纳米氧化锌对海马神经元电生理特性的影响及对PC12细胞生物学效应的机制研究
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摘要
纳米材料是指至少在一维空间上粒径≤100nm的材料,由于其尺寸很小,结构特殊,因此具有许多新的物理化学特性,如小尺寸效应、大的比表面、极高的反应活性、量子效应等。随着纳米技术的产业化,各种纳米材料因其优良特性及新奇功能而具有广泛的应用前景,遍及工业、农业、制造业、军事、医疗等诸多领域。而日常的生活用品,如化妆品、食品、织物、涂料、抗菌材料等,也含有纳米材料,人们接触纳米材料的机会日益增多。由此,纳米材料的生物效应和安全性问题也凸显出来,尤其是纳米颗粒对人体健康、生存环境和社会安全等方面是否存在潜在的负面影响。毒理学研究结果表明纳米颗粒可以各种途径进入人体或生物体,包括吸入、摄食吸收、皮肤渗透等,随后在生物体的不同水平产生毒理学效应。最近的研究显示中枢神经系统亦是纳米颗粒作用的重要靶器官。因此纳米颗粒对中枢神经系统的影响也得到更多的关注,纳米颗粒可以通过最强的生物屏障,如血脑屏障。可以通过嗅神经途径进入中枢神经系统,并转至不同脑区沉积。且脑区中的海马亦是纳米颗粒作用主要的靶点。
纳米ZnO因其独特的光、电、磁学等性能的重要应用而取得突破性的成就,并倍受瞩目。同时,在化妆品、纺织、涂料、陶瓷、催化、抗菌、医疗诊断等方面都有很好的应用。目前体内外的实验证实纳米ZnO可在不同程度上对细菌、水生生态动物、哺乳动物细胞及哺乳动物产生毒性作用,然而纳米ZnO对神经系统的影响鲜有报道。本文采用神经生长因子(NGF)诱导分化的PC12细胞,利用四甲基偶氮唑盐法(MTT)检测细胞存活率、荧光标记法测定ROS含量、流式细胞仪分析凋亡细胞比例等方法,探索纳米ZnO对PC12细胞的神经毒性影响。
由于中枢神经系统神经细胞膜表达多种类型的离子通道,细胞膜上离子通道开放引起的电活动是一切细胞生理功能活动的基础。离子通道参与递质释放、激素分泌、信号转导、代谢调控及细胞生长乃至学习和记忆等重要生理过程的调控。而离子通道又是许多药物和毒物作用的靶点,因此,实验进一步采用全细胞膜片钳技术,研究记录了纳米ZnO对海马锥体神经元离子通道的影响,包括对电压门控钠通道、钾通道、钙通道及其神经元兴奋性活动的影响,以分析纳米ZnO对神经系统作用的潜在机制。
主要实验结果如下：
1.MTT法检测细胞存活率：不同浓度的纳米ZnO(10-6g/ml,10-5g/ml,10-4 g/ml)与神经生长因子(NGF)诱导分化的PC12细胞共孵育6、12、24h后,细胞存活率随着浓度和时间增大而下降,表现为时间依赖性和浓度依赖性。而10-4g/ml的纳米ZnO可明显降低PC12细胞的存活率(P<0.05)。
2.细胞内ROS含量的变化：不同浓度的纳米ZnO(10-6g/m1,10-5g/ml,10-4 g/ml)与PC12细胞共孵育6h后,经GENMED工作液和GENMED保存液处理。使用倒置荧光显微镜观察,设定激发光波长为490nm,散发波长530nm。与对照组的荧光强度相比,ZnO处理组的荧光强度随浓度增加而逐渐增强,说明细胞内ROS含量增高。
3.流式细胞仪分析凋亡细胞比例：不同浓度的纳米ZnO(10-6g/ml,10-5g/ml, 10-4g/ml)与PC12细胞共孵育24h后,与正常细胞凋亡率(8.75%)相比,10-4g/ml的纳米ZnO促进PC12细胞的凋亡(34.24%,P<0.05)；而预先给培养的PC12细胞加入ROS清除剂MPG(3 mM),再用10-4g/ml的纳米ZnO处理PC12细胞24h,凋亡比例降至15.78%(P<0.05)。提示ROS清除剂可抑制纳米ZnO诱导PC12细胞凋亡
4.ROS清除剂的保护作用：培养的PC12细胞用3 mM的ROS清除剂MPG预处理30min后,加入10-4g/ml的纳米ZnO孵育24h,PC12细胞的存活率增大,与10-4g/ml的纳米ZnO组相比,差异显著(P<0.05)。
5.纳米ZnO对海马锥体神经元电压门控钠通道的影响：10-4g/ml的纳米ZnO在阶跃电位-50mV～+20mV显著提高了海马神经元电压门控钠电流(INa)的电流幅度(P<0.05),I-V曲线下移；药物作用前后激活曲线无明显改变；稳态失活曲线左移且Vh变化明显,分别为-52.54±0.43 mV和-54.67±0.39mV(P<0.01),k值没有明显变化；失活后恢复曲线左移,药物作用前后时间常数(τ)分别为5.40±0.19 ms和3.95±0.15 ms(P<0.01)
6.纳米ZnO对海马锥体神经元电压门控钾通道的影响：10-4g/ml的纳米ZnO提高了海马神经元瞬时外向钾电流(IA)和延迟整流钾电流(IK)的电流幅度,其中在阶跃电位+20mV～+90mV更为显著地提高了IK的电流幅度(P<0.05)；而药物作用前后IA和IK的激活曲线变化不明显；并且,药物作用前后IA的稳态失活曲线及失活后恢复曲线也未有显著改变。
7.纳米ZnO对海马锥体神经元高电压激活的钙通道的影响：在实验组和对照组,海马锥体神经元高电压激活的钙电流表现为run up和随后的run down现象。而10-4 g/ml的纳米ZnO对海马神经元高电压激活的钙电流有上调作用,从最初作用的10分钟开始,到记录结束的30分钟纳米ZnO在阶跃电位-15 mV～+15 mV显著地提高了高电压激活的钙电流幅度(P<0.05)；与对照组相比,激活曲线及稳态失活曲线没有显著改变。
