptic mechanisms, the foundation of neuronal function and viability, were investigated in both model rats of ischemic stroke and healthy rats after NO2exposure. Transmission electron microscope (TEM) observation showed that5mg/m3NO2exposure not only exacerbated the ultrastructural impairment of synapses in stroke model rats, but also induced neuronal damage in healthy rats. Meantime, we found that the expression of synaptophysin (SYP) and postsynaptic density protein95(PSD-95), two structural markers of synapses in ischemic stroke model were inhibited by NO2inhalation; and so it was with the key proteins mediating long-term potentiation (LTP), the major form of synaptic plasticity. On the contrary, NO2inhalation induced the expression of nearly all these proteins in healthy rats in a concentration-dependent manner. All the proteins expression were examined by Western blotting method. Our results indicated that NO2exposure could increase the risk of VaD through inducing excitotoxicity in healthy rats but weakening synaptic plasticity directly in stroke model rats.
In conclusion, this work revealed the damage effect of NO2inhalation on the heart and brain, confirmed an association between NO2inhalation and increased risk for ischemic stroke as well as VaD, elucidated the related molecular mechanisms and explored the molecular markers for indicating these effects, which will help us open up therapeutic approaches to prevent, ameliorate, or treate heart and brain disorders resulting from NO2exposure in its polluting areas.
近年来,关于NO2诱导各类疾病病死率上升的流行病学数据大量涌现,特别是有学者指出,NO2会影响心脑血管系统和神经功能,并提示肺和支气管不是NO2毒性作用的唯一靶器官。因此在第一部分实验中,我们首先对正常大鼠进行了不同浓度(O、5、10和20mg/m3)NO2的吸入染毒处理,进而从氧化应激、炎性反应和细胞凋亡等多个角度考察了NO2对心脑组织的毒性作用。其中,组织病理损伤采用常规HE染色技术,而细胞凋亡则通过TUNEL标记法进行定量检测；抗氧化酶Cu/Zn-SOD、Mn-SOD和GPx的活性及NO和氧化产物MDA含量检测采用试剂盒法,PCO含量检测采用DNPH比色法；炎性因子TNF-α和IL-1β水平检测采用Elisa试剂盒法；即早和凋亡相关基因mRNA的表达检测采用实时定量RT-PCR技术。结果,在心肌组织中发现,NO2吸入可引起心肌组织的轻度病理学损伤,表现为心肌纤维排列紊乱,间隙变宽,心肌细胞收缩,染色质崩解团块,细胞核肿胀或收缩,并伴随浓度依赖性的炎性浸润。NO2吸入可促进或抑制抗氧化物酶的活性,促进氧化产物的形成；上调炎性因子TNF-α和IL-1p的表达与活性；上调凋亡相关基因p53的表达及bax与bcl-2的比值,导致细胞凋亡数目增加。与此同时,在大脑组织中检测到了与心肌组织中相类似的毒性损伤表现,包括组织病理损伤、细胞凋亡数量增加、抗氧化系统失调(Cu/Zn-SOD、Mn-SOD、GPx和NO活性及PCO含量)、即早基因(c-fos、c-jun)和凋亡基因(p53、bax和bcl-2)表达改变等多个方面。以上研究充分说明NO2吸入暴露可引起心肌和大脑毒性损伤,这可能会导致心脑血.管系统和神经系统疾病易感性的增加。
缺血性中风是当今社会导致人类死亡的第二大疾病,也是世界上致残性最强的疾病,其发病率极高,每年影响大约0.2%的人群的生命健康。在中国,缺血性中风每年以约9%的速度在增长。在美国,缺血性中风趋于年轻化,近十年5-44岁之间人群该病的发病率增长了近3倍之多。令人担忧的是,到目前为止,关于诱导缺血性中风发生的致病因子还未被完全揭示,也尚未找到对该疾病病死率进行控制的有效措施。近十年来,越来越多的流行病学调查报道,户外大气污染与中风的病死率相关,其效应污染物主要包括NO2、SO2、O3、CO和PM10等。不仅如此,更有学者发现N02可影响缺血性中风的发展结局,导致患者的早期死亡。然而,流行病学结果受样本量、调查范围和评定方法等方面的局限,且混杂因素较多,使得其结果可靠性较低,无法给出定性而统一的结论,更不能阐明相关分子机制。因此,在上一部分内容的基础上,我们重点探讨了N02与缺血性中风发生发展的相关性。血液流变学指标的检测采用宏润达YDA-IV全自动血液流变仪和旋转粘度仪进行测定；缺血性中风模型制备采用可逆性大脑中动脉闭塞(MCAO)线栓法；神经功能检测采用症状评分法；缺血局灶采用TTC染色法；组织病理和细胞凋亡分别采用HE和TUNEL法。结果发现,N02长期低浓度(5mg/m3)吸入可引起健康大鼠血液黏度,红细胞聚集指数、电泳指数和刚性指数等指标的上升,这一现象类似于缺血性中风患者的血液流变学特征。与此同时,我们建立了大鼠缺血中风模型并对其进行相同浓度的N02暴露,为期一周,结果发现,N02可时间依赖性地抑制MCAO大鼠神经结构和功能的恢复,加重MCAO引起的组织病理损伤和细胞凋亡。通过以上研究,我们证实了N02暴露诱导缺血性中风发生发展的效应。
内皮和炎性反应是缺血性中风发生发展过程中的两大主要病理机制。为了进一步阐明N02暴露诱导缺血性中风发生发展的具体分子机制,我们对Wistar大鼠进行了不同浓度N02的吸入染毒处理并考察了中风相关内皮和炎症因子的表达情况,结果发现,N02吸入可诱导大脑皮层内皮收缩因子ET-1、诱生型一氧化氮合酶iNOS、环氧化酶COX-2和细胞间黏附分子ICAM-1等因子mRNA和蛋白的表达而抑制内皮型一氧化氮合酶eNOS和脑型一氧化氮合酶nNOS的表达。在此基础上,我们又考察和比对了MCAO中风模型大鼠N02暴露前后大脑皮层以上因子的表达变化情况,结果发现MCAO处理同样引起了大鼠大脑皮层的内皮功能失调和炎症反应,而N02暴露会进一步加剧该损伤过程。本部分内容中中风相关因子mRNA和蛋白的表达分别采用了RT-PCR和Western blot技术,研究结果提示N02吸入通过内皮和炎性机制诱导了缺血性中风的发生发展,即：一方面打破内皮收缩因子的拮抗平衡,引起脑部血流减少,进而造成缺血损伤；另一方面诱导I1-1p、TNF-α的释放和iNOS、COX-2、ICAM-1的过表达,促进血液中炎性细胞的黏附和浸润,进而引起血液凝固,促进血栓形成,最终影响脑部血液供应,造成神经元凋亡和坏死。为了验证以上结果,我们又对健康大鼠进行了长时间的暴露染毒,发现eNOS、COX-2和ICAM-1在长期暴露后表达趋势与短期暴露结果相吻合,提示其可作为指示N02诱导缺血性中风效应发生的生物标记。
血管性痴呆是指因各种脑血管疾病,尤其是脑缺血等引起的脑功能障碍而造成的获得性智能障碍综合征,是缺血性中风的主要并发症或后遗症。我们的研究发现,N02吸入暴露引起了中风模型大鼠神经功能恢复的推迟,在一定程度上提示N02可能会增加血管性痴呆发生的风险。然而,到目前为止,该效应还未被阐明,相关分子机制则更不清楚。由于突触可塑性是大脑进行正常功能活动的分子细胞学机制和神经系统生长发育、神经损伤修复以及学习记忆的神经生物学基础,因此在本研究中将突触可塑性变化作为切入点来研究N02增加血管性痴呆患病风险的效应及其可能的分子机制。电镜观察结果显示,5mg/m3的N02吸入暴露不仅会加重缺血性中风模型大鼠大脑海马区神经元和突触的超微结构损伤,同时会诱导健康大鼠的神经元损伤效应。与此同时的Western Blot实验证明,N02吸入抑制了中风模型大鼠突触结构可塑性标记分子SYP和PSD-95的表达,以及突触功能可塑性LTP过程中关键调控因子蛋白的表达。与此相反,在健康大鼠中N02吸入却诱导了以上绝大部分蛋白的表达上调,并呈现出一定的浓度依赖性。以上结果提示,NO2吸入暴露会通过诱导健康大鼠的神经兴奋性毒性和降低中风模型大鼠的突触可塑性增加血管性痴呆发生的风险。
本课题实验结果揭示了N02对心脏和大脑组织的损伤效应,其分子机制与NO2对组织细胞的氧化作用有关,通过刺激炎症反应最终导致细胞的大量死亡,为肺以外其它组织中N02的毒性效应研究提供了一定的实验依据；阐明了N02与缺血性中风发生发展的相关性及其分子机制,建立了进行检测和危险度评价的生物标记；探讨了NO2与血管性痴呆发生发展的相关性及其突触机制,为污染事件发生时的临床治疗提供理论依据。
As important as TSP, PM10and SO2, NO2, the major component of nitrogen oxides (NOx), also represents an important urban pollutant in most developed cities of the world. People are widely exposed to NO2discharged from multiple sources including automobile exhaust, fossil fuel burning industries, gas cooking stoves, tobacco smoking and some others in occupational environment. Peak levels of up to0.2parts per million (ppm) are encountered in the outdoors, particularly along kerbsides in downtown areas with heavy motor vehicular traffic. Indoors NO2concentrations are often greater than those found outdoors, with peak levels exceeding2ppm in homes with unvented sources of combustion. In garages, ferries, skating ice rinks and kitchens with gas cookers, it can even reach up to4ppm. Herein, NO2-related health risks have become the global focal point. Due to the inhalation route of exposure, respiratory damage effect of NO2was always considered to be a key concern either in epidemiological or laboratory studies, while other effects were always ignored.
Recently, some epidemiological literatures linked NO2pollution with increasing risk of cardiovascular diseases and neurological disorders, which implied that lung is not the only target of NO2. To explore the toxicological effects of NO2on the heart and brain, a role for oxidative stress, inflammatory responses and cell apoptosis in the both tissues of rats treated with different concentrations of NO2(0,5,10and20mg/m3) was investigated. The pathological change was observed by Hematoxylin and eosin (HE) staining, and the number of apoptotic cells was quantified by TUNEL method; The activity or contents of Cu/Zn-SOD, Mn-SOD, GPx, MDA and NO were measured with test kits, while PCO were measured by DNPH assay; the levels of TNF-a and Ⅱ-1β were examined by ELISA; the mRNA expression of oncogenes and apoptosis-related genes were examined through real-time RT-PCR analysis. For the heart, mild pathology occurred after7-d exposure (6h/d); marked oxidative stresses were induced as reduction/induction of antioxidants (Cu/Zn-SOD, Mn-SOD and GPx) activity and increasing formation of MDA and PCO; mRNA and protein biomarkers of inflammation (TNF-α and IL-1β) were up-regulated, and p53mRNA expression, bax/bcl-2ratio and the mean number of TUNEL-positive myocytes were increased as well. For the brain, observable adverse effects were induced encompassing mild brain pathology, increased neuronal apoptosis, altered antioxidants (Cu/Zn-SOD, Mn-SOD, GPx and NO) activity and increasing formation of PCO after7-day exposure (6h/day); NO2inhalation also induced augment of oncogenes (c-fos, c-jun) levels, and deregulation of apoptosis-related genes (p53, bax and bcl-2) expression. With all above data, the present report provided essential information for the characterization of the cardiotoxic and neurotoxic hazard of NO2, which is required in response to the general concern about the vulnerability of the cardiovascular and neurological system to it.
Ischemic stroke is the second leading cause of death and the most frequent disease leading to disability in the world, with a high incidence affecting up to0.2%of the population every year. In China, the rate of ischemic stroke increased by almost9%every year. In USA, stroke rates in five to44-year-olds rose by about a third within10years. Worryingly, the risk factors for ischemic stroke have not been fully clarified, and the effective means to control its morbidity and mortality have not been found. In the last decade, an increasing body of epidemiologic literatures has provided compelling evidence to link outdoor air pollution to stroke mortality, with positive associations being observed for NO2, sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO) and particulate matter (PM). Moreover, it was reported that NO2could also influence the outcome of stroke patients. These effects, however, are not conclusive given the limited number of studies, their small size and their methodological constraints, which also leads to some contrary results. Moreover, relative molecular mechanisms cannot be elucidated by epidemiologic studies. Here the correlativity between NO2and ischemic stroke was determined. The hemorheological parameters were measured using YDA-IV blood viscosity apparatus; the rat model of ischemic stroke was set up using MCAO method; the behavioral deficits were measured through symptom scoring; the infarct volume were measured by TTC method; the pathological change and quantification of apoptosis cell number were measured by HE and TUNEL methods respectively. First, we found that blood viscosity, red blood cell (RBC) aggregation-, electrophoresis-and rigidity-index in healthy rats were increased after exposure to5mg/m3NO2for one-and three-month, which were very similar with the clinical phenomenon observed from ischemic stroke patients. Then, we set up stroke rat model and exposed them to NO2at the same concentration for one week, and found that NO2exposure time-dependently delayed neurological structure and function recovery of MCAO (middle cerebral artery occlusion) rat, and worsened pathological injuries and apoptosis induced by MCAO operation. Trough these studies, we confirmed the relevance of NO2exposure and ischemic stroke.
