Cytisine Exerts an Anti-Epileptic Effect via α7nAChRs in a Rat Model of Temporal Lobe Epilepsy.
Cytisine Exerts an Anti-Epileptic Effect via α7nAChRs in a Rat Model of Temporal Lobe Epilepsy.
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金雀花碱通过 α7nAChR 在颞叶癫痫大鼠模型中发挥抗癫痫作用
DOI：
10.3389/fphar.2021.706225
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Zheng JJ;Zhang TY;Liu HT;Huang ZX;Teng JM;Deng JX;Zhong JG;Qian X;Sheng XW;Ding JQ;He SQ;Zhao X;Ji WD;Qi DF;Li W;Zhang M
背景与目的：颞叶癫痫（Temporal lobe epilepsy，TLE）是一种常见的慢性神经系统疾病，抗癫痫药物对TLE无效。越来越多的研究表明乙酰胆碱（acetylcholine，ACh）和胆碱能神经传递参与癫痫的病理生理过程。金雀花碱是α7烟碱乙酰胆碱受体（α 7 nAChRs）的完全激动剂和α4β 2 nAChRs的部分激动剂，已被广泛应用于戒烟，并在神经系统疾病中显示出神经保护作用。然而，金雀花碱是否在治疗TLE中起作用尚未确定。 实验方法：采用匹罗卡品致痫大鼠，腹腔注射野靛碱，连续3周。α-银环蛇毒素（α-bungarotoxin，α-bgt）是一种特异性的α 7 nAChR拮抗剂。采用视频监视和Morris水迷宫检测大鼠癫痫发作和认知功能。尼氏染色和高尔基体染色观察海马神经元损伤和突触结构。此外，还测定了谷氨酸、γ-氨基丁酸（GABA）、ACh和α 7 nAChRs的水平。 结果：金雀花碱能明显减轻TLE大鼠的癫痫发作和海马损伤，改善认知功能，抑制突触重构。此外，金雀花碱降低TLE大鼠海马谷氨酸水平而不改变GABA水平，并增加ACh水平和α 7 nAChR表达。α-bgt可拮抗野靛碱的上述作用。 结论和启示：总之，这些结果表明，野靛碱通过激活α 7 nAChR，降低谷氨酸水平，抑制突触重塑，改善海马胆碱能传递，在TLE大鼠中发挥抗癫痫和神经保护作用。因此，我们的研究结果不仅表明野靛碱是一种有前途的抗癫痫药物，而且为α 7 nAChRs作为TLE的新治疗靶点提供了证据。
Background and Purpose: Temporal lobe epilepsy (TLE) is a common chronic neurological disease that is often invulnerable to anti-epileptic drugs. Increasing data have demonstrated that acetylcholine (ACh) and cholinergic neurotransmission are involved in the pathophysiology of epilepsy. Cytisine, a full agonist of α7 nicotinic acetylcholine receptors (α7nAChRs) and a partial agonist of α4β2nAChRs, has been widely applied for smoking cessation and has shown neuroprotection in neurological diseases. However, whether cytisine plays a role in treating TLE has not yet been determined. Experimental Approach: In this study, cytisine was injected intraperitoneally into pilocarpine-induced epileptic rats for three weeks. Alpha-bungarotoxin (α-bgt), a specific α7nAChR antagonist, was used to evaluate the mechanism of action of cytisine. Rats were assayed for the occurrence of seizures and cognitive function by video surveillance and Morris water maze. Hippocampal injuries and synaptic structure were assessed by Nissl staining and Golgi staining. Furthermore, levels of glutamate, γ-aminobutyric acid (GABA), ACh, and α7nAChRs were measured. Results: Cytisine significantly reduced seizures and hippocampal damage while improving cognition and inhibiting synaptic remodeling in TLE rats. Additionally, cytisine decreased glutamate levels without altering GABA levels, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. α-bgt antagonized the above-mentioned effects of cytisine treatment. Conclusion and Implications: Taken together, these findings indicate that cytisine exerted an anti-epileptic and neuroprotective effect in TLE rats via activation of α7nAChRs, which was associated with a decrease in glutamate levels, inhibition of synaptic remodeling, and improvement of cholinergic transmission in the hippocampus. Hence, our findings not only suggest that cytisine represents a promising anti-epileptic drug, but provides evidence of α7nAChRs as a novel therapeutic target for TLE.
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