8.纳米ZnO对海马锥体神经元兴奋性活动的影响：电流钳结果显示,10-4 g/ml的纳米ZnO提高了单个动作电位的幅值及超射(P<0.01),缩短了动作电位的半宽时程(P<0.05)；提高了连续动作电位的频率(P<0.05)；提高了自发放电的频率(P<0.05)。
主要实验结论如下：
1.纳米ZnO可降低PC12细胞的存活率,表现为时间依赖性和浓度依赖性；并促进细胞凋亡；细胞内ROS的增加是纳米ZnO诱导PC12细胞凋亡的机制之一。
2.纳米ZnO通过延迟整流钾通道增加K+外流使细胞质中K+减少而诱导细胞凋亡
3.纳米ZnO上调HVA Ca2+通道,引起细胞内Ca2+浓度升高,将导致ROS产生,并由此促进细胞凋亡。
4.纳米ZnO通过增加钠通道的电流幅度,并使钠通道快速失活,及失活后快速恢复而提高神经元的兴奋性,进而可能对神经元产生去极化诱导的损伤；纳米ZnO通过上调HVA Ca2+通道将改变细胞内钙稳态,将由此增强神经退行性过程。
5.纳米ZnO通过增大INa、IK及HVA Ca2+电流的电流幅度而导致神经元兴奋性增加,并使单个动作电位的幅值及超射增加,动作电位的半宽时程缩短；提高了连续动作电位和自发放电的频率。后续重复放电的跨膜电位幅度和超射值的减小与纳米ZnO造成的Na+-K+-ATP酶的功能不足有关。
Nanomaterials have been defined as material with one dimension of less than 100 nm. Due to their small size and the special structure, they have many new physical and chemical properties, such as small size effect, the large specific surface, high reactivity, quantum size effects. With the industrialization of nanotechnology, a variety of nanomaterials have a broad range of applications across industry, agriculture, manufacturing, military, medical and many other fields because of their excellent properties and novel functions. Nanomaterials are also widely used in daily life products, such as cosmetics, food, fabrics, coatings, antibacterial materials, etc., and public exposure to nanoparticles are increasing daily. Therefore, the biological effects and safety issues of nanomaterials have also been raised, especially the potential negative impacts of nanoparticles on human health, living environment and social security. Toxicological studies have shown that nanoparticles could enter into the human body through several distinct routes including inhalation, ingestion, and dermal penetration. Subsequently they could elicit toxicological effects at different levels of biological systems. Recent studies have shown that the central nervous system (CNS) is an important target organ for nanoparticles. Therefore, the effects of nanoparticles on the CNS have also gained more attention. Nanoparticles can cross most strong biological barriers such as blood-brain barrier and via the olfactory neuronal pathway enter into the CNS and accumulate in different brain regions. So the hippocampus is also the main target for nanoparticles.