Endothelial and inflammatory responses are two common cellular pathomechanisms involved in ischemic brain damage. To elucidate the detailed mechanisms of ischemic stroke induced by NO2inhalation, we treated Wistar rats with NO2at various concentrations and determined the messenger RNA (mRNA) and protein expression of endothelin-1(ET-1), nitric oxide synthases (NOSs), cyclooxygenase-2(COX-2), and intercellular adhesion molecule1(ICAM-1) in the cortex, all of which are the endothelial and inflammatory biomarkers in stroke. The results showed that NO2elevated the levels of ET-1, iNOS, COX-2and ICAM-1mRNA and protein but inhibited the expression of eNOS and nNOS in a concentration-dependent manner. Then, we set up stroke rat model and exposed them to the lowest dose (5mg/m3) of NO2for one week, and found that endothelial injuries and inflammation were induced in cortex by MCAO treatment and exacerbated by followed NO2inhalation. The related mRNA and protein expression were examined via real-time RT-PCR technique as well as Western blotting method. In the present study, the upregulation of ET-1expression in rat cortex suggests the reduction of cerebral blood and a tendency to ischemic injuries via endothelial dysfunction following NO2inhalation. NO2inhalation-induced excessive expression of iNOS, COX-2and ICAM-1, as well as release of Ⅱ-1β and TNF-a could promote blood-borne inflammatory cell adherence and infiltration. Consequently, leukocytes exacerbated brain injury by physically obstructing capillaries and reducing blood flow during reperfusion and/or by migrating into the brain parenchyma and releasing cytotoxic products. Our data implicates the occurrence and development of ischemic injuries in rat brains via endothelial and inflammatory mechanisms after NO2exposure. Expression of eNOS, COX-2and ICAM-1protein after sub-chronic NO2exposure showed the same response as that observed after one-week exposure at higher concentrations, providing evidence that endothelial nitric oxide synthase (eNOS), cyclooxygenase-2(COX-2) and intercellular adhesion molecule1(ICAM-1) can be potential indicators for NO2-induced ischemic stroke.
As above reported, NO2could delay the recovery of nerve function after stroke, which implied a possible risk of vascular dementia (VaD) with NO2inhalation, which is often a common cognitive complication resulting from stroke. However, the effect and detailed mechanisms have not been fully elucidated. In the present study, synaptic mechanisms, the foundation of neuronal function and viability, were investigated in both model rats of ischemic stroke and healthy rats after NO2exposure. Transmission electron microscope (TEM) observation showed that5mg/m3NO2exposure not only exacerbated the ultrastructural impairment of synapses in stroke model rats, but also induced neuronal damage in healthy rats. Meantime, we found that the expression of synaptophysin (SYP) and postsynaptic density protein95(PSD-95), two structural markers of synapses in ischemic stroke model were inhibited by NO2inhalation; and so it was with the key proteins mediating long-term potentiation (LTP), the major form of synaptic plasticity. On the contrary, NO2inhalation induced the expression of nearly all these proteins in healthy rats in a concentration-dependent manner. All the proteins expression were examined by Western blotting method. Our results indicated that NO2exposure could increase the risk of VaD through inducing excitotoxicity in healthy rats but weakening synaptic plasticity directly in stroke model rats.
In conclusion, this work revealed the damage effect of NO2inhalation on the heart and brain, confirmed an association between NO2inhalation and increased risk for ischemic stroke as well as VaD, elucidated the related molecular mechanisms and explored the molecular markers for indicating these effects, which will help us open up therapeutic approaches to prevent, ameliorate, or treate heart and brain disorders resulting from NO2exposure in its polluting areas.
引文
[1]奚旦立,孙裕生,刘秀英.《环境监测》第3版.北京,高等教育出版社,2004.
[2]郝吉明,马广大,王书肖.《大气污染控制工程》第2版.北京,高等教育出版社,2010.
[3]侯棻.二氧化氮和硝酸酸雾对植物的毒性效应研究.山西大学硕士论文,2012.
[4]Olsen DB, Kohls M, Arney G Impact of oxidation catalysts on exhaust NO2/NOX ratio from lean-burn natural gas engines. J Air Waste Manag Assoc,2010,60: 867-874.
[5]张雅倩.城市交通性污染研究及其对成人呼吸系统健康的影响分析.天津大学硕士论文,2012.
[6]中国疾病预防控制中心,国际环保组织绿色和平.《煤炭的真实成本——大气污染与公众健康》,北京,2010.
[7]张兴赢,张鹏,张艳,等.近10a中国对流层N02的变化趋势、时空分布特征及其来源解析.中国科学,2007,37：1409-1416.
[8]中华人民共和国环境保护部.http://jcs.mep.gov.cn/hjzl/zkgb/201 lzkgb
[9]Report on a WHO Working Group. Health Aspects of Air Pollution with Particulate Matter, Ozone and Nitrogen Dioxide,13-15 January 2003, Bonn, Germany, www.euro.who.int/document/e79097.pdf
[10]GreenRacts. http://www.greenfacts.org/en/nitrogen-dioxide-no2/level-2/ 03-exposure.htm#3
[11]Frampton MW, Boscia J, Jr Roberts NJ, et al. Nitrogen dioxide exposure:effects on airway and blood cells. Am J Physiol Lung Cell Mol Physiol,2002,282: L155-165.
[12]Yin W, Zhang H, Wang C, et al. Spatial Distribution of Motor Vehicle Pollutions on the Streets in Taiyuan Based on GIS. Environmental Science and Management, 2010,35:25-29.
[13]医学知识库.http://pmmp.cnki.net/Disease/Details.aspx?id=809
[14]孟紫强.环境毒理学.北京中国环境科学出版社,2000.
[15]Hesterberg TW, Bunn WB, McClellan RO, et al. Critical review of the human data on short-term nitrogen dioxide (NO2) exposures:evidence for NO2 no-effect levels. Crit Rev Toxicol,2009,39:743-781.
[16]Pathmanathan S, Krishna MT, Blomberg A, et al. Repeated daily exposure to 2 ppm nitrogen dioxide upregulates the expression of IL-5, IL-10, IL-13, and ICAM-1 in the bronchial epithelium of healthy human airways. Occup Environ Med,2003,60:892-896.
[17]Hussain I, Jain VV, O'Shaughnessy P, et al. Effect of nitrogen dioxide exposure on allergic asthma in a murine model. Chest,2004,126:198-204.
[18]Ponka A, Virtanen M. Chronic bronchitis, emphysema, and low-level air pollution in Helsinki,1987-1989. Environ Res,1994,65:207-217.
[19]Takenoue Y, Kaneko T, Miyamae T, et al. Influence of outdoor NO(2) exposure on asthma in childhood:Meta-analysis. Pediatr Int,2012,54:762-769.
[20]Faustini A, Stafoggia M, Cappai G, et al. Short-term effects of air pollution in a cohort of patients with chronic obstructive pulmonary disease. Epidemiology, 2012,23:861-879.
[21]Tango T. Effect of air pollution on lung cancer:a Poisson regression model based on vital statistics. Environ Health Perspect,1994,102 Suppl 8:41-45.
[22]Richters A, Richters V. Nitrogen dioxide (NO2) inhalation, formation of microthrombi in lungs and cancer metastasis. J Environ Pathol Toxicol Oncol, 1989,9:45-51.
[23]Poynter ME, Persinger RL, Irvin CG, et al. Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse. Am J Physiol Lung Cell Mol Physiol,2006,290:L144-152.
[24]Goldstein E, Peek NF, Parks NJ, et al. Fate and distribution of inhaled nitrogen dioxide in rhesus monkeys. Am Rev Respir Dis,1977,115(3):403-412.
[25]Postlethwait EM, Mustafa MG. Fate of inhaled nitrogen dioxide in isolated perfused rat lung. J Toxicol Environ Health,1981,7:861-872.
[26]Saul RL, Archer MC. Nitrate formation in rats exposed to nitrogen dioxide. Toxicol Appl Pharmacol,1983,67:284-291.
[27]Parkinson DR, Stephens RJ. Morphological surface changes in the terminal bronchiolar region of NO2-exposed rat lung. Environ Res,1973,6:37-51.
[28]Kleinerman J. Some effects of nitrogen dioxide on the lung. Fed Proc,1977,36: 1714-1718.
[29]Ranga V, Kleinerman J. A quantitative study of ciliary injury in the small airways of mice:the effects of nitrogen dioxide. Exp Lung Res,1981,2:49-55.
[30]Barth PJ, Miiller B, Wagner U, et al. Quantitative analysis of parenchymal and vascular alterations in NO2-induced lung injury in rats. Eur Respir J,1995,8: 1115-1121.
[31]Gregory RE, Pickrell JA, Hahn FF, et al. Pulmonary effects of intermittent subacute exposure to low-level nitrogen dioxide. J Toxicol Environ Health,1983 11:405-414.
[32]Suzuki AK, Tsubone H, Kubota K. Changes of gaseous exchange in the lung of mice acutely exposed to nitrogen dioxide. Toxicol Lett,1982,10:327-335.
[33]Suzuki AK, Ichinose T, Tsubone H, et al. Effects of acute nitrogen dioxide exposure on swimming performance of mice. J Toxicol Environ Health,1982,9: 165-172.
[34]Voisin C, Aerts C, Jakubczak E, et al. Effects of nitrogen dioxide on alveolar macrophages surviving in the gas phase. A new experimental model for the study of in vitro cytotoxicity of toxic gases (author's transl). Bull Eur Physiopathol Respir,1977,13:137-144. [Article in French]
[35]Rasmussen RE, Mannix RC, Oldham MJ, et al. Effects of nitrogen dioxide on respiratory tract clearance in the ferret. J Toxicol Environ Health,1994,41: 109-120.
[36]Evans MJ, Cabral LJ, Stephens RJ, et al. Renewal of alveolar epithelium in the rat following exposure to NO2. Am J Pathol,1973,70:175-198.
[37]Evans MJ, Cabral LJ, Stephens RJ, et al. Cell division of alveolar macrophages in rat lung following exposure to NO2. Am J Pathol,1973,70:199-208.
[38]Sagai M, Ichinose T, Oda H, et al. Studies on biochemical effects of nitrogen dioxide. II. Changes of the protective systems in rat lungs and of lipid peroxidation by acute exposure. J Toxicol Environ Health,1982,9:153-164.
[39]Husain MM, Dehnen W. Effect of NO2 and SO2 inhalation on benzo(a)pyrene metabolism in rat lung. Arch Toxicol,1978,40:207-210.
[40]Rynbrandt D. Nitrogen dioxide and pulmonary proteolytic enzymes. Effect on lung tissue and macrophages. Arch Environ Health,1977,32:165-172.
[41]Chaudhari A, Dutta S. Effect of an acute exposure of guinea pigs to NO2 on pulmonary prostaglandin dehydrogenase and angiotensin converting enzyme. Bull Environ Contam Toxicol,1980,25:816-823.
[42]Maitani T, Suzuki KT, Kubota K. Changes of essential metal contents in lungs of rats acutely exposed to nitrogen dioxide. Toxicol Lett,1981,7(4-5):289-295.
[43]Creasia DA, Nettesheim P, Kim JC. Stimulation of DNA synthesis in the lungs of hamsters exposed intermittently to nitrogen dioxide. J Toxicol Environ Health, 1977,2:1173-1181.
[44]Walles SA, Victorin K, Lundborg M. DNA damage in lung cells in vivo and in vitro by 1,3-butadiene and nitrogen dioxide and their photochemical reaction products. Mutat Res,1995,328:11-19.
[45]Richters A, Kuraitis K. Inhalation of NO2 and blood borne cancer cell spread to the lungs. Arch Environ Health,1981,36:36-39.
[46]Ballester F, Rodriguez P, Iniguez C, et al. Air pollution and cardiovascular admissions association in Spain:results within the EMECAS project. J Epidemiol Community Health,2006,60:328-336.
[47]Wong CM, Vichit-Vadakan N, Vajanapoom N, et al. Public health and air pollution in Asia (PAPA):a combined analysis of four studies of air pollution and mortality. Res Rep Health Eff Inst,2010, (154):377-418.
[48]Osman Y. Environmental surveys conducted in the Gulf region following the Gulf War to identify possible neurobehavioral consequences. Environ Res,1997,73: 207-210.
[49]Liao D, Duan Y, Whitsel EA, et al. Association of higher levels of ambient criteria pollutants with impaired cardiac autonomic control:a population-based study. Am J Epidemiol,2004,159:768-777.
[50]Nafstad P, Haheim LL, Wisl(?)ff T, et al. Urban air pollution and mortality in a cohort of Norwegian men. Environ Health Perspect,2004,112:610-615.
[51]D'Ippoliti D, Forastiere F, Ancona C, et al. Air pollution and myocardial infarction in Rome:a case-crossover analysis. Epidemiology,2003,14:528-535.
[52]Mann JK, Tager IB, Lurmann F, et al. Air pollution and hospital admissions for ischemic heart disease in persons with congestive heart failure or arrhythmia. Environ Health Perspect,2002,110:1247-1252.
[53]Llorca J, Salas A, Prieto-Salceda D, et al. Nitrogen dioxide increases cardiorespiratory admissions in Torrelavega (Spain). J Environ Health,2005,68: 30-35.
[54]von Klot S, Peters A, Aalto P, et al. Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation,2005,112:3073-3079.
[55]Yang CY. Air pollution and hospital admissions for congestive heart failure in a subtropical city:Taipei, Taiwan./Toxicol Environ Health A,2008,71: 1085-1090.
