Abstract：
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.
摘要：
记忆障碍和情绪障碍是癫痫患者常见的两种临床合并症。必须开发新的治疗剂或策略。6-氯-7,8-二羟基-3-甲基-1-（3-甲基苯基）-2,3,4,5-四氢-1H-3-苯并氮杂卓（SKF83959）是多巴胺-1受体激动剂和sigma-1受体变构调节剂，显示神经元保护和抗神经炎症活性。我们使用小鼠癫痫持续状态模型检查了SKF83959对癫痫潜伏期记忆障碍和情绪障碍的影响。我们发现SKF83959改善了记忆障碍和抑郁样情绪，减轻了海马神经元损伤和胶质增生的形成，抑制促炎细胞因子的升高，包括肿瘤坏死因子-α和白细胞介素-1β，并在癫痫潜伏期诱导一氧化氮合酶。此外,SKF83959显著抑制钙调磷酸酶和糖原合成酶激酶-3β的活性。所有这些保护作用被BD1047(sigma-1受体拮抗剂)逆转。此外,海马内注射酮康唑(脱氢表雄酮合成抑制剂)也逆转了SKF83959的保护活性.因此，我们得出的结论是,SKF83959通过变构激活sigma-1受体并随后抑制钙调磷酸酶/糖原合酶激酶-3β途径,改善了癫痫患者的记忆障碍和抑郁样情绪.