Breaking achievements and great attention have been gained in the important applications of Nano-ZnO because of its unique optical, electrical and magnetic properties. Meanwhile, Nano-ZnO have excellent applications in cosmetics, textiles, paints, ceramics, catalysis, antibacterial, medical diagnostics. Some researchers have demonstrated that nanostructures of ZnO were toxic to the bacteria, the aquatic biota or eco-relevant species, the mammalian cells and mammals. However, little is known about the possible impacts of manufactured nano-ZnO on the CNS. In the present study, differentiated PC12 cells induced by nerve growth factor (NGF) were used to investigate the cytotoxicity of the nano-ZnO. The viability of the cells was observed by a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the generation of ROS for the cells was evaluated by a fluorometry assay. The apoptosis of cells were detected and analyzed by flow cytometry.
The neurons in the CNS express various types of ion channels, and the cell electrical activity caused by the opening of ion channels are the basis of physiological function. Ion channels involved in transmitter release, hormone secretion, signal transduction, metabolic regulation and cell growth as well as learning and memory and other important physiological processes, and they are also targets for many toxins and drugs. Therefore, whole-cell patch clamp technique was used to study the effects of nano-ZnO on ion channels of hippocampal pyramidal neurons, including voltage-gated sodium channels, potassium channels, calcium channels and neuronal excitability, and investigate the potential mechanism of nano-ZnO on the CNS. The main results are as follows:
1. MTT cell viability assay:Nerve growth factor (NGF) induced differentiation of PC12 cells were incubated with different concentrations of the nano-ZnO (10-6 g/ml,10-5 g/ml,10-4 g/ml) for the periods 6,12,24 hours, and cell viability was decreased in a dose-dependent and time-dependent manner. Nano-ZnO (10-4 g/ml) caused a significant decrease in cell viability (P<0.05).
2. Changes in intracellular ROS levels:PC12 cells were incubated with different concentrations of the nano-ZnO (10-6 g/ml,10-5 g/ml,10-4 g/ml) for 6h, and then treated by GENMED working solution and GENMED preserving fluid. Using the inverted fluorescence microscope, setting the excitation wavelength at 490nm and 530nm, the fluorescence intensity of nano-ZnO treatment group gradually increased with the increasing concentration of nano-ZnO compared to that of the control group. The result indicated that intracellular ROS levels were increased.