[56]Rosenlund M, Picciotto S, Forastiere F, et al. Traffic-related air pollution in relation to incidence and prognosis of coronary heart disease. Epidemiology,2008, 19:121-128.
[57]Larrieu S, Jusot JF, Blanchard M, et al. Short term effects of air pollution on hospitalizations for cardiovascular diseases in eight French cities:the PSAS program. Sci Total Environ,2007,387(1-3):105-112.
[58]Vrijheid M, Martinez D, Manzanares S, et al. Ambient air pollution and risk of congenital anomalies:a systematic review and meta-analysis. Environ Health Perspect,2011,119:598-606.
[59]Huang YC, Rappold AG, Graff DW, et al. Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans. Inhal Toxicol,2012,24:790-797.
[60]Williams R, Brook R, Bard R, et al. Impact of personal and ambient-level exposures to nitrogen dioxide and paniculate matter on cardiovascular function. Int J Environ Health Res,2012,22:71-91.
[61]Villeneuve PJ, Chen L, Stieb D, et al. Associations between outdoor air pollution and emergency department visits for stroke in Edmonton, Canada. Eur J Epidemiol,2006,21:689-700.
[62]Metzger KB, Tolbert PE, Klein M, et al. Ambient air pollution and cardiovascular emergency room visits. Epidemiology,2004,15:46-56.
[63]Hong YC, Lee JT, Kim H, et al. Air pollution:a new risk factor in ischemic stroke mortality. Stroke,2002,33:2165-2169.
[64]Vidale S, Bonanomi A, Guidotti M, et al. Air pollution positively correlates with daily stroke admission and in hospital mortality:a study in the urban area of Como, Italy. Neurol Sci,2010,31:179-182.
[65]Wellenius GA, Schwartz J, Mittleman MA. Air pollution and hospital admissions for ischemic and hemorrhagic stroke among medicare beneficiaries. Stroke,2005, 36:2549-2553.
[66]Andersen ZJ, Kristiansen LC, Andersen KK, et al. Stroke and long-term exposure to outdoor air pollution from nitrogen dioxide:a cohort study. Stroke,2012,43: 320-325.
[67]Maheswaran R, Pearson T, Smeeton NC, et al. Impact of outdoor air pollution on survival after stroke:population-based cohort study. Stroke,2010,41:869-877.
[68]Koken PJ, Piver WT, Ye F, et al. Temperature, air pollution, and hospitalization for cardiovascular diseases among elderly people in Denver. Environ Health Perspect,2003,111:1312-1317.
[69]Tsubone H, Oda H, Suzuki AK, et al. Electrocardiographic abnormalities in rats by acute exposure to nitrogen dioxide. Toxicol Lett,1982,12:125-129.
[70]Tsubone H, Suzuki AK, Sagai M, et al. Changes of cardiac and respiratory rhythm in non-and tracheostomized rats exposed to nitrogen dioxide. Environ Res,1984,35:197-203.
[71]Linn WS, Solomon JC, Trim SC, et al. Effects of exposure to 4 ppm nitrogen dioxide in healthy and asthmatic volunteers. Arch Environ Health,1985,40: 234-239.
[72]Freire C, Ramos R, Puertas RJ, et al. Association of traffic-related air pollution with cognitive development in children. Epidemiol Community Health,2010,64: 223-228.
[73]Wang S, Zhang J, Zeng X, et al. Association of traffic-related air pollution with children's neurobehavioral functions in Quanzhou, China. Environ Health Perspect,2009,117:1612-1618.
[74]Chen JC, Schwartz J. Neurobehavioral effects of ambient air pollution on cognitive performance in US adults. Neurotoxicology,2009,30:231-239.
[75]Ranft U, Schikowski T, Sugiri D, et al. Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environ Res,2009, 109:1004-1011.
[76]Power MC, Weisskopf MG, Alexeeff SE, et al. Traffic-related air pollution and cognitive function in a cohort of older men. Environ Health Perspect,2011,119: 682-687.
[77]Nattero G, Enrico A. Outdoor pollution and headache. Headache,1996,36: 243-245.
[78]Mikhailichenko KIu, Kas'ianenko AA, Shchelkunova IG, et al. Risk for environment-induced diseases due to air pollution from motor vehicles in road-patrol officers. Gig Sanit,2010, (3):39-42. [Article in Russian]
[79]Levesque S, Surace MJ, McDonald J, et al. Air pollution & the brain:Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J Neuroinflammation,2011,8:105.
[80]Win-Shwe TT, Fujitani Y, Hirano S, et al. Exposure to nanoparticle-rich diesel exhaust affects hippocampal functions in mice. Nihon Eiseigaku Zasshi,2011,66: 628-633. [Article in Japanese]
[81]Tsukue N, Watanabe M, Kumamoto T, et al. Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum. Arch Toxicol,2009,83:985-1000.
[82]Farahani H, Hasan M. Nitrogen dioxide induced changes in level of free fatty acids, triglyceride, esterified fatty acid, ganglioside and lipase activity in the guinea pig brain. J Environ Sci Health B,1992,27:53-71.
[83]Farahani H, Hasan M. Effect of NO2 on lipids and lipid peroxidation in the CNS of the guinea-pig. Pharmacol Toxicol,1990,66:146-149.
[84]孙存普,张建中,段绍瑾.自由基生物学导论.合肥：中国科学技术大学出版社,1999.
[85]武冬梅.二氧化硫对小鼠不同组织器官的氧化应激、DNA损伤及细胞因子的影响.山西大学博士论文,2004.
[86]赵克然,杨毅军,曹道俊.氧自由基与临床.北京：中国医药科技出版社,2000.
[87]Winterbourn CC, Hampton MB. Thiol chemistry and specificity in redox signaling. Free Radical Biology & Medicine,2008,45:549-561.
[88]Paulsen CE, Carroll KS. Orchestrating Redox Signaling Networks through Regulatory Cysteine Switches. Acs Chemical Biology,2010,5:47-62.
[89]Misra MK, Sarwat M, Bhakuni P, et al. Oxidative stress and ischemic myocardial syndromes. Med Sci Monit,2009,15:RA209-219.
[90]Valko M, Rhodes CJ, Moncol J, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact,2006,160:1-40.
[91]Dalle-Donne I, Scaloni A, Giustarini D, et al. Proteins as biomarkers of oxidative/nitrosative stress in diseases:the contribution of redox proteomics. Mass Spectrom Rev,2005,24:55-99.
[92]Filipcik P, Cente M, Ferencik M, et al. The role of oxidative stress in the pathogenesis of Alzheimer's disease. Bratisl Lek Listy,2006,107:384-394.
[93]Calabrese V, Guagliano E, Sapienza M, et al. Redox regulation of cellular stress response in neurodegenerative disorders. Ital J Biochem,2006,55:263-282.
[94]Trushina E, McMurray CT. Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience,2007,145:1233-1248.
[95]Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem,1992,59:1609-1623.
[96]Ganesana M, Erlichman JS, Andreescu S. Real-time monitoring of superoxide accumulation and antioxidant activity in a brain slice model using an electrochemical cytochrome c biosensor. Free Radic Biol Med,2012,53: 2240-2249.
[97]Beal MF. Oxidative damage in neurodegenerative diseases. Neuroscientist,1997, 3:21-27.
[98]L6pez N, Tormo C, De Bias I, et al. Oxidative Stress in Alzheimer's Disease and Mild Cognitive Impairment with High Sensitivity and Specificity. J Alzheimers Dis,2012,33:823-829.
[99]Wikipedia. http://en.wikipedia.org/wiki/Inflammation,2013.
[100]Margaritescu O, Mogoanta L, Pirici I, et al. Histopathological changes in acute ischemic stroke. Rom JMorphol Embryol,2009,50:327-339.
[101]Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain,2009,132:1175-1189.
[102]吴荣谦,徐迎新,宋旭华,等.脓毒症小鼠肝肺组织细胞因子mRNA表达的比较.中国危重病急救医学,2000,12：588-590.
[103]Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci,2001,2:734-744.
[104]Beattie EC, Stellwagen D, Morishita W, et al. Control of synaptic strength by glial TNF-alpha. Science,2002,295:2282-2285.
[105]Merrill JE, Benveniste EN. Cytokines in inflammatory brain lesion:helpful and harmful trends. Neurosci,1996,19:331-339.
[106]Butler MP, O'Connor JJ, Moynagh PN. Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogenactivated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neurosci,2004,124:319-326.
[107]Suzuki K, Nakaji S, Yamada M. Systemicirdlammatory response to exhaustive exercise Cytokine kinetics. Exe Immunol Rev,2002,8:6-48.
[108]Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol,2005,5:629-640.
[109]Rothwell NJ, Luheshi GN. Interleukin 1 in the brain:biology, pathology and therapeutic target. Trends Neurosci,2000,23:618-625.
[110]Katsuki H, Nakai S, Hirai Y, et al. Interleukin-1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices. Eur J Pharmacol, 1990,181:323-326.
[111]Bazan NG, Flower RJ. Lipid signals in pain control. Nature,2002,420:135-138.
[112]Patrignani P, Tacconelli S, Sciulli MG, et al. New insights into COX-2 biology and inhibition. Brain Res Rev,2005,48:352-359.
[113]Kaufmann WE, Worley PF, Pegg J, et al. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA,1996,93:2317-2321.
[114]Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenase)-1 and -2. JBiol Chem,1996,271:33157-33160.
[115]Vane JR, Bakhle YS, Botting RM. Cyclooxygenase 1 and 2. Annu Rev Pharmacol Toxicol,1998,38:97-120.
[116]Bazan NG. COX-2 as a multifunctional neuronal modulator. Nat Med,2001,7: 414-415.
[117]Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation. JPhysiol Pharmacol,2003,54:469-487.
[118]Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiological flow rates:distinction from and prerequisite for adhesion through integrins. Cell,1991, 65:859-873.
[119]张刚,程锦泉,彭绩,等.细胞间粘附分子-1与心脑血管疾病相关性.中国公共卫生,2006,22：1404-1406.
[120]Li RJ, Meng ZQ, Xie JF. Effects of sulfur dioxide on the expressions of MUC5AC and ICAM-1 in airway of asthmatic rats. Regulatory Toxicology and Pharmacology,2007,48:284-291.
[121]Calderon-Garciduenas L, Reed W, Maronpot RR, et al. Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution. Toxicol Pathol,2004,32:650-658.
[122]Calderon-Garciduenas L, Azzarelli B, Acuna H, et al. Air pollution and brain damage. Toxicol Pathol,2002,30:373-389.
[123]桑楠,云洋,侯丽.SO2吸入对大鼠海马组织炎性因子水平、钙稳态和即早基因表达的影响.环境科学学报,2008,28：2315-2321.
[124]Campbell A, Araujo JA, Li H, et al. Particulate matter induced enhancement of inflammatory markers in the brains of apolipoprotein E knockout mice. J Nanosci Nanotechnol,2009,9:5099-5104.
[125]朱铁梁,郝素云,段姚尧,等.脑缺血后Bcl-2家族、即早基因的表达与细胞凋亡.武警医学院学报,2006,15：166-169.
[126]白剑英.二氧化硫及其衍生物对小鼠几种脏器超微结构和细胞凋亡的影响.山西大学博士论文,2004.
[127]Wolozin B, Behl C. Mechanisms of Neurodegenerative Disorders. Arch neurol, 2000,57：801-804.
[128]杨小慧,戴雪伶,姜招峰.阿尔茨海默病的脑神经元凋亡机制.生命的化学,2007,27：307-310.
[129]Kalalian-Moghaddam H, Baluchnejadmojarad T, Roghani M, et al. Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. Eur J Pharmacol,2012,698:259-266.
[130]Stephenson CP, Hunt GE, Topple AN, et al. The distribution of 3,4-methylened ioxymethamp-hetamine "ecstasy"-induced c-fos expression in rat brain. Neuroscience,1999,92:1011-1023.
[131]Verma IM, Sassone-Corsi P. Proto-oncogene fos:complex but versatile regulation. Cell,1987,51:513-514.
[132]Smeyne RJ, Vendrell M, Hayward M, et al. Continuous c-fos expression precedes programmed cell death in vivo. Nature,1993,363:166-169.
[133]Kang PM, Izumo S. Apoptosis and heart failure:a critical review of the literature. CircRes,2000,86:1107-1113.
[134]Gross A, McDonnell JM, Korsmeyer SJ. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev,1999,13:1899-1911.
[135]Xu J, Ji LD, Xu LH. Lead-induced apoptosis in PC 12 cells:Involvement of p53, Bcl-2 family and caspase-3. Toxicol Lett,2006,166:160-166.
[136]Levine A. p53, The celular gatekeeper for growth and division. Cell,1997,88: 323-331.
[137]尹欣.内皮功能障碍与心血管疾病.中国中医药报,2003.
[138]熊石龙,王前,郑磊,等.急性缺血性心脑血管疾病组织因子途径的改变.解放军医学杂志,2008,33：93-95.
[139]Shin-ichi S, Naomi Y, Fumiki Y, et al. Endothelin A receptor blockade and endothelin B receptor blockade improve hypokalemic nephropathy by different mechanism. Am soc Nephrol,2003,14:397.
[140]张建,华崎,李静.高血压代谢综合症.人民卫生出版社,2003：368-369.
[141]Lee KB, Oh HG, Roh H, et al. Can we discriminate stroke mechanisms by analyzing the infarct patterns in the striatocapsular region. Eur Neurol,2008,60: 79-84.
[142]Tsai NW, Chang WN, Shaw CF, et al. The value of leukocyte adhesion molecules in patients after ischemic stroke. Neurol,2009,256:1296-1232.
