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S-oxiracetam Facilitates Cognitive Restoration after Ischemic Stroke by Activating α7nAChR and the PI3K-Mediated Pathway

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Abstract

S-oxiracetam (S-ORC), a nootropic drug, was used to protect against ischemic stroke by lessening the blood brain barrier dysfunction and inhibiting neuronal apoptosis. However, the potential effects of S-ORC in the recovery of cognitive functions after ischemic stroke and the underlying mechanisms remains unclear. In this study, middle cerebral artery occlusion/reperfusion (MCAO/R) in rats was used as the animal model. By using Y-maze test, Morris water maze, triphenyl tetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTp) nick end labeling (TUNEL) assay, hematoxylin and eosin, immunohistochemical staining and western blot to evaluate the protective effect of S-ORC on cognitive recovery, we were able to confirm that S-ORC ameliorated spatial learning impairment, tissue loss, and hippocampal neuronal apoptosis and injury induced by MCAO/R in rats. These cognitive effects were achieved by restoring the normal function of synaptophysin and increasing PSD95 expression in the hippocampus. Furthermore, we found that methyllycaconitine, the antagonist of α7 nicotinic acetylcholine receptor (α7nAChR), and LY294002, the inhibitor of phosphoinositide 3-kinase (PI3K), were able to block the cognitive effects of S-ORC after MCAO/R in rats. In conclusion, α7nAChR and PI3K are key molecules that mediated the signaling pathway leading to S-ORC-induced cognitive restoration after MCAO/R.

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Acknowledgements

We appreciate the technical support from the Public Platform of Medical Research Center, Academy of Chinese Medical Science, Zhejiang Chinese Medical University.

Funding

This work was supported by the National Natural Science Foundation of China (81701313), and by the Fundamental Research Funds for the Central Universities (2242020K40175).

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Authors and Affiliations

  1. Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Wenxiang Fan & Xiaomin Li

  2. Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China

    Ying Zhang & Chi Xu

  3. State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, Jiangsu, China

    Ying Zhang

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  1. Wenxiang Fan
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Fan, W., Zhang, Y., Li, X. et al. S-oxiracetam Facilitates Cognitive Restoration after Ischemic Stroke by Activating α7nAChR and the PI3K-Mediated Pathway. Neurochem Res 46, 888–904 (2021). https://doi.org/10.1007/s11064-021-03233-0

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