3. The proportion of apoptotic cells by flow cytometry analysis:PC12 cells were incubated with different concentrations of the nano-ZnO (10-6 g/ml,10-5 g/ml,10-4 g/ml) for 24 hours, and the apoptosis rate of PC12 cells was increased from 8.75% in control group to 34.24% (P<0.05) after the cell exposure to the nano-ZnO (10-4 g/ml) for 24h, However, a pre-treatment to the cells using MPG (3 mM) and then treatment to PC12 cells 24h with nano-ZnO (10-4 g/ml) reduced the cellular apoptosis to 15.78% (P<0.05). The result indicated that pre-treated the ROS scavenger can inhibit the nano-ZnO induced apoptosis in PC 12 cells.
4. Protective effects of ROS scavengers:PC12 cells were pre-treated with MPG (3 mM) for 30 min and then were incubated with nano-ZnO (10-4 g/ml) for 24h.The viability of PC 12 cells was significantly increased compared to that of the nano-ZnO treatment group (P<0.05).
5. Effects of nano-ZnO on voltage-gated sodium channels in hippocampal pyramidal neurons:In the present of final concentration of 10-4g/ml nano-ZnO, the peak amplitudes of INa were increased considerably from-50 mV to+20 mV(P<0.05), and the current-voltage curve of sodium current (INa) was decreased. Meanwhile, the values of Vh for inactivation of Ina before and after addition of nanoparticle ZnO are-52.54±0.43 mV and-54.67±0.39mV (P<0.01); The time constants (r) before and after addition of nano-ZnO were 5.40±0.19 ms and 3.95±0.15 ms (P<0.01), respectively. However, the steady-state activation curve of INa was not shifted by the nano-ZnO.
6. Effects of nano-ZnO on voltage-gated potassium channels in hippocampal pyramidal neurons:The amplitudes of transient outward potassium current (IA) were increased by the nano-ZnO solution (10-4g/ml), while the current-voltage curve of delayed rectifier potassium current (Ik) was significantly increased from+20 mV to +90 mV (P<0.05). However, it is apparent that the nano-ZnO solution didn't shift the steady-state activation curve of IA and IK, and neither had significant effects on the inactivation and the recovery from inactivation of IA.
7. Effects of nano-ZnO on high-voltage activated (HVA) calcium currents in hippocampal pyramidal neurons:HVA calcium currents had a tendency of enhancement (run up) in the first 5 minutes of the recording in both the experimental and control groups, and were followed by a decline (run down) with time. At 10 minutes of the recording,10-4g/ml nano-ZnO first altered the current-voltage curve and the peak amplitudes of HVA calcium currents (P<0.05), and at the end of 30 minutes the peak current amplitudes were increased significantly from-15 mV to+15 mV(P<0.05) compared to that of the control group. But there were no statistically significance the steady-state activation curve and the steady-state inactivation curve of HVA calcium currents compared with that of the control group.
8. Effects of nano-ZnO on excitable activity in hippocampal pyramidal neurons excitability:the results of current clamp showed that peak amplitude and overshoot of the evoked single action potential were increased in the presence of the 10"4g/ml nano-ZnO solution (P<0.05) and half-width was diminished (P<0.05). Simultaneously, a prolonged depolarizing current injection enhanced repetitive firing evoked firing rate(P<0.05) and firing rate of spontaneous firing was also increased (P<0.05).
The main conclusions are as follows:
1. Nano-ZnO can cause a significant decrease in cell viability in a dose-dependent and time-dependent manner and promote apoptosis in PC 12 cells; while the increase of intracellular ROS are one of potential mechanisms of cellular apoptosis induced by nano-ZnO.
2. Nano-ZnO could involve in the neuronal apoptosis caused by the loss of cytoplasmic K+ due to increased K+ efflux through delayed rectifier potassium channels.
3. Nano-ZnO could cause the elevation of cytosolic calcium levels by up-regulation HVA calcium channels, which would increase the generation of intracellular ROS, and consequently, promote neuronal apoptosis.