[143]Haeusler KG, Schmidt WU, Fohring F, et al. Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis,2008,25:50-58.
[144]陈等,吴亚宁,张俊武.线粒体与阿尔茨海默病.基础医学与临床,2001,21：395-399.
[145]Tabeuchi A. Excitatery amino acid transmitters:past, present, and future. In: Kanazawal, ed Neurotransmittors focus on excitatory amino acids. Tokyo: Exeerpta,1998,395.
[146]Pulsinelli WA. Cerebral blood flow in the fourvessel occlusion rat model. Stroke, 1983,14:832-840.
[147]徐仁泗.兴奋性氨基酸与脑缺血损伤的研究概况.国外医学·神经病学神经外科学分册,1998,25：62-64.
[148]Castillo J, Davaios A, Nareiro J, et al. Neuroexcitatory amino acids and their relation to infarct size and neurological deficit in ischemic stroke. Stroke,1996, 27:1060-1065.
[149]Pietropaoli JA, Rogers FB, Shackford SR, et al. The deleterious effects of intraoperative hypotension on outcome in patients with severe head in-juries. J Traima,1992,33:403-407.
[150]Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxi-cischemic brain damge. Ann Neuro,1986,19:105-111.
[151]Liu F, Day M, Muniz LC, et al. Activation of estrogen receptor-b regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci,2008,11: 334-343.
[152]席艳,万建华,邓锦波.突触可塑性的生物物理学基础和体视学测量研究进展.中国医药生物技术,2009,4：370-373.
[153]许绍芬.《神经生物学》2版.上海：上海医科大学出版社,1999：389-400.
[154]Goosens KA, Maren S. Long-term potentiation as a substrate for memory: evidence from studies of amygdaloid plasticity and Pavlovian fear conditioning. Hippocampus,2002,12:592-599.
[155]German IP, Carlos AB. Timed changes of synaptic zinc, synaptophysin and MAP2 in medial extended amygdala of epileptic animals are suggestive of reactive neuroplasticity. Brain Res,2010,1328:130-138.
[156]Tian Y, Wang Y, Deng Y, et al. Methylphenidate improves spatial memory of spontaneously hypertensive rats:evidence in behavioral and ultrastructural changes. Neurosci Lett,2009,461:106-109.
[157]Sturgill JF, Steiner P, Czervionke BL, et al. Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking. J Neurosci,2009,29:12845-12854.
[158]徐春,章晓辉.学习和记忆的突触模型：长时程突触可塑性.自然杂志,2009,31：136-141.
[159]Sheng M, Kim MJ. Postsynaptic Signaling and Plasticity Mechanisms. Science, 2002,298:776-780.
[160]Restituito S, Ziff EB. Methods for Uncovering the Mechanisms of AMPA Receptor Trafficking. In:Kittler JT, Moss SJ, editors. The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. Boca Raton (FL):CRC Press; 2006. Chapter 1.
[161]Lau CG, Takeuchi K, Rodenas-Ruano A, et al. Regulation of NMD A receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans,2009,37:1369-1374.
[162]Moriguchi S, Shiodaa N, Yamamotoa Y, et al. Platelet-activating factor-induced synaptic facilitation is associated with increased calcium/calmodulin-dependent protein kinase II, protein kinase C and extracellular signal-regulated kinase activities in the rat hippocampal CA1 region. Neuroscience,2010,166: 1158-1166.
[163]Masliah E. Recent advances in the understanding of the role of synapfic proteinsin Alzheimer's Disease and other neurodegenerative disorders. J Alzheimer's Disease,2001,3:121-129.
[164]Lin CS, Tao PL, Jong YJ, et al. Prenatal morphine alters the synaptic complex of postsynaptic density 95 with N-methyl-d-aspartate receptor subunit in hippocampal CA1 subregion of rat offspring leading to long term cognitive deficits. Neuroscience,2009,158:1326-1337.
[165]Kandel ER. The molecular biology of memory storage:a dialogue between genes and synapses. Science,2001,294:1030-1038.
[166]Rosenzweig ES, Barnes CA. Impact of aging on hippocampal function:plasticity, network dynamics, and cognition. Prog Neurobiol,2003,69:143-179.
[167]Johnston MV, Ishida A, Ishida WN, et al. Plasticity and injury in the developing brain. Brain Dev,2009,31:1-10.
[168]Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev,2007,54:34-66.
[169]Leuba G, Savioz A, Vernay A, et al. Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein. JAlzheimers Dis,2008,15:139-151.
[170]杨牧祥,于文涛,丁宁,等.中风康对局灶性脑缺血大鼠脑病理形态学的影响.中医研究,2006,19：7-10.
[171]Thomson EM, Kumarathasana P, Calderon-Garciduenas L, et al. Air pollution alters brain and pituitary endothelin-1 and inducible nitric oxide synthase gene expression. Environmental Research,2007,105:224-233.
[172]Banerjee I, Gupta V, Ahmed T, et al. Inflammatory system gene polymorphism and the risk of stroke:A case-control study in an Indian population. Brain Research Bulletin,2008,75:158-165.
[173]Callow AD. Endothelial dysfunction in atherosclerosis. Vascul Pharm acol,2002, 38:257-258.
[174]郝延磊,普传强,朱克,等.血脑屏障内皮细胞与细胞间黏附分子-1在鼠脑缺血性脑水肿发生机制中的作用.中华神经科杂志,2000,33：86-89.
[175]Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:an integrated view. Trends Neurosci,1999,22:391-397.
[176]Volpe M, Cosentino F. Abnormalities of endothelial function in the pathogenesis of stroke:the importance of endothelin. J Cardiovasc Pharmacol,2000,35: 45-48.
[177]Yenari MA, Han HS. Influence of hypothermia on post-ischemic inflammation: Role of nuclear factor kappa B (NF-κB). Neurochemistry International,2006,49: 164-169.
[178]Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene,1999,18:6853-6866.
[179]Minami M, Satoh M. Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury. Life Sciences,2003,74: 321-327.
[180]Minami M, Satoh M. Role of Chemokines in Ischemic Neuronal Stress. Neuro Molecular Medicine,2005,7:149-155.
[181]del Zoppo G, Ginis I, Hallenbeck JM, et al. Inflammation and Stroke:Putative Role for Cytokines, Adhesion Molecules and iNOS in Brain Response to Ischemia. Brain Pathology,2000,10:95-112.
[182]Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol, 2002,2:725-734.
[183]Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surgical Neurology,2006,66:232-245.
[184]Thomas WS, Mori E, Copeland BR, et al. Tissue factor contributes to microvascular defects after focal cerebral ischemia. Stroke,1993,24:847-853.
[185]Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation, 2002,102:2434-2440.
[186]张红珍,李丽.内皮素、一氧化氮与动脉粥样硬化及缺血性心脑血管疾病关.中西医结合心脑血管病杂志,2004,2：171-173.
[187]王黎.电针治疗血管性痴呆的实验研究.广州中医药大学博士论文,2002.
[188]田金洲,王永炎.血管性痴呆研究评述.北京中医药大学学报,1997,2O：2-7
[189]李义召.《脑血管病治疗学》第1版.山东人学出版社,1998.
[190]贾建平.血管性痴呆的诊断和治疗进展.引进国外医药技术与设备,1999,5：6-9.
[191]张朝阳.血管性痴呆研究进展.国外医学·老年医学丛册,2000.
[192]钱采韻.血管性痴呆与血管性认知功能障碍.中国医学科学院学报,2004,26：198-200.
[193]Ford GA, Bryant CA, Mangoni AA, et al. Stroke, dementia, and drug delivery. Br J Clin Pharmacol,2004,57:15-26.
[194]蔺心敬,胡长林,李吕力,等.血管性痴呆发生机制的研究.脑与神经疾病杂志,2003,11：235-236.
[195]张兰英,王玉良.血管性痴呆的发病与突触可塑性.中国临床康复,9：130-132.
[196]赵小贞,王伟,康仲函,等.血管性痴呆大鼠海马突触结构参数的变化.解剖学杂志,2002,25：30-34.
[197]盛树力.老年性痴呆发病机理研究进展和药物治疗未来战略.中国医学科学院学报,2004,26：101-103.
[198]Sekhon LH, Spence I, Morgan MK, et al. Chronic cerebral hyooperfusion inhibits calcium-induced long-term potentiation in rats. Stroke,1997,28: 1043-1048.
[199]Mori K, Yoshioka M, Suda N, et al. An incomplete cerebral isehemia produced a delayed dysfunction in rat hippocampal system. Bnmt Res,1998,795:221-226.
[200]Hakim J. Reactive oxygen species and inflammation. C R Seances Soc Biol Fil, 1993,187:286-295. [Article in French]
[201]Esmann L, Idel C, Sarkar A, et al. Phagocytosis of apoptotic cells by neutrophil granulocytes:diminished proinflammatory neutrophil functions in the presence of apoptotic cells. J Immunol,2010,184:391-400.
[202]Sang N, Hou L, Yun Y, et al. SO2 inhalation induces protein oxidation, DNA-protein crosslinks and apoptosis in rat hippocampus. Ecotoxicol Environ Saf, 2009,72:79-84.
[203]Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 1976,72:248-254.
[204]姚泰.生理学.人民卫生出版社,2001.
[205]MohanKumar SM, Campbell A, Block M, et al. Particulate matter, oxidative stress and neurotoxicity. Neurotoxicology,2008,29:479-488.
[206]维基百科.http://zh.wikipedia.org/wiki/%E8%84%91
[207]Taylor RM. Reexamining the definition and criteria of death. Semin Neurol,1997, 17:265-270.
[208]de Burbure CY, Heilier JF, Neve J, et al. Lung permeability, antioxidant status, and NO2 inhalation:a selenium supplementation study in rats. J Toxicol Environ Health A,2007,70:284-294.
[209]Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol,2007,39: 44-84.
[210]Fetoui H, Makni M, Mouldi Garoui E, et al. Toxic effects of lambda-cyhalothrin, a synthetic pyrethroid pesticide, on the rat kidney:Involvement of oxidative stress and protective role of ascorbic acid. Exp Toxicol Pathol,2010,62: 593-599.
[211]Gabrashanska M, Teodorova SE, Petkova S, et al. Selenium supplementation at low doses contributes to the antioxidant status in Trichinella spiralis-infected rats. Parasitol Res,2010,106:561-570.
[212]Bazan NG. Synaptic lipid signaling:significance of polyunsaturated fatty acids and platelet-activating factor. Lipid Res,2003,44:2221-2233.
[213]Kougias P, Chai H, Lin PH, et al. Effects of adipocyte-derived cytokines on endothelial functions:implication of vascular disease. J Surg Res,2005,126: 121-129.
[214]Hengartner MO. The biochemistry of apoptosis. Nature,2000,407:770-776.
[215]Bouts YM, Wolthuis DF, Dirkx MF, et al. Apoptosis and NET formation in the pathogenesis of SLE. Autoimmunity,2012,45:597-601.
[216]Ouyang L, Shi Z, Zhao S, et al. Programmed cell death pathways in cancer:a review of apoptosis, autophagy and programmed necrosis. Cell Prolif,2012,45: 487-498.
[217]Huttemann M, Lee I, Grossman LI, et al. Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human* disease. Adv Exp Med Biol,2012,748: 237-264.
[218]Rosello A, Warnes G, Meier UC. Cell death pathways and autophagy in the central nervous system and its involvement in neurodegeneration, immunity and central nervous system infection:to die or not to die--that is the question. Clin Exp Immunol,2012,168:52-57.
[219]Hong LZ, Zhao XY, Zhang HL. P53-mediated neuronal cell death in ischemic brain injury. Neurosci Bull,2010,26:232-240.
[220]Yang XY, Liu QN, Zhang L, et al. Neuroprotective effect of dauricine after transient middle cerebral artery occlusion in rats:involvement of Bcl-2 family proteins. Am J Chin Med,2010,38:307-318.
[221]Bernstein C, Bernstein H, Payne CM, et al. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways:fail-safe protection against carcinogenesis. Mutat Res,2002,511:145-178.
[222]Andrieu-Abadie N, Gouaze V, Salvayre R, et al. Ceramide in apoptosis signaling: relationship with oxidative stress. Free Radic Biol Med,2001,31:717-728.
[223]Yun Y, Li H, Li G, et al. SO(2) inhalation modulates the expression of apoptosis-related genes in rat hippocampus via its derivatives in vivo. Inhal Toxicol,2010,22:919-929.
[224]Cai CF, Feng L, Wang L, et al. Tetrazolium violet induces apoptosis via caspases-8,-9 activation and Fas/FasL up-regulation in rat C6 glioma cells. Arch Pharm Res,2009,32:575-581.
[225]Reed JC. Regulation of apoptosis by Bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol,1995,7:541-546.
[226]Wu AG, Liu YG, et al. Prolonged expression of c-Fos and c-Jun in the cerebral cortex of rats after deltamethrin treatment. Mol Brain Res,2003,110:147-151.
[227]Shimokawa N, Miyazaki W, Iwasaki T, et al. Low dose hydroxylated PCB induces c-Jun expression in PC12 cells. Neurotoxicology,2006,27,176-183.
[228]Liu X, Liu W, Jin Y, et al. Effects of subchronic perfluorooctane sulfonate exposure of rats on calcium-dependent signaling molecules in the brain tissue. Arch Toxicol,2010,84:471-479.
