摘要
第一部分稳态有效血药浓度下丙戊酸钠对惊厥持续状态大鼠空间学习记忆能力的影响
实验研究一维持丙戊酸钠及苯巴比妥稳态有效血药浓度给药方案的确立
目的:确立不同龄期不同性别的Wistar鼠维持丙戊酸钠(sodium valproate, VPA)、苯巴比妥(Phenobarbital, PB)稳态有效血药浓度的给药方案。
方法:选择生后15天(P15)、生后35天(P35)日龄Wistar鼠,分别以不同剂量、不同时间间隔经口灌胃给药。VPA给药后2天、PB给药后5天经尾静脉取血,以荧光偏振免疫分析方法检测血药浓度。
结果:(1)P15雄性大鼠维持VPA、PB稳态有效血药浓度的给药方案分别为每次75 mg/kg(12次/日)、每次10 mg/kg(2次/日),P35雄性大鼠维持VPA、PB稳态有效血药浓度的给药方案分别为每次350 mg/kg(6次/日)、每次35 mg/kg(2次/日);(2)P15、P35大鼠在每次200 mg/kg(6次/日)VPA给药方案下血药浓度分别为150.00±0.00μg/ml、34.83±8.47μg/ml,在每次30 mg/kg(2次/日)的PB给药方案下P15、P35大鼠血药浓度分别为42.15±6.34μg/ml、13.00±3.47μg/ml;(3)每次分别为200 mg/kg、300 mg/kg、400 mg/kg,6次/日的给药方案中VPA血药浓度在雄性大鼠显著高于雌性大鼠,每次45 mg/kg、60 mg/kg,2次/日PB给药方案中其血药浓度雄性大鼠血药浓度显著低于雌性大鼠;(4)维持VPA稳态有效血药浓度的用药剂量与其致死剂量接近,每日用量分别为2400 mg/kg、2700 mg/kg。
结论:(1)维持VPA稳态有效血药浓度的给药方案在P15、P35大鼠分别为每次75 mg/kg(12次/日)、每次350 mg/kg(6次/日),PB给药方案分别为每次10 mg/kg(2次/日)、每次35 mg/kg(2次/日);(2)VPA、PB代谢存在年龄依赖性,P35大鼠代谢速度高于P15大鼠;(3)VPA、PB代谢存在性别依赖性,VPA在雌性大鼠代谢快于雄性大鼠,PB在雄性大鼠代谢快于雌性大鼠,且雌性大鼠不适合于VPA稳态有效血药浓度条件下的实验。
?实验研究二稳态有效血药浓度VPA对CSE大鼠空间学习记忆知能力的影响
目的:以PB为对照,研究稳态有效血药浓度条件下VPA对惊厥性癫痫持续状态(convulsive status epilepticus, CSE)后Wistar鼠空间学习记忆能力的影响。
方法:制作氯化锂-匹罗卡品CSE模型,利用Morris水迷宫实验检测VPA对CSE后不同年龄Wistar鼠空间参考记忆(spatial reference memory, SRM)与空间工作记忆(spatial working memory, SWM)的影响。
结果:(1)P35大鼠CSE后学习记忆能力损伤损伤严重,而在P15大鼠损伤不明显,VPA可改善P35大鼠CSE后空间学习记忆能力,且对SRM与SWM的作用具有一致性;(2)VPA对P15、P35正常大鼠空间学习记忆能力均具有损伤作用,且对SRM与SWM的作用具有一致性;(3)稳态有效血药浓度条件下,服药期间VPA、PB对不同龄期CSE大鼠及正常大鼠的空间学习记忆能力的影响程度类似。
结论: VPA可显著改善P35大鼠CSE后空间认知功能障碍,但VPA对正常P15、P35大鼠空间记忆力造成明显损伤。稳态有效血药浓度条件下,VPA与PB对正常及模型动物空间认知功能的影响作用一致。
第二部分有效治疗浓度VPA对CSE模型大鼠海马脑区长时程增强的影响
实验研究一丙戊酸钠在体干预对海马脑区LTP的影响
目的:探索在体维持稳态有效浓度条件下VPA对CSE后海马脑区长时程增强(long-term potentiation, LTP)现象的影响,并针对LTP形成机制中的关键分子研究VPA影响LTP变化的内在可能机制。
方法:制作CSE模型并给予VPA干预,制备急性海马脑片,利用膜片钳平台观察高频电刺激(high frequency stimulation, HFS)后VPA干预对兴奋性突触后场电位(field excitatory postsynaptic potential, fEPSP)的影响,利用Western blot检测钙/钙调蛋白依赖性蛋白激酶Ⅱ(calcium/calmodulin dependent protein kinase-Ⅱ,CaMKⅡ)与磷酸化CaMKⅡ(P-CaMKⅡ)表达的影响。
结果:(1)P35大鼠CSE后LTP诱导成功率与维持时间明显低于对照组,VPA在体干预可提高P35大鼠CSE后LTP诱导成功率及维持时间;而CSE对P15大鼠海马脑片LTP诱导成功率与维持时间的影响未出现统计学差异,仅fEPSPS幅度存在增大趋势。VPA在体干预对正常P15、P35大鼠LTP的诱导与维持则无明显影响;(2)CSE对P15大鼠CaMKⅡ及p-CaMKⅡ的表达均无明显影响,而VPA在体干预可抑制CaMKⅡ及p-CaMKⅡ的表达; CSE对P35大鼠CaMKⅡ及p-CaMKⅡ表达的影响均未出现统计学差异,仅p-CaMKⅡ的表达出现增高趋势,VPA干预可抑制p-CaMKⅡ的表达,但对CaMKⅡ的表达未体现抑制作用。