4. Nano-ZnO could enhance the neuronal excitability by increasing the peak amplitudes of INa and promoting the inactivation and the recovery from inactivation of INa, which may involve in depolarization-induced neuronal injury by activation of voltage-gated Na+ channels. Meanwhile, nano-ZnO would potentially perturb cellular calcium homeostasis by up-regulation HVA calcium channels, and contribute to the neurodegenerative process.
5. Nano-ZnO could enhance the neuronal excitability by increasing the peak amplitudes of INa, IK and HVA calcium currents, and therefore increase the peak amplitude and overshoot of the evoked single action potential and diminish half-width. Simultaneously, firing rate of repetitive firing and spontaneous firing were aslso increased. The decrease of peak amplitude and overshoot of the subsequent action potentials of repetitive firing may due to the dysfunction or deficiency of Na+-K+-ATPase.
纳米ZnO因其独特的光、电、磁学等性能的重要应用而取得突破性的成就,并倍受瞩目。同时,在化妆品、纺织、涂料、陶瓷、催化、抗菌、医疗诊断等方面都有很好的应用。目前体内外的实验证实纳米ZnO可在不同程度上对细菌、水生生态动物、哺乳动物细胞及哺乳动物产生毒性作用,然而纳米ZnO对神经系统的影响鲜有报道。本文采用神经生长因子(NGF)诱导分化的PC12细胞,利用四甲基偶氮唑盐法(MTT)检测细胞存活率、荧光标记法测定ROS含量、流式细胞仪分析凋亡细胞比例等方法,探索纳米ZnO对PC12细胞的神经毒性影响。
由于中枢神经系统神经细胞膜表达多种类型的离子通道,细胞膜上离子通道开放引起的电活动是一切细胞生理功能活动的基础。离子通道参与递质释放、激素分泌、信号转导、代谢调控及细胞生长乃至学习和记忆等重要生理过程的调控。而离子通道又是许多药物和毒物作用的靶点,因此,实验进一步采用全细胞膜片钳技术,研究记录了纳米ZnO对海马锥体神经元离子通道的影响,包括对电压门控钠通道、钾通道、钙通道及其神经元兴奋性活动的影响,以分析纳米ZnO对神经系统作用的潜在机制。
主要实验结果如下：
1.MTT法检测细胞存活率：不同浓度的纳米ZnO(10-6g/ml,10-5g/ml,10-4 g/ml)与神经生长因子(NGF)诱导分化的PC12细胞共孵育6、12、24h后,细胞存活率随着浓度和时间增大而下降,表现为时间依赖性和浓度依赖性。而10-4g/ml的纳米ZnO可明显降低PC12细胞的存活率(P<0.05)。
2.细胞内ROS含量的变化：不同浓度的纳米ZnO(10-6g/m1,10-5g/ml,10-4 g/ml)与PC12细胞共孵育6h后,经GENMED工作液和GENMED保存液处理。使用倒置荧光显微镜观察,设定激发光波长为490nm,散发波长530nm。与对照组的荧光强度相比,ZnO处理组的荧光强度随浓度增加而逐渐增强,说明细胞内ROS含量增高。
3.流式细胞仪分析凋亡细胞比例：不同浓度的纳米ZnO(10-6g/ml,10-5g/ml, 10-4g/ml)与PC12细胞共孵育24h后,与正常细胞凋亡率(8.75%)相比,10-4g/ml的纳米ZnO促进PC12细胞的凋亡(34.24%,P<0.05)；而预先给培养的PC12细胞加入ROS清除剂MPG(3 mM),再用10-4g/ml的纳米ZnO处理PC12细胞24h,凋亡比例降至15.78%(P<0.05)。提示ROS清除剂可抑制纳米ZnO诱导PC12细胞凋亡
4.ROS清除剂的保护作用：培养的PC12细胞用3 mM的ROS清除剂MPG预处理30min后,加入10-4g/ml的纳米ZnO孵育24h,PC12细胞的存活率增大,与10-4g/ml的纳米ZnO组相比,差异显著(P<0.05)。
5.纳米ZnO对海马锥体神经元电压门控钠通道的影响：10-4g/ml的纳米ZnO在阶跃电位-50mV～+20mV显著提高了海马神经元电压门控钠电流(INa)的电流幅度(P<0.05),I-V曲线下移；药物作用前后激活曲线无明显改变；稳态失活曲线左移且Vh变化明显,分别为-52.54±0.43 mV和-54.67±0.39mV(P<0.01),k值没有明显变化；失活后恢复曲线左移,药物作用前后时间常数(τ)分别为5.40±0.19 ms和3.95±0.15 ms(P<0.01)
6.纳米ZnO对海马锥体神经元电压门控钾通道的影响：10-4g/ml的纳米ZnO提高了海马神经元瞬时外向钾电流(IA)和延迟整流钾电流(IK)的电流幅度,其中在阶跃电位+20mV～+90mV更为显著地提高了IK的电流幅度(P<0.05)；而药物作用前后IA和IK的激活曲线变化不明显；并且,药物作用前后IA的稳态失活曲线及失活后恢复曲线也未有显著改变。