[229]Estus S, Zaks W J, Freeman R S, et al. Altered gene expression in neurons during programmed cell death:identification of c-jun as necessary for neuronal apoptosis. J Cell Biol,1994,127:1717-1727.
[230]Ham J, Babij C, Whitfield J, et al. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron,1995,14:927-939.
[231]Bossy-Wetzel E, Bakiri L, et al. Induction of apoptosis by the transcription factor c-Jun. EMBO J,1997,16:1695-1709.
[232]Martinez-Murillo R, Fernandez AP, Serrano J, et al. The nitric oxide donor LA 419 decreases brain damage in a focal ischemia model. Neurosci Lett,2007,415: 149-153.
[233]Zhao D, Liu J, Wang W, et al. Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke,2008,39:1668-1674.
[234]George MG, Tong X, Kuklina EV, et al.. Trends in stroke hospitalizations and associated risk factors among children and young adults,1995-2008. Ann Neurol, 2011,70:713-721.
[235]Zea Longa E, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without cra-niectomy in rats. Stroke,1989,20:84-91.
[236]Garcia JH, Wagner S, Liu KF, et al. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke 1995,26(4):627-634; discussion 635.
[237]李志强.细辛醚对AD大鼠学习记忆的影响及血管保护机制研究.暨南大学博士论文,2010.
[238]Kowal P, Marcinkowska-Gapinska A. Hemorheological changes dependent on the time from the onset of ischemic stroke. J Neurol Sci,2007,258:132-136.
[239]Szapary L, Horvath B, Marton Z, et al. Hemorheological disturbances in patients with chronic cerebrovascular diseases. Clin Hemorheol Microcir,2004,31:1-9.
[240]Schwartz J. Air pollution and blood markers of cardiovascular risk. Environ Health Perspect,2001,109(Suppl 3):405-409.
[241]Sun Q, Wang A, Jin X, et al. Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. JAMA,2005, 294:3003-3010.
[242]Ionita CC, Xavier AR, Kirmani JF, et al. What proportion of stroke is not explained by classic risk factors? Prev Cardiol,2005,8:41-46.
[243]刘敬霞,李建生.线栓法制备大鼠局灶性脑缺血模型的进展及评价.中国比较医学杂志,2004,14：374-377.
[244]程发峰.精制清开灵注射液对脑缺血的治疗作用及对兴奋性毒性级联损伤的调控机制.北京中医药大学博士论文,2011.
[245]Sicard KM, Fisher M. Animal models of focal brain ischemia. Exp Transl Stroke Med,2009,1:7.
[246]Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta,2010,1802:80-91.
[247]Chen P, Shibata M, Zidovetzki R, et al. Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures. JNeuroimmunol,2001,116,62-73.
[248]Leung JWC, Chung SSM, Chung SK. Endothelial endothelin-1 over-expression using receptor tyrosine kinase tie-1 promoter leads to more severe vascular permeability and blood brain barrier breakdown after transient middle cerebral artery occlusion. Brain Res,2009,1266:121-129.
[249]Sang N, Yun Y, Li H, et al. SO2 inhalation contributes to the development and progression of ischemic stroke in the brain. Toxicol Sci,2010,114:226-236.
[250]胡泽平.替米沙坦对高血压和动脉粥样硬化血管内皮功能的影响及其机制.安徽医科大学博士论文,2011.
[251]Andresen J, Shafi NI, Bryan Jr RM. Endothelial influences on cerebrovascular tone. JAppl Physiol,2006,100:318-327.
[252]Markewitz BA, Michael JR, Kohan DE. Endothelin-1 inhibits the expression of inducible nitric oxide synthase. Am J Physiol,1997,272:L1078-L1083.
[253]Rodrigo J, Fernandez AP, Serrano J, et al. The role of free radicals in cerebral hypoxia and ischemia. Free Radical Biology & Medicine,2005,39:26-50.
[254]Luo CX, Zhu XJ, Zhou QG, et al. Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression. J Neurochem,2007,103:1872-1882.
[255]Armstead WM, Mirro R, Zuckerman SL, et al. Transforming growth factor-beta attenuates ischemia-induced alterations in cerebrovascular responses. Am J Physiol,1993,264:H381-385.
[256]Barone FC, Schmidt DB, Hillegass LM, et al. Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke,1992,23: 1337-1347.
[257]Pantoni L, Sarti C, Inzitari D. Cytokines and cell adhesion molecules in cerebral ischemia. Arterioscler Thromb Vasc Biol,1998,18:503-513.
[258]Yoshimoto T, Houkin K, Tada M, et al. Induction of cytokines, chemokines and adhesion molecule mRNA in a rat forebrain reperfusion model. Acta Neuropathol (Berl),1997,93:154-158.
[259]李琴,张红,郭云良.肌苷对脑缺血再灌注后COX-2表达的调节作用.中国老年杂志,2004,7：640-642.
[260]Knopman DS. Cerebrovascular disease and dementia. British Institute of Radiology,2007,80:S121-S127.
[261]National Stroke Association. http://www.stroke.org/site/PageServer?pagename=VADEM.
[262]Igoumenou A, Ebmeier KP. Diagnosing and managing vascular dementia. Practitioner,2012,256:13-6,2.
[263]World Health Organization. http://www.who.int/mediacentre/news/releases/2012/dementia_20120411/en/inde x.html,2012.
[264]Peters A, Sethares C, Luebke JI. Synapses are lost during aging in the primate prefrontal cortex. Neuroscience,2008,152:970-981.
[265]Barnes DE, Haight TJ, Mehta KM, et al. Secondhand smoke, vascular disease, and dementia incidence:findings from the cardiovascular health cognition study. Am JEpidemiol,2010,171:292-302.
[266]Costain WJ, Rasquinha I, Sandhu JK, et al. Cerebral ischemia causes dysregulation of synaptic adhesion in mouse synaptosomes. J Cereb Blood Flow Metab,2008,28:99-110.
[267]Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke,1995,26:2135-2144.
[268]Campos AC, Ferreira FR, da Silva WA Jr, et al. Predator threat stress promotes long lasting anxiety-like behaviors and modulates synaptophysin and CB1 receptors expression in brain areas associated with PTSD symptoms. Neurosci Lett,2013,533,34-38.
[269]Beique JC, Andrade R. PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J Physiol,2003,546,859-867.
[270]Di FM, Tozzi A, Costa C, et al. Plasticity and repair in the post-ischemic brain. Neuropharmacology,2008,55:353-362.
[271]Xu X, Ye L, Ruan Q. Environmental enrichment induces synaptic structural modification after transient focal cerebral ischemia in rats. Exp Biol Med (Maywood),2009,234:296-305.
[272]Kerchner GA, Nicoll RA. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci,2008,9:813-825.
[273]Lynch M. Long-term potentiation and memory. Physiol Rev,2004,84:87-136.
[274]Akaneya Y, Tsumoto T. Bidirectional trafficking of prostaglandin E2 receptors involved in long-term potentiation in visual cortex. J Neurosci,2006,26, 10209-10221.
[275]Serrano P, Yao Y, Sacktor T. Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation. J Neurosci,2005,25:1979-1984.
[276]Sweatt J. Toward a molecular explanation for long-term potentiation. Learn Mem, 1999,6:399-416.
[277]Alberini CM. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev,2009,89:121-145.
[278]Cristina MA. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev,2009,89:121-145.
[279]Lee HT, Chang YC, Wang LY, et al. cAMP response element-binding protein activation in ligation preconditioning in neonatal brain. Ann Nenrol,2004,56: 611-623.
[280]Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron,2002,35:605-623.
[281]Sawe N, Steinberg G, Zhao H. Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res,2008,86:1659-1669.
[282]Zhang M, Shan H, Gu Z, et al. Increased expression of calcium/calmodulin-dependent protein kinase type Ⅱ subunit delta after rat traumatic brain injury. JMol Neurosci,2012,46:631-643.
[283]Kim KH, Pessah IN. Perinatal exposure to environmental polychlorinated biphenyls sensitizes hippocampus to excitotoxicity ex vivo. Neurotoxicology, 2011,32:981-985.
[284]Meli E, Picca R, Attucci S, et al. Activation of mGlul but not mGlu5 metabotropic glutamate receptors contributes to postischemic neuronal injury in vitro and in vivo. Pharmacol Biochem Behav,2002,73:439-446.
[285]Edling Y, Ingelman-Sundberg M, Simi A. Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM. Glia,2007,55:328-340.
[286]Lee HK, Choi SS, Han EJ, et al. Role of nicotinic acetylcholine receptors in the regulation of kainic acid-induced hippocampal cell death in mice. Brain Res Bull, 2004,64:309-317.
[2]郝吉明,马广大,王书肖.《大气污染控制工程》第2版.北京,高等教育出版社,2010.
[3]侯棻.二氧化氮和硝酸酸雾对植物的毒性效应研究.山西大学硕士论文,2012.
[4]Olsen DB, Kohls M, Arney G Impact of oxidation catalysts on exhaust NO2/NOX ratio from lean-burn natural gas engines. J Air Waste Manag Assoc,2010,60: 867-874.
[5]张雅倩.城市交通性污染研究及其对成人呼吸系统健康的影响分析.天津大学硕士论文,2012.
[6]中国疾病预防控制中心,国际环保组织绿色和平.《煤炭的真实成本——大气污染与公众健康》,北京,2010.
[7]张兴赢,张鹏,张艳,等.近10a中国对流层N02的变化趋势、时空分布特征及其来源解析.中国科学,2007,37：1409-1416.
[8]中华人民共和国环境保护部.http://jcs.mep.gov.cn/hjzl/zkgb/201 lzkgb
[9]Report on a WHO Working Group. Health Aspects of Air Pollution with Particulate Matter, Ozone and Nitrogen Dioxide,13-15 January 2003, Bonn, Germany, www.euro.who.int/document/e79097.pdf
[10]GreenRacts. http://www.greenfacts.org/en/nitrogen-dioxide-no2/level-2/ 03-exposure.htm#3
[11]Frampton MW, Boscia J, Jr Roberts NJ, et al. Nitrogen dioxide exposure:effects on airway and blood cells. Am J Physiol Lung Cell Mol Physiol,2002,282: L155-165.
[12]Yin W, Zhang H, Wang C, et al. Spatial Distribution of Motor Vehicle Pollutions on the Streets in Taiyuan Based on GIS. Environmental Science and Management, 2010,35:25-29.
[13]医学知识库.http://pmmp.cnki.net/Disease/Details.aspx?id=809
[14]孟紫强.环境毒理学.北京中国环境科学出版社,2000.
[15]Hesterberg TW, Bunn WB, McClellan RO, et al. Critical review of the human data on short-term nitrogen dioxide (NO2) exposures:evidence for NO2 no-effect levels. Crit Rev Toxicol,2009,39:743-781.
[16]Pathmanathan S, Krishna MT, Blomberg A, et al. Repeated daily exposure to 2 ppm nitrogen dioxide upregulates the expression of IL-5, IL-10, IL-13, and ICAM-1 in the bronchial epithelium of healthy human airways. Occup Environ Med,2003,60:892-896.
[17]Hussain I, Jain VV, O'Shaughnessy P, et al. Effect of nitrogen dioxide exposure on allergic asthma in a murine model. Chest,2004,126:198-204.
[18]Ponka A, Virtanen M. Chronic bronchitis, emphysema, and low-level air pollution in Helsinki,1987-1989. Environ Res,1994,65:207-217.
[19]Takenoue Y, Kaneko T, Miyamae T, et al. Influence of outdoor NO(2) exposure on asthma in childhood:Meta-analysis. Pediatr Int,2012,54:762-769.
[20]Faustini A, Stafoggia M, Cappai G, et al. Short-term effects of air pollution in a cohort of patients with chronic obstructive pulmonary disease. Epidemiology, 2012,23:861-879.
[21]Tango T. Effect of air pollution on lung cancer:a Poisson regression model based on vital statistics. Environ Health Perspect,1994,102 Suppl 8:41-45.
[22]Richters A, Richters V. Nitrogen dioxide (NO2) inhalation, formation of microthrombi in lungs and cancer metastasis. J Environ Pathol Toxicol Oncol, 1989,9:45-51.
[23]Poynter ME, Persinger RL, Irvin CG, et al. Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse. Am J Physiol Lung Cell Mol Physiol,2006,290:L144-152.
[24]Goldstein E, Peek NF, Parks NJ, et al. Fate and distribution of inhaled nitrogen dioxide in rhesus monkeys. Am Rev Respir Dis,1977,115(3):403-412.
[25]Postlethwait EM, Mustafa MG. Fate of inhaled nitrogen dioxide in isolated perfused rat lung. J Toxicol Environ Health,1981,7:861-872.
[26]Saul RL, Archer MC. Nitrate formation in rats exposed to nitrogen dioxide. Toxicol Appl Pharmacol,1983,67:284-291.
[27]Parkinson DR, Stephens RJ. Morphological surface changes in the terminal bronchiolar region of NO2-exposed rat lung. Environ Res,1973,6:37-51.
[28]Kleinerman J. Some effects of nitrogen dioxide on the lung. Fed Proc,1977,36: 1714-1718.
[29]Ranga V, Kleinerman J. A quantitative study of ciliary injury in the small airways of mice:the effects of nitrogen dioxide. Exp Lung Res,1981,2:49-55.
[30]Barth PJ, Miiller B, Wagner U, et al. Quantitative analysis of parenchymal and vascular alterations in NO2-induced lung injury in rats. Eur Respir J,1995,8: 1115-1121.