结论:(1)CSE对LTP诱导成功率与维持时间的影响存在年龄依赖性,幼年鼠轻于青春期大鼠,其损伤机制与CaMKⅡ的表达与磷酸化无因果联系;(2)VPA改善CSE后大鼠空间认知功能与提高LTP诱导成功率及延长LTP维持时间密切相关;(3)VPA抑制CaMKⅡ的表达与磷酸化而对LTP未表现明显抑制作用的矛盾可能与VPA的洗脱作用有关。
实验研究二丙戊酸钠离体干预对海马脑区LTP的影响
目的:排除VPA洗脱作用,探索VPA离体干预对海马脑区LTP现象的影响,并针对LTP形成机制中的关键分子研究VPA影响LTP变化的内在可能机制。
方法:制备急性海马脑片,利用膜片钳平台观察VPA对双脉冲易化(paired-pulse facilitation, PPF)的影响,并观察HFS前后VPA干预对fEPSP的影响,利用Western blot检测CaMKⅡ及P-CaMKⅡ在LTP诱导成功脑片中的表达情况。
结果:(1)有效药物浓度条件下VPA抑制基础刺激下fEPSP幅度,但对PPF无明显抑制作用;(2)VPA体外干预可抑制LTP现象的诱导,但对已诱导成功LTP的维持阶段无明显抑制作用;(3)VPA预干预可降低p-CaMKⅡ的表达,LTP诱导成功后VPA对p-CaMKⅡ的表达无明显抑制作用;而CaMKⅡ表达无论在LTP诱导或维持阶段给予VPA均无明显变化。
结论:有效药物浓度VPA预干预可能仅通过突触后机制影响神经元内CaMKⅡ的磷酸化进而抑制LTP的诱导与维持,对已经诱导成功的LTP现象无抑制作用。
实验研究三VPA对神经元胞内Ca2+浓度的影响
目的:探索NMDA作用下VPA对海马神经元内Ca2+浓度的影响
方法:培养7天的海马神经元进行神经元鉴定及活性检测,然后分为3组,即对照组、VPA组、阴性对照组,三组均给予0.1 mM NMDA进行刺激,利用钙离子测定仪观察神经元内Ca2+浓度的变化。VPA组在给予NMDA刺激前10 min给予70μg/ml VPA进行预处理。
结果:VPA可显著降低NMDA刺激后340nm、380nm两荧光比值,神经元胞体呈现明亮的红色或橙红色变暗。?
结论:VPA可显著降低由NMDA刺激引起的神经元内Ca2+浓度的提高。
第三部分丙戊酸钠对癫痫发作后干细胞增殖与新生神经元迁移的影响
目的:研究稳态有效血药浓度条件下,VPA对CSE后海马脑区神经干细胞(neural stem/progenitor cells, NSCs/NPCs )增殖、迁移及新生神经元迁移的影响。
方法:制作CSE模型,在体5-溴2-脱氧尿嘧啶核苷(5-bromo 2-deoxyuridine, BrdU)标记新生细胞。采用免疫组化方法分别检测BrdU阳性细胞与Doublecortin(DCX)阳性神经元在VPA干预后在海马齿状回、CA1区的表达变化。
结果: P15与P15大鼠CSE后海马颗粒细胞层较对照组分散,齿状回颗粒细胞下层(subgranular zone, SGZ)区BrdU阳性细胞与DCX阳性神经元明显增多,部分出现于齿状回门区,且有向CA1区迁移的趋势。VPA干预显著降低了SGZ区内BrdU阳性细胞与DCX阳性神经元数量,并可抑制其向CA1区的迁移趋势。CSE后除新生神经元出数量增加外,新生神经元的轴突也较对照组明显增多且增长,VPA干预可显著减轻上述改变。
结论:VPA可抑制CSE后新增殖细胞及新生神经元的异常增生与分化。
PART ONE THE EFFECTS OF SODIUM VALPROATE ON SPATIAL LEARNING AND MEMORY OF RATS WITH CONVULSIVE STATUS EPILEPTICUS AT EFFECTIVE STEADY STATE PLASMA CONCENTRATION
STUDY ONE ESTABLISHMENT OF DOSAGE REGIMEN TO MAINTAIN SODIUM VALPROATE AND PHENOBARBITAL TO BE AT EFFECTIVE STEADY STATE PLASMA CONCENTRATION
Objective: To establish the dosage regimen to maintain sodium valproate (VPA) and phenobarbital (PB) to be at effective steady state plasma concentration in Wistar rats of different ages in different gender.