7.纳米ZnO对海马锥体神经元高电压激活的钙通道的影响：在实验组和对照组,海马锥体神经元高电压激活的钙电流表现为run up和随后的run down现象。而10-4 g/ml的纳米ZnO对海马神经元高电压激活的钙电流有上调作用,从最初作用的10分钟开始,到记录结束的30分钟纳米ZnO在阶跃电位-15 mV～+15 mV显著地提高了高电压激活的钙电流幅度(P<0.05)；与对照组相比,激活曲线及稳态失活曲线没有显著改变。
8.纳米ZnO对海马锥体神经元兴奋性活动的影响：电流钳结果显示,10-4 g/ml的纳米ZnO提高了单个动作电位的幅值及超射(P<0.01),缩短了动作电位的半宽时程(P<0.05)；提高了连续动作电位的频率(P<0.05)；提高了自发放电的频率(P<0.05)。
主要实验结论如下：
1.纳米ZnO可降低PC12细胞的存活率,表现为时间依赖性和浓度依赖性；并促进细胞凋亡；细胞内ROS的增加是纳米ZnO诱导PC12细胞凋亡的机制之一。
2.纳米ZnO通过延迟整流钾通道增加K+外流使细胞质中K+减少而诱导细胞凋亡
3.纳米ZnO上调HVA Ca2+通道,引起细胞内Ca2+浓度升高,将导致ROS产生,并由此促进细胞凋亡。
4.纳米ZnO通过增加钠通道的电流幅度,并使钠通道快速失活,及失活后快速恢复而提高神经元的兴奋性,进而可能对神经元产生去极化诱导的损伤；纳米ZnO通过上调HVA Ca2+通道将改变细胞内钙稳态,将由此增强神经退行性过程。
5.纳米ZnO通过增大INa、IK及HVA Ca2+电流的电流幅度而导致神经元兴奋性增加,并使单个动作电位的幅值及超射增加,动作电位的半宽时程缩短；提高了连续动作电位和自发放电的频率。后续重复放电的跨膜电位幅度和超射值的减小与纳米ZnO造成的Na+-K+-ATP酶的功能不足有关。
Nanomaterials have been defined as material with one dimension of less than 100 nm. Due to their small size and the special structure, they have many new physical and chemical properties, such as small size effect, the large specific surface, high reactivity, quantum size effects. With the industrialization of nanotechnology, a variety of nanomaterials have a broad range of applications across industry, agriculture, manufacturing, military, medical and many other fields because of their excellent properties and novel functions. Nanomaterials are also widely used in daily life products, such as cosmetics, food, fabrics, coatings, antibacterial materials, etc., and public exposure to nanoparticles are increasing daily. Therefore, the biological effects and safety issues of nanomaterials have also been raised, especially the potential negative impacts of nanoparticles on human health, living environment and social security. Toxicological studies have shown that nanoparticles could enter into the human body through several distinct routes including inhalation, ingestion, and dermal penetration. Subsequently they could elicit toxicological effects at different levels of biological systems. Recent studies have shown that the central nervous system (CNS) is an important target organ for nanoparticles. Therefore, the effects of nanoparticles on the CNS have also gained more attention. Nanoparticles can cross most strong biological barriers such as blood-brain barrier and via the olfactory neuronal pathway enter into the CNS and accumulate in different brain regions. So the hippocampus is also the main target for nanoparticles.