[31]Gregory RE, Pickrell JA, Hahn FF, et al. Pulmonary effects of intermittent subacute exposure to low-level nitrogen dioxide. J Toxicol Environ Health,1983 11:405-414.
[32]Suzuki AK, Tsubone H, Kubota K. Changes of gaseous exchange in the lung of mice acutely exposed to nitrogen dioxide. Toxicol Lett,1982,10:327-335.
[33]Suzuki AK, Ichinose T, Tsubone H, et al. Effects of acute nitrogen dioxide exposure on swimming performance of mice. J Toxicol Environ Health,1982,9: 165-172.
[34]Voisin C, Aerts C, Jakubczak E, et al. Effects of nitrogen dioxide on alveolar macrophages surviving in the gas phase. A new experimental model for the study of in vitro cytotoxicity of toxic gases (author's transl). Bull Eur Physiopathol Respir,1977,13:137-144. [Article in French]
[35]Rasmussen RE, Mannix RC, Oldham MJ, et al. Effects of nitrogen dioxide on respiratory tract clearance in the ferret. J Toxicol Environ Health,1994,41: 109-120.
[36]Evans MJ, Cabral LJ, Stephens RJ, et al. Renewal of alveolar epithelium in the rat following exposure to NO2. Am J Pathol,1973,70:175-198.
[37]Evans MJ, Cabral LJ, Stephens RJ, et al. Cell division of alveolar macrophages in rat lung following exposure to NO2. Am J Pathol,1973,70:199-208.
[38]Sagai M, Ichinose T, Oda H, et al. Studies on biochemical effects of nitrogen dioxide. II. Changes of the protective systems in rat lungs and of lipid peroxidation by acute exposure. J Toxicol Environ Health,1982,9:153-164.
[39]Husain MM, Dehnen W. Effect of NO2 and SO2 inhalation on benzo(a)pyrene metabolism in rat lung. Arch Toxicol,1978,40:207-210.
[40]Rynbrandt D. Nitrogen dioxide and pulmonary proteolytic enzymes. Effect on lung tissue and macrophages. Arch Environ Health,1977,32:165-172.
[41]Chaudhari A, Dutta S. Effect of an acute exposure of guinea pigs to NO2 on pulmonary prostaglandin dehydrogenase and angiotensin converting enzyme. Bull Environ Contam Toxicol,1980,25:816-823.
[42]Maitani T, Suzuki KT, Kubota K. Changes of essential metal contents in lungs of rats acutely exposed to nitrogen dioxide. Toxicol Lett,1981,7(4-5):289-295.
[43]Creasia DA, Nettesheim P, Kim JC. Stimulation of DNA synthesis in the lungs of hamsters exposed intermittently to nitrogen dioxide. J Toxicol Environ Health, 1977,2:1173-1181.
[44]Walles SA, Victorin K, Lundborg M. DNA damage in lung cells in vivo and in vitro by 1,3-butadiene and nitrogen dioxide and their photochemical reaction products. Mutat Res,1995,328:11-19.
[45]Richters A, Kuraitis K. Inhalation of NO2 and blood borne cancer cell spread to the lungs. Arch Environ Health,1981,36:36-39.
[46]Ballester F, Rodriguez P, Iniguez C, et al. Air pollution and cardiovascular admissions association in Spain:results within the EMECAS project. J Epidemiol Community Health,2006,60:328-336.
[47]Wong CM, Vichit-Vadakan N, Vajanapoom N, et al. Public health and air pollution in Asia (PAPA):a combined analysis of four studies of air pollution and mortality. Res Rep Health Eff Inst,2010, (154):377-418.
[48]Osman Y. Environmental surveys conducted in the Gulf region following the Gulf War to identify possible neurobehavioral consequences. Environ Res,1997,73: 207-210.
[49]Liao D, Duan Y, Whitsel EA, et al. Association of higher levels of ambient criteria pollutants with impaired cardiac autonomic control:a population-based study. Am J Epidemiol,2004,159:768-777.
[50]Nafstad P, Haheim LL, Wisl(?)ff T, et al. Urban air pollution and mortality in a cohort of Norwegian men. Environ Health Perspect,2004,112:610-615.
[51]D'Ippoliti D, Forastiere F, Ancona C, et al. Air pollution and myocardial infarction in Rome:a case-crossover analysis. Epidemiology,2003,14:528-535.
[52]Mann JK, Tager IB, Lurmann F, et al. Air pollution and hospital admissions for ischemic heart disease in persons with congestive heart failure or arrhythmia. Environ Health Perspect,2002,110:1247-1252.
[53]Llorca J, Salas A, Prieto-Salceda D, et al. Nitrogen dioxide increases cardiorespiratory admissions in Torrelavega (Spain). J Environ Health,2005,68: 30-35.
[54]von Klot S, Peters A, Aalto P, et al. Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation,2005,112:3073-3079.
[55]Yang CY. Air pollution and hospital admissions for congestive heart failure in a subtropical city:Taipei, Taiwan./Toxicol Environ Health A,2008,71: 1085-1090.
[56]Rosenlund M, Picciotto S, Forastiere F, et al. Traffic-related air pollution in relation to incidence and prognosis of coronary heart disease. Epidemiology,2008, 19:121-128.
[57]Larrieu S, Jusot JF, Blanchard M, et al. Short term effects of air pollution on hospitalizations for cardiovascular diseases in eight French cities:the PSAS program. Sci Total Environ,2007,387(1-3):105-112.
[58]Vrijheid M, Martinez D, Manzanares S, et al. Ambient air pollution and risk of congenital anomalies:a systematic review and meta-analysis. Environ Health Perspect,2011,119:598-606.
[59]Huang YC, Rappold AG, Graff DW, et al. Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans. Inhal Toxicol,2012,24:790-797.
[60]Williams R, Brook R, Bard R, et al. Impact of personal and ambient-level exposures to nitrogen dioxide and paniculate matter on cardiovascular function. Int J Environ Health Res,2012,22:71-91.
[61]Villeneuve PJ, Chen L, Stieb D, et al. Associations between outdoor air pollution and emergency department visits for stroke in Edmonton, Canada. Eur J Epidemiol,2006,21:689-700.
[62]Metzger KB, Tolbert PE, Klein M, et al. Ambient air pollution and cardiovascular emergency room visits. Epidemiology,2004,15:46-56.
[63]Hong YC, Lee JT, Kim H, et al. Air pollution:a new risk factor in ischemic stroke mortality. Stroke,2002,33:2165-2169.
[64]Vidale S, Bonanomi A, Guidotti M, et al. Air pollution positively correlates with daily stroke admission and in hospital mortality:a study in the urban area of Como, Italy. Neurol Sci,2010,31:179-182.
[65]Wellenius GA, Schwartz J, Mittleman MA. Air pollution and hospital admissions for ischemic and hemorrhagic stroke among medicare beneficiaries. Stroke,2005, 36:2549-2553.
[66]Andersen ZJ, Kristiansen LC, Andersen KK, et al. Stroke and long-term exposure to outdoor air pollution from nitrogen dioxide:a cohort study. Stroke,2012,43: 320-325.
[67]Maheswaran R, Pearson T, Smeeton NC, et al. Impact of outdoor air pollution on survival after stroke:population-based cohort study. Stroke,2010,41:869-877.
[68]Koken PJ, Piver WT, Ye F, et al. Temperature, air pollution, and hospitalization for cardiovascular diseases among elderly people in Denver. Environ Health Perspect,2003,111:1312-1317.
[69]Tsubone H, Oda H, Suzuki AK, et al. Electrocardiographic abnormalities in rats by acute exposure to nitrogen dioxide. Toxicol Lett,1982,12:125-129.
[70]Tsubone H, Suzuki AK, Sagai M, et al. Changes of cardiac and respiratory rhythm in non-and tracheostomized rats exposed to nitrogen dioxide. Environ Res,1984,35:197-203.
[71]Linn WS, Solomon JC, Trim SC, et al. Effects of exposure to 4 ppm nitrogen dioxide in healthy and asthmatic volunteers. Arch Environ Health,1985,40: 234-239.
[72]Freire C, Ramos R, Puertas RJ, et al. Association of traffic-related air pollution with cognitive development in children. Epidemiol Community Health,2010,64: 223-228.
[73]Wang S, Zhang J, Zeng X, et al. Association of traffic-related air pollution with children's neurobehavioral functions in Quanzhou, China. Environ Health Perspect,2009,117:1612-1618.
[74]Chen JC, Schwartz J. Neurobehavioral effects of ambient air pollution on cognitive performance in US adults. Neurotoxicology,2009,30:231-239.
[75]Ranft U, Schikowski T, Sugiri D, et al. Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environ Res,2009, 109:1004-1011.
[76]Power MC, Weisskopf MG, Alexeeff SE, et al. Traffic-related air pollution and cognitive function in a cohort of older men. Environ Health Perspect,2011,119: 682-687.
[77]Nattero G, Enrico A. Outdoor pollution and headache. Headache,1996,36: 243-245.
[78]Mikhailichenko KIu, Kas'ianenko AA, Shchelkunova IG, et al. Risk for environment-induced diseases due to air pollution from motor vehicles in road-patrol officers. Gig Sanit,2010, (3):39-42. [Article in Russian]
[79]Levesque S, Surace MJ, McDonald J, et al. Air pollution & the brain:Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J Neuroinflammation,2011,8:105.
[80]Win-Shwe TT, Fujitani Y, Hirano S, et al. Exposure to nanoparticle-rich diesel exhaust affects hippocampal functions in mice. Nihon Eiseigaku Zasshi,2011,66: 628-633. [Article in Japanese]
[81]Tsukue N, Watanabe M, Kumamoto T, et al. Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum. Arch Toxicol,2009,83:985-1000.
[82]Farahani H, Hasan M. Nitrogen dioxide induced changes in level of free fatty acids, triglyceride, esterified fatty acid, ganglioside and lipase activity in the guinea pig brain. J Environ Sci Health B,1992,27:53-71.
[83]Farahani H, Hasan M. Effect of NO2 on lipids and lipid peroxidation in the CNS of the guinea-pig. Pharmacol Toxicol,1990,66:146-149.
[84]孙存普,张建中,段绍瑾.自由基生物学导论.合肥：中国科学技术大学出版社,1999.
[85]武冬梅.二氧化硫对小鼠不同组织器官的氧化应激、DNA损伤及细胞因子的影响.山西大学博士论文,2004.
[86]赵克然,杨毅军,曹道俊.氧自由基与临床.北京：中国医药科技出版社,2000.
[87]Winterbourn CC, Hampton MB. Thiol chemistry and specificity in redox signaling. Free Radical Biology & Medicine,2008,45:549-561.
[88]Paulsen CE, Carroll KS. Orchestrating Redox Signaling Networks through Regulatory Cysteine Switches. Acs Chemical Biology,2010,5:47-62.
[89]Misra MK, Sarwat M, Bhakuni P, et al. Oxidative stress and ischemic myocardial syndromes. Med Sci Monit,2009,15:RA209-219.
[90]Valko M, Rhodes CJ, Moncol J, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact,2006,160:1-40.
[91]Dalle-Donne I, Scaloni A, Giustarini D, et al. Proteins as biomarkers of oxidative/nitrosative stress in diseases:the contribution of redox proteomics. Mass Spectrom Rev,2005,24:55-99.
[92]Filipcik P, Cente M, Ferencik M, et al. The role of oxidative stress in the pathogenesis of Alzheimer's disease. Bratisl Lek Listy,2006,107:384-394.
[93]Calabrese V, Guagliano E, Sapienza M, et al. Redox regulation of cellular stress response in neurodegenerative disorders. Ital J Biochem,2006,55:263-282.
[94]Trushina E, McMurray CT. Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience,2007,145:1233-1248.
[95]Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem,1992,59:1609-1623.
[96]Ganesana M, Erlichman JS, Andreescu S. Real-time monitoring of superoxide accumulation and antioxidant activity in a brain slice model using an electrochemical cytochrome c biosensor. Free Radic Biol Med,2012,53: 2240-2249.
[97]Beal MF. Oxidative damage in neurodegenerative diseases. Neuroscientist,1997, 3:21-27.
[98]L6pez N, Tormo C, De Bias I, et al. Oxidative Stress in Alzheimer's Disease and Mild Cognitive Impairment with High Sensitivity and Specificity. J Alzheimers Dis,2012,33:823-829.
[99]Wikipedia. http://en.wikipedia.org/wiki/Inflammation,2013.
[100]Margaritescu O, Mogoanta L, Pirici I, et al. Histopathological changes in acute ischemic stroke. Rom JMorphol Embryol,2009,50:327-339.
[101]Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain,2009,132:1175-1189.
[102]吴荣谦,徐迎新,宋旭华,等.脓毒症小鼠肝肺组织细胞因子mRNA表达的比较.中国危重病急救医学,2000,12：588-590.
[103]Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci,2001,2:734-744.
[104]Beattie EC, Stellwagen D, Morishita W, et al. Control of synaptic strength by glial TNF-alpha. Science,2002,295:2282-2285.
[105]Merrill JE, Benveniste EN. Cytokines in inflammatory brain lesion:helpful and harmful trends. Neurosci,1996,19:331-339.
[106]Butler MP, O'Connor JJ, Moynagh PN. Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogenactivated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neurosci,2004,124:319-326.
[107]Suzuki K, Nakaji S, Yamada M. Systemicirdlammatory response to exhaustive exercise Cytokine kinetics. Exe Immunol Rev,2002,8:6-48.
[108]Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol,2005,5:629-640.