Method: The subjects selected for this study were postnatal 15days age (P15) and postage 35days age (P35) Wistar rats. All rats were divided into many groups with differrent dosage regimen and VPA and PB drugs level in plasma were determined by fluorescence polarization immunoassay after 2days and 5days therapeutic period.
Results: (1) The dosage regimen to maintain VPA and PB to be at effective steady state plasma concentration in P15 male rats were 75 mg/kg (12/day), 10 mg/kg (2/day) and the dosage regimen in P35 male rats were 350 mg/kg (6/day)、35 mg/kg (2/day); (2) With 200 mg/kg (6/day) dosage regimen, the VPA plasma concentration in P15 and P35 male rats were 150.00±0.00μg/ml,34.83±8.47μg/ml, however with 30 mg/kg (2/day) dosage regimen, the PB plasma concentration in P15 and P35 male rats were 42.15±6.34μg/ml, 13.00±3.47μg/ml; (3) With dosage regimen of 200 mg/kg, 300 mg/kg and 400 mg/kg (6/day), the VPA plasma concentration were higher in male rats than in female rats, but with dosage regimen of 45 mg/kg, 60 mg/kg (2/day) the PB plasma concentration were higher in female rats than in male rats; (4) The effective dose and lethal dose of VPA were closely 2400 mg/kg/day, 2700 mg/kg/day.
Conclusions: (1) The dosage regimen to maintain VPA to be at effective steady state plasma concentration in P15 and P35 male rats were75 mg/kg (12/day), 350 mg/kg (6/day), and the dosage regimen of PB were 10 mg/kg (2/day), 35 mg/kg (2/day); (2) The rate of VPA and PB metabolism were age-dependent, which were faster in P35 rats than P15 rats; (3) The rate of VPA and PB metabolism were gender-dependent. The rate of VPA metabolism were faster in female rats than male rats while the rate of PB metabolism were faster in male rats than female rats and female rats were not suitable for studies wich require VPA plasma concentration to be at effective steady state.
STUDY TWO THE EFFECTS OF VPA ON SPATIAL LEARNING AND MEMORY OF RATS WITH CONVULSIVE STATUS EPILEPTICUS AT EFFECTIVE STEADY STATE PLASMA CONCENTRATION
Objective: To study the effects of sodium valproate on spatial learning and memory of rats with convulsive status epilepticus (CSE) at effective steady state plasma concentration compared with PB treatment.
Method: CSE was induced in P15 andP35 Wistar rats injected with lithium and pilocarpine intraperitoneally and controlled 60 minutes later. The effects of VPA and PB on spatial reference memory(SRM) and spatial working memory(SWM) were assessed by Morris water maze.
Results: (1) The spatial cognition after CSE in P35 rats was more serious than in P15 rats, and with VPA treatment SRM and SWM impairment could be eased; (2) The VPA treatment could induce SRM and SWM impairment in P15 and P35 rats; (3) Within effective steady state plasma concentration the spatial cognition impairment in VPA-treated P15 and P35 rats were similar with PB-treated rats.
Conclusions: VPA treatment could improve the spatial cognition after CSE in P35 rats, but with normal rats VPA treatment could induce the spatial cognition impairment in P15 and P35 rats. Within effective steady state plasma concentration there were no differences in spatial cognition impairment in CSE and non-CSE rats compared with PB-treated rats.
PART TWO THE EFFECTS OF VPA ON LONG-TERM POTENTIATION IN CA1 AREA OF HIPPOCAMPAL SLICES PREPARED FROM RATS WITH CSE WITH EFFECTIVE CONCENTRATION
STUDY ONE THE EFFECTS OF VPA ON LONG-TERM POTENTIATION IN CA1 AREA OF HIPPOCAMPAL SLICES WITH INTERVENTION IN THE BODY.
Objective: To explore the effects of VPA on long-term potentiation (LTP) in CA1 area of hippocampal slices prepared from rats with CSE at effective steady state concentration and to study the possible underline mechanisms.
