SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor.
SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor.
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DOI：
10.1021/acschemneuro.2c00629
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发表时间：
2022-11
影响因子：
5
通讯作者：
Lin Guo;Tianyu Gao;Xiaoxia Jia;Ce Gao;Hao Tian;Yaqin Wei;Wenchun Lu;Zhidong Liu;Yun Wang
中科院分区：
文献类型：
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作者：
Lin Guo;Tianyu Gao;Xiaoxia Jia;Ce Gao;Hao Tian;Yaqin Wei;Wenchun Lu;Zhidong Liu;Yun Wang
记忆障碍和情绪障碍是癫痫患者两种常见的临床合并症。因此，迫切需要开发一种新的治疗药物或策略。6-Chloro-7，8-dihydroxy-3-methyl-1-（3-methylphenyl）-2，3，4，5-tetrahydro-1H-3-benzazepine（SKF 83959）是一种多巴胺-1受体激动剂和σ-1受体变构调节剂，具有神经保护和抗神经炎症活性。本研究采用小鼠癫痫持续状态模型，观察SKF 83959对癫痫潜伏期记忆障碍和情绪障碍的影响。我们发现SKF 83959可改善癫痫大鼠的记忆障碍和抑郁样情绪，减轻海马神经元损伤和胶质增生，抑制致炎细胞因子（包括肿瘤坏死因子-α和白细胞介素-1 β）的升高，诱导癫痫潜伏期一氧化氮合酶的表达。此外，SKF 83959显著抑制钙调磷酸酶和糖原合成酶激酶-3 β的活性。所有这些保护作用都被BD 1047（一种sigma-1受体拮抗剂）逆转。此外，海马内注射酮康唑（一种脱氢表雄酮合成抑制剂）也逆转了SKF 83959的保护活性。因此，我们得出结论，SKF 83959通过变构激活sigma-1受体并随后抑制钙调神经磷酸酶/糖原合成酶激酶-3 β途径改善癫痫患者的记忆障碍和抑郁样情绪。
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-α and interleukin-1β, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3β. 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-3β pathway.