[109]Rothwell NJ, Luheshi GN. Interleukin 1 in the brain:biology, pathology and therapeutic target. Trends Neurosci,2000,23:618-625.
[110]Katsuki H, Nakai S, Hirai Y, et al. Interleukin-1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices. Eur J Pharmacol, 1990,181:323-326.
[111]Bazan NG, Flower RJ. Lipid signals in pain control. Nature,2002,420:135-138.
[112]Patrignani P, Tacconelli S, Sciulli MG, et al. New insights into COX-2 biology and inhibition. Brain Res Rev,2005,48:352-359.
[113]Kaufmann WE, Worley PF, Pegg J, et al. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA,1996,93:2317-2321.
[114]Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenase)-1 and -2. JBiol Chem,1996,271:33157-33160.
[115]Vane JR, Bakhle YS, Botting RM. Cyclooxygenase 1 and 2. Annu Rev Pharmacol Toxicol,1998,38:97-120.
[116]Bazan NG. COX-2 as a multifunctional neuronal modulator. Nat Med,2001,7: 414-415.
[117]Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation. JPhysiol Pharmacol,2003,54:469-487.
[118]Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiological flow rates:distinction from and prerequisite for adhesion through integrins. Cell,1991, 65:859-873.
[119]张刚,程锦泉,彭绩,等.细胞间粘附分子-1与心脑血管疾病相关性.中国公共卫生,2006,22：1404-1406.
[120]Li RJ, Meng ZQ, Xie JF. Effects of sulfur dioxide on the expressions of MUC5AC and ICAM-1 in airway of asthmatic rats. Regulatory Toxicology and Pharmacology,2007,48:284-291.
[121]Calderon-Garciduenas L, Reed W, Maronpot RR, et al. Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution. Toxicol Pathol,2004,32:650-658.
[122]Calderon-Garciduenas L, Azzarelli B, Acuna H, et al. Air pollution and brain damage. Toxicol Pathol,2002,30:373-389.
[123]桑楠,云洋,侯丽.SO2吸入对大鼠海马组织炎性因子水平、钙稳态和即早基因表达的影响.环境科学学报,2008,28：2315-2321.
[124]Campbell A, Araujo JA, Li H, et al. Particulate matter induced enhancement of inflammatory markers in the brains of apolipoprotein E knockout mice. J Nanosci Nanotechnol,2009,9:5099-5104.
[125]朱铁梁,郝素云,段姚尧,等.脑缺血后Bcl-2家族、即早基因的表达与细胞凋亡.武警医学院学报,2006,15：166-169.
[126]白剑英.二氧化硫及其衍生物对小鼠几种脏器超微结构和细胞凋亡的影响.山西大学博士论文,2004.
[127]Wolozin B, Behl C. Mechanisms of Neurodegenerative Disorders. Arch neurol, 2000,57：801-804.
[128]杨小慧,戴雪伶,姜招峰.阿尔茨海默病的脑神经元凋亡机制.生命的化学,2007,27：307-310.
[129]Kalalian-Moghaddam H, Baluchnejadmojarad T, Roghani M, et al. Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. Eur J Pharmacol,2012,698:259-266.
[130]Stephenson CP, Hunt GE, Topple AN, et al. The distribution of 3,4-methylened ioxymethamp-hetamine "ecstasy"-induced c-fos expression in rat brain. Neuroscience,1999,92:1011-1023.
[131]Verma IM, Sassone-Corsi P. Proto-oncogene fos:complex but versatile regulation. Cell,1987,51:513-514.
[132]Smeyne RJ, Vendrell M, Hayward M, et al. Continuous c-fos expression precedes programmed cell death in vivo. Nature,1993,363:166-169.
[133]Kang PM, Izumo S. Apoptosis and heart failure:a critical review of the literature. CircRes,2000,86:1107-1113.
[134]Gross A, McDonnell JM, Korsmeyer SJ. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev,1999,13:1899-1911.
[135]Xu J, Ji LD, Xu LH. Lead-induced apoptosis in PC 12 cells:Involvement of p53, Bcl-2 family and caspase-3. Toxicol Lett,2006,166:160-166.
[136]Levine A. p53, The celular gatekeeper for growth and division. Cell,1997,88: 323-331.
[137]尹欣.内皮功能障碍与心血管疾病.中国中医药报,2003.
[138]熊石龙,王前,郑磊,等.急性缺血性心脑血管疾病组织因子途径的改变.解放军医学杂志,2008,33：93-95.
[139]Shin-ichi S, Naomi Y, Fumiki Y, et al. Endothelin A receptor blockade and endothelin B receptor blockade improve hypokalemic nephropathy by different mechanism. Am soc Nephrol,2003,14:397.
[140]张建,华崎,李静.高血压代谢综合症.人民卫生出版社,2003：368-369.
[141]Lee KB, Oh HG, Roh H, et al. Can we discriminate stroke mechanisms by analyzing the infarct patterns in the striatocapsular region. Eur Neurol,2008,60: 79-84.
[142]Tsai NW, Chang WN, Shaw CF, et al. The value of leukocyte adhesion molecules in patients after ischemic stroke. Neurol,2009,256:1296-1232.
[143]Haeusler KG, Schmidt WU, Fohring F, et al. Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis,2008,25:50-58.
[144]陈等,吴亚宁,张俊武.线粒体与阿尔茨海默病.基础医学与临床,2001,21：395-399.
[145]Tabeuchi A. Excitatery amino acid transmitters:past, present, and future. In: Kanazawal, ed Neurotransmittors focus on excitatory amino acids. Tokyo: Exeerpta,1998,395.
[146]Pulsinelli WA. Cerebral blood flow in the fourvessel occlusion rat model. Stroke, 1983,14:832-840.
[147]徐仁泗.兴奋性氨基酸与脑缺血损伤的研究概况.国外医学·神经病学神经外科学分册,1998,25：62-64.
[148]Castillo J, Davaios A, Nareiro J, et al. Neuroexcitatory amino acids and their relation to infarct size and neurological deficit in ischemic stroke. Stroke,1996, 27:1060-1065.
[149]Pietropaoli JA, Rogers FB, Shackford SR, et al. The deleterious effects of intraoperative hypotension on outcome in patients with severe head in-juries. J Traima,1992,33:403-407.
[150]Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxi-cischemic brain damge. Ann Neuro,1986,19:105-111.
[151]Liu F, Day M, Muniz LC, et al. Activation of estrogen receptor-b regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci,2008,11: 334-343.
[152]席艳,万建华,邓锦波.突触可塑性的生物物理学基础和体视学测量研究进展.中国医药生物技术,2009,4：370-373.
[153]许绍芬.《神经生物学》2版.上海：上海医科大学出版社,1999：389-400.
[154]Goosens KA, Maren S. Long-term potentiation as a substrate for memory: evidence from studies of amygdaloid plasticity and Pavlovian fear conditioning. Hippocampus,2002,12:592-599.
[155]German IP, Carlos AB. Timed changes of synaptic zinc, synaptophysin and MAP2 in medial extended amygdala of epileptic animals are suggestive of reactive neuroplasticity. Brain Res,2010,1328:130-138.
[156]Tian Y, Wang Y, Deng Y, et al. Methylphenidate improves spatial memory of spontaneously hypertensive rats:evidence in behavioral and ultrastructural changes. Neurosci Lett,2009,461:106-109.
[157]Sturgill JF, Steiner P, Czervionke BL, et al. Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking. J Neurosci,2009,29:12845-12854.
[158]徐春,章晓辉.学习和记忆的突触模型：长时程突触可塑性.自然杂志,2009,31：136-141.
[159]Sheng M, Kim MJ. Postsynaptic Signaling and Plasticity Mechanisms. Science, 2002,298:776-780.
[160]Restituito S, Ziff EB. Methods for Uncovering the Mechanisms of AMPA Receptor Trafficking. In:Kittler JT, Moss SJ, editors. The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. Boca Raton (FL):CRC Press; 2006. Chapter 1.
[161]Lau CG, Takeuchi K, Rodenas-Ruano A, et al. Regulation of NMD A receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans,2009,37:1369-1374.
[162]Moriguchi S, Shiodaa N, Yamamotoa Y, et al. Platelet-activating factor-induced synaptic facilitation is associated with increased calcium/calmodulin-dependent protein kinase II, protein kinase C and extracellular signal-regulated kinase activities in the rat hippocampal CA1 region. Neuroscience,2010,166: 1158-1166.
[163]Masliah E. Recent advances in the understanding of the role of synapfic proteinsin Alzheimer's Disease and other neurodegenerative disorders. J Alzheimer's Disease,2001,3:121-129.
[164]Lin CS, Tao PL, Jong YJ, et al. Prenatal morphine alters the synaptic complex of postsynaptic density 95 with N-methyl-d-aspartate receptor subunit in hippocampal CA1 subregion of rat offspring leading to long term cognitive deficits. Neuroscience,2009,158:1326-1337.
[165]Kandel ER. The molecular biology of memory storage:a dialogue between genes and synapses. Science,2001,294:1030-1038.
[166]Rosenzweig ES, Barnes CA. Impact of aging on hippocampal function:plasticity, network dynamics, and cognition. Prog Neurobiol,2003,69:143-179.
[167]Johnston MV, Ishida A, Ishida WN, et al. Plasticity and injury in the developing brain. Brain Dev,2009,31:1-10.
[168]Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev,2007,54:34-66.
[169]Leuba G, Savioz A, Vernay A, et al. Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein. JAlzheimers Dis,2008,15:139-151.
[170]杨牧祥,于文涛,丁宁,等.中风康对局灶性脑缺血大鼠脑病理形态学的影响.中医研究,2006,19：7-10.
[171]Thomson EM, Kumarathasana P, Calderon-Garciduenas L, et al. Air pollution alters brain and pituitary endothelin-1 and inducible nitric oxide synthase gene expression. Environmental Research,2007,105:224-233.
[172]Banerjee I, Gupta V, Ahmed T, et al. Inflammatory system gene polymorphism and the risk of stroke:A case-control study in an Indian population. Brain Research Bulletin,2008,75:158-165.
[173]Callow AD. Endothelial dysfunction in atherosclerosis. Vascul Pharm acol,2002, 38:257-258.
[174]郝延磊,普传强,朱克,等.血脑屏障内皮细胞与细胞间黏附分子-1在鼠脑缺血性脑水肿发生机制中的作用.中华神经科杂志,2000,33：86-89.
[175]Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:an integrated view. Trends Neurosci,1999,22:391-397.
[176]Volpe M, Cosentino F. Abnormalities of endothelial function in the pathogenesis of stroke:the importance of endothelin. J Cardiovasc Pharmacol,2000,35: 45-48.
[177]Yenari MA, Han HS. Influence of hypothermia on post-ischemic inflammation: Role of nuclear factor kappa B (NF-κB). Neurochemistry International,2006,49: 164-169.
[178]Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene,1999,18:6853-6866.
[179]Minami M, Satoh M. Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury. Life Sciences,2003,74: 321-327.
[180]Minami M, Satoh M. Role of Chemokines in Ischemic Neuronal Stress. Neuro Molecular Medicine,2005,7:149-155.
[181]del Zoppo G, Ginis I, Hallenbeck JM, et al. Inflammation and Stroke:Putative Role for Cytokines, Adhesion Molecules and iNOS in Brain Response to Ischemia. Brain Pathology,2000,10:95-112.
[182]Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol, 2002,2:725-734.
[183]Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surgical Neurology,2006,66:232-245.
[184]Thomas WS, Mori E, Copeland BR, et al. Tissue factor contributes to microvascular defects after focal cerebral ischemia. Stroke,1993,24:847-853.
[185]Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation, 2002,102:2434-2440.
[186]张红珍,李丽.内皮素、一氧化氮与动脉粥样硬化及缺血性心脑血管疾病关.中西医结合心脑血管病杂志,2004,2：171-173.
[187]王黎.电针治疗血管性痴呆的实验研究.广州中医药大学博士论文,2002.
[188]田金洲,王永炎.血管性痴呆研究评述.北京中医药大学学报,1997,2O：2-7
[189]李义召.《脑血管病治疗学》第1版.山东人学出版社,1998.
[190]贾建平.血管性痴呆的诊断和治疗进展.引进国外医药技术与设备,1999,5：6-9.
[191]张朝阳.血管性痴呆研究进展.国外医学·老年医学丛册,2000.
[192]钱采韻.血管性痴呆与血管性认知功能障碍.中国医学科学院学报,2004,26：198-200.
[193]Ford GA, Bryant CA, Mangoni AA, et al. Stroke, dementia, and drug delivery. Br J Clin Pharmacol,2004,57:15-26.
[194]蔺心敬,胡长林,李吕力,等.血管性痴呆发生机制的研究.脑与神经疾病杂志,2003,11：235-236.
[195]张兰英,王玉良.血管性痴呆的发病与突触可塑性.中国临床康复,9：130-132.
[196]赵小贞,王伟,康仲函,等.血管性痴呆大鼠海马突触结构参数的变化.解剖学杂志,2002,25：30-34.
[197]盛树力.老年性痴呆发病机理研究进展和药物治疗未来战略.中国医学科学院学报,2004,26：101-103.
[198]Sekhon LH, Spence I, Morgan MK, et al. Chronic cerebral hyooperfusion inhibits calcium-induced long-term potentiation in rats. Stroke,1997,28: 1043-1048.
[199]Mori K, Yoshioka M, Suda N, et al. An incomplete cerebral isehemia produced a delayed dysfunction in rat hippocampal system. Bnmt Res,1998,795:221-226.