Method: Hippocampal slices were prepared from male Wistar rats on postnatal 35 days. The effects of VPA on field excitatory postsynaptic potentials (fEPSPs) after high-frequency stimulation (HFS) were examined with patch clamp technique. The expression of calmodulin-dependent protein kinaseⅡ(CaMKⅡ) and phosphorylated CaMKⅡ(p-CaMKⅡ) were examined by Western Blot analysis.
Results: (1) CSE in P35 rats significantly reduced the successful induction rate and maintenance but no influence in P15 rats, and VPA treatment could improve the successful induction rate and maintenance in P35 rats; (2) The expression of p-CaMKⅡand CaMKⅡhad no changes in P15 and P35 rats after CSE and VPA teatment could reduce p-CaMKⅡand CaMKⅡexpression in P15 rats. However in P35 rats VPA teatment only reduced p-CaMKⅡexpression but CaMKⅡexpression.
Conclusions: (1) The influence of CSE on LTP was age-dependent which was gental in P15 rats than in P35 rats, and there were no relationship between the negative influence and p-CaMKⅡand CaMKⅡexpression; (2) The spatial cognition improvement of CSE rats after VPA treatment maybe due to the change of LTP induction and maintenance; (3) The contradiction between inhibition of p-CaMKⅡand CaMKⅡexpression and no-changes in LTP maybe due to the washing-out effect.
STUDY TWO THE EFFECTS OF VPA ON LONG-TERM POTENTIATION IN CA1 AREA OF HIPPOCAMPAL SLICES WITH ISOLATED INTERVENTION
Objective: To explore the effects of VPA on LTP in CA1 area of hippocampal slices and the possible underline mechanisms.
Method: Hippocampal slices were prepared from male Wistar rats on postnatal 35 days. The effects of VPA on field excitatory postsynaptic potentials (fEPSPs) after high-frequency stimulation (HFS) or double-pulse stimulation were examined with patch clamp technique. The expression of calmodulin-dependent protein kinaseⅡ(CaMKⅡ) and phosphorylated CaMKⅡ(p-CaMKⅡ) were examined by Western Blot analysis.
Results: (1) VPA inhibited fEPSPs without modifying paired-pulse facilitation (PPF) which solely occured presynaptically as a simple form of synaptic plasticity; (2) pretreatment with VPA before HFS decreased the fEPSPs slope; (3) no significant effects of VPA on fEPSPs slope were found in two maintenance phase of LTP; (4) expression of p-CaMKⅡbut CaMKⅡdecreased in VPA pre-treatment group, and however no differences were detected of p-CaMKⅡand CaMKⅡexpression in VPA early-treatment group and VPA late- treatment group.
Conclusions: VPA inhibited the induction of LTP postsynaptically through inhibiting the expression of p-CaMKⅡwithout modifying presynaptic neurotransmitter release and VPA had no significant influence on the two maintenance phase of LTP with no effects on the expression of CaMKⅡand p-CaMKⅡ.
STUDY THREE THE EFFECTS OF VPA ON CA2+ CONCENTRATION IN HIPPOCAMPAL NEURONS WITH NMDA APPLICATION
Objective: To explore the effects of VPA on Ca2+ concentration in hippocampal neurons with NMDA application.
Method: Neonatal rat hippocampal neurons were isolated and cultured in the serum-free B27 supplemented culture media. Primary hippocampal neurons cultured for 7 days were randomly divided into 3 groups: control group, VPA-treated group and negetive control group. All groups were interrupted with NMDA and the Ca2+ concentration in cultured hippocampal neurons were detected with furo-2.
Results: VPA at effective concentration signicantly reduced ratio of fluorescence at 340nm, 380nm.
Conclusions: VPA could reduce Ca2+ concentration in hippocampal neurons after NMDA application.
PART THREE THE INFLUENCE OF VPA ON NEUROGENESIS AND MIGRATION OF NEWBORN NEURONS AFTER CSE
Objective: To explore the influence of VPA at effective steady state plasma concentration on neurogenesis and migration of newborn neurons after CSE.
Method: Rats were induced by chemoconvulsants lithium-pilocarpine and all rats received injections of bromodeoxyuridine (BrdU). Animals were perfused and brains were processed for immunocytochemistry antibodies against BrdU and Doublecortin (DCX).
Results: The amount of BrdU positive cells and DCX positive neurons increased in dentate gyrus granule cell layer after CSE and some appeared in hilus of dentate gyrus. There were BrdU positive cells and DCX positive neurons in CA1 area. VPA treatment could decrease the amount of BrdU positive cells and DCX positive neurons in dentate gyrus and CA1 area. Inadition there were more and longer axons in the DCX positive neurons and VPA treatment could inhibit the abnormal phenomenon.
Conclusions: VPA treatment could inhibit the neurogenesis and abnormal migration of newborn neurons.
引文
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