Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats
Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats
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DOI：
10.1016/j.phymed.2018.01.025
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发表时间：
2018-03-01
期刊：
影响因子：
7.9
通讯作者：
Gong, Qihai
中科院分区：
文献类型：
--
作者：
He, Lianzi;Deng, Yuanyuan;Gong, Qihai
背景资料：兴奋性毒性被广泛认为是神经元死亡的主要病理过程，并已被证明在阿尔茨海默病（AD）中起关键作用。ICS II是一种从淫羊藿中提取的黄酮类化合物，因其具有神经保护作用而引起广泛关注，目的：探讨ICS II对兴奋性神经毒素鹅膏蕈氨酸（IBO）诱导的大鼠认知功能障碍和细胞凋亡的影响。双侧海马注射IBO的大鼠分别灌胃给予4、8和16 mg/kg ICS II或0.6 mg/kg多奈哌齐，每日1次，连续20 d。Morris水迷宫检测大鼠学习记忆功能。HE染色和尼氏染色观察海马神经元形态学变化。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）检测神经细胞凋亡。结果：海马注射IBO可引起大鼠学习记忆障碍、神经元损伤和丢失，并可引起促凋亡反应。ICS II以8和16 mg/kg的剂量给药不仅挽救了行为表现，而且通过抑制Bax/Bcl-2比值的升高和caspase-3的活化来保护海马神经元免受神经毒性。同时，ICS II抑制IBO诱导的Calbindin蛋白的下调。结论：ICS II可能通过调节钙结合蛋白的表达和抑制凋亡反应，减轻IBO诱导的认知功能障碍。此外，MAPK信号通路与ICS II对抗IBO诱导的兴奋性毒性的潜在机制有关，表明ICS II是治疗兴奋性毒性相关疾病（包括AD）的有前景的化合物。
Background: Excitotoxicity is extensively recognized as a major pathological process of neuronal death and has been proved to play a key role in Alzheimer's disease (AD). ICS II, a flavonoid compound from Herba Epimedii Maxim, is attracting great interests due to its neuroprotective properties.Purpose: The present study was aimed to explore the effects of ICS II on cognitive dysfunction and apoptotic response induced by excitatory neurotoxin ibotenic acid (IBO) injection in rats.Methods: Rats subjected to bilateral hippocampal injection of IBO were intragastrically administered with 4, 8 and 16 mg/kg ICS II or 0.6 mg/kg donepezil once a day for continuous 20 days. Learning and memory functions were tested by Morris water maze. The neuronal morphology in hippocampus was examined by HE staining and Nissl staining, respectively. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The expression of apoptosis-related proteins and the activation of mitogen-activated protein kinase (MAPK) pathway were detected by Western blot.Results: It was uncovered that hippocampal injection of IBO caused learning and memory impairment, neuronal damage and loss, as well as pro-apoptotic response. ICS II administrated at doses of 8 and 16 mg/kg not only rescued behavioral performance, but also protected hippocampal neurons against neurotoxicity via suppressing the elevation of Bax/Bcl-2 ratio and the activation of caspase-3. Meanwhile, ICS II repressed the down-regulation of calbindin protein induced by IBO. Additionally, ICS II exerted an inhibitory effect on MAPK (p38, ERK1/2 and JNK) pathway phosphorylation.Conclusion: These results suggest that ICS II attenuates IBO-induced cognitive deficits, possibly via the regulation of calbindin expression and the inhibition of apoptotic response. In addition, the MAPK signaling pathway is implicated in the potential mechanisms of ICS II against IBO-induced excitotoxicity, indicating that ICS II is a promising compound for treatment of excitotoxicity-related diseases, including AD.