[200]Hakim J. Reactive oxygen species and inflammation. C R Seances Soc Biol Fil, 1993,187:286-295. [Article in French]
[201]Esmann L, Idel C, Sarkar A, et al. Phagocytosis of apoptotic cells by neutrophil granulocytes:diminished proinflammatory neutrophil functions in the presence of apoptotic cells. J Immunol,2010,184:391-400.
[202]Sang N, Hou L, Yun Y, et al. SO2 inhalation induces protein oxidation, DNA-protein crosslinks and apoptosis in rat hippocampus. Ecotoxicol Environ Saf, 2009,72:79-84.
[203]Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 1976,72:248-254.
[204]姚泰.生理学.人民卫生出版社,2001.
[205]MohanKumar SM, Campbell A, Block M, et al. Particulate matter, oxidative stress and neurotoxicity. Neurotoxicology,2008,29:479-488.
[206]维基百科.http://zh.wikipedia.org/wiki/%E8%84%91
[207]Taylor RM. Reexamining the definition and criteria of death. Semin Neurol,1997, 17:265-270.
[208]de Burbure CY, Heilier JF, Neve J, et al. Lung permeability, antioxidant status, and NO2 inhalation:a selenium supplementation study in rats. J Toxicol Environ Health A,2007,70:284-294.
[209]Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol,2007,39: 44-84.
[210]Fetoui H, Makni M, Mouldi Garoui E, et al. Toxic effects of lambda-cyhalothrin, a synthetic pyrethroid pesticide, on the rat kidney:Involvement of oxidative stress and protective role of ascorbic acid. Exp Toxicol Pathol,2010,62: 593-599.
[211]Gabrashanska M, Teodorova SE, Petkova S, et al. Selenium supplementation at low doses contributes to the antioxidant status in Trichinella spiralis-infected rats. Parasitol Res,2010,106:561-570.
[212]Bazan NG. Synaptic lipid signaling:significance of polyunsaturated fatty acids and platelet-activating factor. Lipid Res,2003,44:2221-2233.
[213]Kougias P, Chai H, Lin PH, et al. Effects of adipocyte-derived cytokines on endothelial functions:implication of vascular disease. J Surg Res,2005,126: 121-129.
[214]Hengartner MO. The biochemistry of apoptosis. Nature,2000,407:770-776.
[215]Bouts YM, Wolthuis DF, Dirkx MF, et al. Apoptosis and NET formation in the pathogenesis of SLE. Autoimmunity,2012,45:597-601.
[216]Ouyang L, Shi Z, Zhao S, et al. Programmed cell death pathways in cancer:a review of apoptosis, autophagy and programmed necrosis. Cell Prolif,2012,45: 487-498.
[217]Huttemann M, Lee I, Grossman LI, et al. Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human* disease. Adv Exp Med Biol,2012,748: 237-264.
[218]Rosello A, Warnes G, Meier UC. Cell death pathways and autophagy in the central nervous system and its involvement in neurodegeneration, immunity and central nervous system infection:to die or not to die--that is the question. Clin Exp Immunol,2012,168:52-57.
[219]Hong LZ, Zhao XY, Zhang HL. P53-mediated neuronal cell death in ischemic brain injury. Neurosci Bull,2010,26:232-240.
[220]Yang XY, Liu QN, Zhang L, et al. Neuroprotective effect of dauricine after transient middle cerebral artery occlusion in rats:involvement of Bcl-2 family proteins. Am J Chin Med,2010,38:307-318.
[221]Bernstein C, Bernstein H, Payne CM, et al. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways:fail-safe protection against carcinogenesis. Mutat Res,2002,511:145-178.
[222]Andrieu-Abadie N, Gouaze V, Salvayre R, et al. Ceramide in apoptosis signaling: relationship with oxidative stress. Free Radic Biol Med,2001,31:717-728.
[223]Yun Y, Li H, Li G, et al. SO(2) inhalation modulates the expression of apoptosis-related genes in rat hippocampus via its derivatives in vivo. Inhal Toxicol,2010,22:919-929.
[224]Cai CF, Feng L, Wang L, et al. Tetrazolium violet induces apoptosis via caspases-8,-9 activation and Fas/FasL up-regulation in rat C6 glioma cells. Arch Pharm Res,2009,32:575-581.
[225]Reed JC. Regulation of apoptosis by Bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol,1995,7:541-546.
[226]Wu AG, Liu YG, et al. Prolonged expression of c-Fos and c-Jun in the cerebral cortex of rats after deltamethrin treatment. Mol Brain Res,2003,110:147-151.
[227]Shimokawa N, Miyazaki W, Iwasaki T, et al. Low dose hydroxylated PCB induces c-Jun expression in PC12 cells. Neurotoxicology,2006,27,176-183.
[228]Liu X, Liu W, Jin Y, et al. Effects of subchronic perfluorooctane sulfonate exposure of rats on calcium-dependent signaling molecules in the brain tissue. Arch Toxicol,2010,84:471-479.
[229]Estus S, Zaks W J, Freeman R S, et al. Altered gene expression in neurons during programmed cell death:identification of c-jun as necessary for neuronal apoptosis. J Cell Biol,1994,127:1717-1727.
[230]Ham J, Babij C, Whitfield J, et al. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron,1995,14:927-939.
[231]Bossy-Wetzel E, Bakiri L, et al. Induction of apoptosis by the transcription factor c-Jun. EMBO J,1997,16:1695-1709.
[232]Martinez-Murillo R, Fernandez AP, Serrano J, et al. The nitric oxide donor LA 419 decreases brain damage in a focal ischemia model. Neurosci Lett,2007,415: 149-153.
[233]Zhao D, Liu J, Wang W, et al. Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke,2008,39:1668-1674.
[234]George MG, Tong X, Kuklina EV, et al.. Trends in stroke hospitalizations and associated risk factors among children and young adults,1995-2008. Ann Neurol, 2011,70:713-721.
[235]Zea Longa E, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without cra-niectomy in rats. Stroke,1989,20:84-91.
[236]Garcia JH, Wagner S, Liu KF, et al. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke 1995,26(4):627-634; discussion 635.
[237]李志强.细辛醚对AD大鼠学习记忆的影响及血管保护机制研究.暨南大学博士论文,2010.
[238]Kowal P, Marcinkowska-Gapinska A. Hemorheological changes dependent on the time from the onset of ischemic stroke. J Neurol Sci,2007,258:132-136.
[239]Szapary L, Horvath B, Marton Z, et al. Hemorheological disturbances in patients with chronic cerebrovascular diseases. Clin Hemorheol Microcir,2004,31:1-9.
[240]Schwartz J. Air pollution and blood markers of cardiovascular risk. Environ Health Perspect,2001,109(Suppl 3):405-409.
[241]Sun Q, Wang A, Jin X, et al. Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. JAMA,2005, 294:3003-3010.
[242]Ionita CC, Xavier AR, Kirmani JF, et al. What proportion of stroke is not explained by classic risk factors? Prev Cardiol,2005,8:41-46.
[243]刘敬霞,李建生.线栓法制备大鼠局灶性脑缺血模型的进展及评价.中国比较医学杂志,2004,14：374-377.
[244]程发峰.精制清开灵注射液对脑缺血的治疗作用及对兴奋性毒性级联损伤的调控机制.北京中医药大学博士论文,2011.
[245]Sicard KM, Fisher M. Animal models of focal brain ischemia. Exp Transl Stroke Med,2009,1:7.
[246]Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta,2010,1802:80-91.
[247]Chen P, Shibata M, Zidovetzki R, et al. Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures. JNeuroimmunol,2001,116,62-73.
[248]Leung JWC, Chung SSM, Chung SK. Endothelial endothelin-1 over-expression using receptor tyrosine kinase tie-1 promoter leads to more severe vascular permeability and blood brain barrier breakdown after transient middle cerebral artery occlusion. Brain Res,2009,1266:121-129.
[249]Sang N, Yun Y, Li H, et al. SO2 inhalation contributes to the development and progression of ischemic stroke in the brain. Toxicol Sci,2010,114:226-236.
[250]胡泽平.替米沙坦对高血压和动脉粥样硬化血管内皮功能的影响及其机制.安徽医科大学博士论文,2011.
[251]Andresen J, Shafi NI, Bryan Jr RM. Endothelial influences on cerebrovascular tone. JAppl Physiol,2006,100:318-327.
[252]Markewitz BA, Michael JR, Kohan DE. Endothelin-1 inhibits the expression of inducible nitric oxide synthase. Am J Physiol,1997,272:L1078-L1083.
[253]Rodrigo J, Fernandez AP, Serrano J, et al. The role of free radicals in cerebral hypoxia and ischemia. Free Radical Biology & Medicine,2005,39:26-50.
[254]Luo CX, Zhu XJ, Zhou QG, et al. Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression. J Neurochem,2007,103:1872-1882.
[255]Armstead WM, Mirro R, Zuckerman SL, et al. Transforming growth factor-beta attenuates ischemia-induced alterations in cerebrovascular responses. Am J Physiol,1993,264:H381-385.
[256]Barone FC, Schmidt DB, Hillegass LM, et al. Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke,1992,23: 1337-1347.
[257]Pantoni L, Sarti C, Inzitari D. Cytokines and cell adhesion molecules in cerebral ischemia. Arterioscler Thromb Vasc Biol,1998,18:503-513.
[258]Yoshimoto T, Houkin K, Tada M, et al. Induction of cytokines, chemokines and adhesion molecule mRNA in a rat forebrain reperfusion model. Acta Neuropathol (Berl),1997,93:154-158.
[259]李琴,张红,郭云良.肌苷对脑缺血再灌注后COX-2表达的调节作用.中国老年杂志,2004,7：640-642.
[260]Knopman DS. Cerebrovascular disease and dementia. British Institute of Radiology,2007,80:S121-S127.
[261]National Stroke Association. http://www.stroke.org/site/PageServer?pagename=VADEM.
[262]Igoumenou A, Ebmeier KP. Diagnosing and managing vascular dementia. Practitioner,2012,256:13-6,2.
[263]World Health Organization. http://www.who.int/mediacentre/news/releases/2012/dementia_20120411/en/inde x.html,2012.
[264]Peters A, Sethares C, Luebke JI. Synapses are lost during aging in the primate prefrontal cortex. Neuroscience,2008,152:970-981.
[265]Barnes DE, Haight TJ, Mehta KM, et al. Secondhand smoke, vascular disease, and dementia incidence:findings from the cardiovascular health cognition study. Am JEpidemiol,2010,171:292-302.
[266]Costain WJ, Rasquinha I, Sandhu JK, et al. Cerebral ischemia causes dysregulation of synaptic adhesion in mouse synaptosomes. J Cereb Blood Flow Metab,2008,28:99-110.
[267]Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke,1995,26:2135-2144.
[268]Campos AC, Ferreira FR, da Silva WA Jr, et al. Predator threat stress promotes long lasting anxiety-like behaviors and modulates synaptophysin and CB1 receptors expression in brain areas associated with PTSD symptoms. Neurosci Lett,2013,533,34-38.
[269]Beique JC, Andrade R. PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J Physiol,2003,546,859-867.
[270]Di FM, Tozzi A, Costa C, et al. Plasticity and repair in the post-ischemic brain. Neuropharmacology,2008,55:353-362.
[271]Xu X, Ye L, Ruan Q. Environmental enrichment induces synaptic structural modification after transient focal cerebral ischemia in rats. Exp Biol Med (Maywood),2009,234:296-305.
[272]Kerchner GA, Nicoll RA. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci,2008,9:813-825.
[273]Lynch M. Long-term potentiation and memory. Physiol Rev,2004,84:87-136.
[274]Akaneya Y, Tsumoto T. Bidirectional trafficking of prostaglandin E2 receptors involved in long-term potentiation in visual cortex. J Neurosci,2006,26, 10209-10221.
[275]Serrano P, Yao Y, Sacktor T. Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation. J Neurosci,2005,25:1979-1984.
[276]Sweatt J. Toward a molecular explanation for long-term potentiation. Learn Mem, 1999,6:399-416.
[277]Alberini CM. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev,2009,89:121-145.
[278]Cristina MA. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev,2009,89:121-145.
[279]Lee HT, Chang YC, Wang LY, et al. cAMP response element-binding protein activation in ligation preconditioning in neonatal brain. Ann Nenrol,2004,56: 611-623.
[280]Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron,2002,35:605-623.
[281]Sawe N, Steinberg G, Zhao H. Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res,2008,86:1659-1669.
[282]Zhang M, Shan H, Gu Z, et al. Increased expression of calcium/calmodulin-dependent protein kinase type Ⅱ subunit delta after rat traumatic brain injury. JMol Neurosci,2012,46:631-643.
[283]Kim KH, Pessah IN. Perinatal exposure to environmental polychlorinated biphenyls sensitizes hippocampus to excitotoxicity ex vivo. Neurotoxicology, 2011,32:981-985.
[284]Meli E, Picca R, Attucci S, et al. Activation of mGlul but not mGlu5 metabotropic glutamate receptors contributes to postischemic neuronal injury in vitro and in vivo. Pharmacol Biochem Behav,2002,73:439-446.
[285]Edling Y, Ingelman-Sundberg M, Simi A. Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM. Glia,2007,55:328-340.
[286]Lee HK, Choi SS, Han EJ, et al. Role of nicotinic acetylcholine receptors in the regulation of kainic acid-induced hippocampal cell death in mice. Brain Res Bull, 2004,64:309-317.