Mechanism of synapse redox stress in Okadaic acid (ICV) induced memory impairment: Role of NMDA receptor
Mechanism of synapse redox stress in Okadaic acid (ICV) induced memory impairment: Role of NMDA receptor
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DOI：
10.1016/j.neuint.2014.06.012
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发表时间：
2014-10-01
影响因子：
4.2
通讯作者：
Nath, Chandishwar
中科院分区：
文献类型：
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作者：
Kamat, Pradip K.;Rai, Shivika;Nath, Chandishwar
N-甲基-D-天冬氨酸（NMDA）受体是离子型谷氨酸受体的一种亚型，参与学习和记忆的突触机制，并介导兴奋性毒性神经元损伤。本研究验证了OKA致记忆障碍大鼠皮层和海马NMDA受体亚单位基因表达改变的假说。因此，在本研究中，我们检查了OKA（ICV）对NMDA受体调节和突触功能的影响。OKA可引起大鼠记忆功能异常和突触体Ca~（2+）水平升高，MK 801（0.05 mg/kg. i. p）处理13天。为了阐明NMDA受体的参与，我们估计了NR1，NR2A和NR2B（亚基）在大鼠脑中的表达。结果表明，OKA处理后大鼠脑组织中NR1和NR2B的表达明显增加，而NR2A的表达无明显变化。我们还观察到突触蛋白-1 mRNA和蛋白表达的减少，这表明突触功能障碍。此外，我们检测到突触制备物中MDA和亚硝酸盐水平的增加和GSH水平的降低，这表明突触改变了氧化还原应激。此外，室周皮质和海马神经元的尼氏染色也证实了神经元的损失。氧化应激标志物水平的改变沿着神经元丢失证实了神经毒性。此外，MK 801治疗恢复了NR1、NR2B和突触蛋白-1的表达水平，并保护神经元免于损失和突触氧化还原应激。总之，冈田酸（OKA）诱导的NR1和NR2B的表达恶化了大鼠脑中的突触功能，这被MK 801的神经保护作用所证实。(C)2014爱思唯尔有限公司版权所有。
The N-methyl-D-aspartate (NMDA) receptor is a subtype of ionotropic glutamate receptor that is involved in synaptic mechanisms of learning and memory, and mediates excitotoxic neuronal injury. In this study, we tested the hypothesis that NMDA receptor subunit gene expression is altered in cortex and hippocampus of OKA induced memory impairment. Therefore in the present study, we checked the effect of OKA (ICV) on NMDA receptor regulation and synapse function. The memory function anomalies and synaptosomal calcium ion (Ca2+) level were increased in OKA treated rats brain; which was further protected by MK801 (0.05 mg/kg. i.p) treatment daily for 13 days. To elucidate the involvement of NMDA receptor, we estimated NR1, NR2A and NR2B (subunits) expression in rat brain. Results showed that expression of NR1 and NR2B were significantly increased, but expression of NR2A had no significant change in OKA treated rat brain. We also observed decrease in synapsin-1 mRNA and protein expression which indicates synapse dysfunction. In addition, we detected an increase in MDA and nitrite levels and a decrease in GSH level in synapse preparation which indicates synapse altered redox stress. Moreover, neuronal loss was also confirmed by nissl staining in periventricular cortex and hippocampus. Altered level of oxidative stress markers along with neuronal loss confirmed neurotoxicity. Further, MK801 treatment restored the level of NR1, NR2B and synapsin-1 expression, and protected from neuronal loss and synapse redox stress. In conclusion, Okadaic acid (OKA) induced expression of NR1 and NR2B deteriorates synapse function in rat brain which was confirmed by the neuroprotective effect of MK801. (C) 2014 Elsevier Ltd. All rights reserved.