Breaking achievements and great attention have been gained in the important applications of Nano-ZnO because of its unique optical, electrical and magnetic properties. Meanwhile, Nano-ZnO have excellent applications in cosmetics, textiles, paints, ceramics, catalysis, antibacterial, medical diagnostics. Some researchers have demonstrated that nanostructures of ZnO were toxic to the bacteria, the aquatic biota or eco-relevant species, the mammalian cells and mammals. However, little is known about the possible impacts of manufactured nano-ZnO on the CNS. In the present study, differentiated PC12 cells induced by nerve growth factor (NGF) were used to investigate the cytotoxicity of the nano-ZnO. The viability of the cells was observed by a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the generation of ROS for the cells was evaluated by a fluorometry assay. The apoptosis of cells were detected and analyzed by flow cytometry.
The neurons in the CNS express various types of ion channels, and the cell electrical activity caused by the opening of ion channels are the basis of physiological function. Ion channels involved in transmitter release, hormone secretion, signal transduction, metabolic regulation and cell growth as well as learning and memory and other important physiological processes, and they are also targets for many toxins and drugs. Therefore, whole-cell patch clamp technique was used to study the effects of nano-ZnO on ion channels of hippocampal pyramidal neurons, including voltage-gated sodium channels, potassium channels, calcium channels and neuronal excitability, and investigate the potential mechanism of nano-ZnO on the CNS. The main results are as follows:
1. MTT cell viability assay:Nerve growth factor (NGF) induced differentiation of PC12 cells were incubated with different concentrations of the nano-ZnO (10-6 g/ml,10-5 g/ml,10-4 g/ml) for the periods 6,12,24 hours, and cell viability was decreased in a dose-dependent and time-dependent manner. Nano-ZnO (10-4 g/ml) caused a significant decrease in cell viability (P<0.05).
2. Changes in intracellular ROS levels:PC12 cells were incubated with different concentrations of the nano-ZnO (10-6 g/ml,10-5 g/ml,10-4 g/ml) for 6h, and then treated by GENMED working solution and GENMED preserving fluid. Using the inverted fluorescence microscope, setting the excitation wavelength at 490nm and 530nm, the fluorescence intensity of nano-ZnO treatment group gradually increased with the increasing concentration of nano-ZnO compared to that of the control group. The result indicated that intracellular ROS levels were increased.
3. The proportion of apoptotic cells by flow cytometry analysis:PC12 cells were incubated with different concentrations of the nano-ZnO (10-6 g/ml,10-5 g/ml,10-4 g/ml) for 24 hours, and the apoptosis rate of PC12 cells was increased from 8.75% in control group to 34.24% (P<0.05) after the cell exposure to the nano-ZnO (10-4 g/ml) for 24h, However, a pre-treatment to the cells using MPG (3 mM) and then treatment to PC12 cells 24h with nano-ZnO (10-4 g/ml) reduced the cellular apoptosis to 15.78% (P<0.05). The result indicated that pre-treated the ROS scavenger can inhibit the nano-ZnO induced apoptosis in PC 12 cells.
4. Protective effects of ROS scavengers:PC12 cells were pre-treated with MPG (3 mM) for 30 min and then were incubated with nano-ZnO (10-4 g/ml) for 24h.The viability of PC 12 cells was significantly increased compared to that of the nano-ZnO treatment group (P<0.05).
