Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563003, China.
School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003, China.
Phytomedicine. 2018 Mar 1;41:74-81. doi: 10.1016/j.phymed.2018.01.025. Epub 2018 Jan 31.
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.
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.
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.
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.
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.
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。从淫羊藿中提取的黄酮类化合物 ICS II 因其神经保护特性而引起了极大的兴趣。
本研究旨在探讨 ICS II 对兴奋性神经毒素（IBO）注射诱导的大鼠认知功能障碍和凋亡反应的影响。
将大鼠双侧海马注射 IBO 后，每天给予 ICS II 4、8 和 16mg/kg 或 0.6mg/kg 多奈哌齐灌胃，连续 20 天。通过 Morris 水迷宫测试学习和记忆功能。分别通过 HE 染色和尼氏染色观察海马神经元形态，通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）检测神经元凋亡，通过 Western blot 检测凋亡相关蛋白的表达和丝裂原活化蛋白激酶（MAPK）通路的激活。
发现海马注射 IBO 导致学习记忆障碍、神经元损伤和丢失以及促凋亡反应。ICS II 以 8 和 16mg/kg 的剂量给药不仅挽救了行为表现，而且通过抑制 Bax/Bcl-2 比值升高和 caspase-3 激活来保护海马神经元免受神经毒性。同时，ICS II 抑制了 IBO 诱导的 calbindin 蛋白下调。此外，ICS II 对 MAPK（p38、ERK1/2 和 JNK）通路磷酸化有抑制作用。
这些结果表明，ICS II 通过调节 calbindin 表达和抑制凋亡反应，减轻 IBO 诱导的认知缺陷。此外，MAPK 信号通路可能是 ICS II 对抗 IBO 诱导的兴奋性毒性的潜在机制之一，表明 ICS II 是治疗兴奋性毒性相关疾病（包括 AD）的有前途的化合物。
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