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SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor

文献类型： 外文期刊

作者： Guo, Lin 1 ; Gao, Tianyu 1 ; Jia, Xiaoxia 1 ; Gao, Ce 1 ; Tian, Hao 3 ; Wei, Yaqin 1 ; Lu, Wenchun 4 ; Liu, Zhidong 1 ; Wang, Yun 1 ;

作者机构： 1.Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou 221004, Peoples R China

2.Xuzhou Med Univ, Affiliated Hosp, Dept Pharm, Xuzhou 221004, Peoples R China

3.Yunnan Acad Agr Sci, Agroprod Proc Res Inst, Kunming 650000, Peoples R China

4.Xuzhou Med Univ, Psychol Lab Sch Management, Xuzhou 221004, Peoples R China

关键词： epilepsy; hippocampus injury; neuroinflammation; sigma-1 receptor; SKF83959

期刊名称：ACS CHEMICAL NEUROSCIENCE （ 影响因子：5.78； 五年影响因子：5.42 ）

ISSN： 1948-7193

年卷期：

页码：

收录情况： SCI

摘要： Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6 Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor -a and interleukin-1fi, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3fi. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3fi pathway.

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