5. Effects of nano-ZnO on voltage-gated sodium channels in hippocampal pyramidal neurons:In the present of final concentration of 10-4g/ml nano-ZnO, the peak amplitudes of INa were increased considerably from-50 mV to+20 mV(P<0.05), and the current-voltage curve of sodium current (INa) was decreased. Meanwhile, the values of Vh for inactivation of Ina before and after addition of nanoparticle ZnO are-52.54±0.43 mV and-54.67±0.39mV (P<0.01); The time constants (r) before and after addition of nano-ZnO were 5.40±0.19 ms and 3.95±0.15 ms (P<0.01), respectively. However, the steady-state activation curve of INa was not shifted by the nano-ZnO.
6. Effects of nano-ZnO on voltage-gated potassium channels in hippocampal pyramidal neurons:The amplitudes of transient outward potassium current (IA) were increased by the nano-ZnO solution (10-4g/ml), while the current-voltage curve of delayed rectifier potassium current (Ik) was significantly increased from+20 mV to +90 mV (P<0.05). However, it is apparent that the nano-ZnO solution didn't shift the steady-state activation curve of IA and IK, and neither had significant effects on the inactivation and the recovery from inactivation of IA.
7. Effects of nano-ZnO on high-voltage activated (HVA) calcium currents in hippocampal pyramidal neurons:HVA calcium currents had a tendency of enhancement (run up) in the first 5 minutes of the recording in both the experimental and control groups, and were followed by a decline (run down) with time. At 10 minutes of the recording,10-4g/ml nano-ZnO first altered the current-voltage curve and the peak amplitudes of HVA calcium currents (P<0.05), and at the end of 30 minutes the peak current amplitudes were increased significantly from-15 mV to+15 mV(P<0.05) compared to that of the control group. But there were no statistically significance the steady-state activation curve and the steady-state inactivation curve of HVA calcium currents compared with that of the control group.
8. Effects of nano-ZnO on excitable activity in hippocampal pyramidal neurons excitability:the results of current clamp showed that peak amplitude and overshoot of the evoked single action potential were increased in the presence of the 10"4g/ml nano-ZnO solution (P<0.05) and half-width was diminished (P<0.05). Simultaneously, a prolonged depolarizing current injection enhanced repetitive firing evoked firing rate(P<0.05) and firing rate of spontaneous firing was also increased (P<0.05).
The main conclusions are as follows:
1. Nano-ZnO can cause a significant decrease in cell viability in a dose-dependent and time-dependent manner and promote apoptosis in PC 12 cells; while the increase of intracellular ROS are one of potential mechanisms of cellular apoptosis induced by nano-ZnO.
2. Nano-ZnO could involve in the neuronal apoptosis caused by the loss of cytoplasmic K+ due to increased K+ efflux through delayed rectifier potassium channels.
3. Nano-ZnO could cause the elevation of cytosolic calcium levels by up-regulation HVA calcium channels, which would increase the generation of intracellular ROS, and consequently, promote neuronal apoptosis.
4. Nano-ZnO could enhance the neuronal excitability by increasing the peak amplitudes of INa and promoting the inactivation and the recovery from inactivation of INa, which may involve in depolarization-induced neuronal injury by activation of voltage-gated Na+ channels. Meanwhile, nano-ZnO would potentially perturb cellular calcium homeostasis by up-regulation HVA calcium channels, and contribute to the neurodegenerative process.
5. Nano-ZnO could enhance the neuronal excitability by increasing the peak amplitudes of INa, IK and HVA calcium currents, and therefore increase the peak amplitude and overshoot of the evoked single action potential and diminish half-width. Simultaneously, firing rate of repetitive firing and spontaneous firing were aslso increased. The decrease of peak amplitude and overshoot of the subsequent action potentials of repetitive firing may due to the dysfunction or deficiency of Na+-K+-ATPase.
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