Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, 230038, China.
Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, 230038, China; Anhui Academy of Chinese Medicine, Hefei, 230038, China.
Neuropharmacology. 2020 Sep 1;174:108175. doi: 10.1016/j.neuropharm.2020.108175. Epub 2020 May 31.
Protease activity correlates with depressive or suicidal behaviors, with calpain activation being especially implicated in depression-like behaviors. However, the role of calpain in depression-like behaviors is currently unknown. In this study, the lipopolysaccharide (LPS) - and chronic unpredictable mild stress (CUMS)-induced depression models were used to evaluate the antidepressant effects of calpain inhibitors. Potential mechanisms were determined using pharmacological and biochemical methods. We found that i. p. injection of a calpain inhibitor, calpeptin, prevented LPS-induced depression-like behaviors, activation of astrocytes, inflammation, and reduction of synaptic protein expression levels. LPS injection (i.p.) promoted calpain activity, which degraded suprachiasmatic nucleus circadian oscillatory protein (SCOP). This led to the activation of ERK and nuclear translocation of nuclear factor kappa-B (NF-κB), the promotion of cytokine release, and the reduction of Arc, and PSD95 expression in the hippocampus. In contrast, i. p. injection of calpeptin blocked these changes. Furthermore, intraventricular injection of calpain inhibitor (PD150606) or an ERK inhibitor ameliorated the LPS-induced depression-like behaviors. Administration of calpeptin also remedied CUMS-induced depression-like behaviors, degradation of SCOP, activation of astrocytes, and reduction of synaptic protein expression levels. Finally, we also demonstrated that memantine, an N-methyl-d-aspartic acid (NMDA) receptor antagonist blocks LPS-induced degradation of SCOP. Together, our results show that calpain inhibition ameliorates depression-like behaviors, probably by reducing inflammation and promoting synaptic protein expression in the hippocampus.
蛋白酶活性与抑郁或自杀行为相关，钙蛋白酶的激活尤其与抑郁样行为有关。然而，钙蛋白酶在抑郁样行为中的作用尚不清楚。在这项研究中，使用脂多糖（LPS）和慢性不可预测轻度应激（CUMS）诱导的抑郁模型来评估钙蛋白酶抑制剂的抗抑郁作用。使用药理学和生化方法确定了潜在的机制。我们发现，腹腔注射钙蛋白酶抑制剂 calpeptin 可预防 LPS 诱导的抑郁样行为、星形胶质细胞激活、炎症和突触蛋白表达水平降低。LPS 注射（腹腔内）促进钙蛋白酶活性，降解视交叉上核昼夜节律振荡蛋白（SCOP）。这导致 ERK 的激活和核因子 kappa-B（NF-κB）的核易位，促进细胞因子释放，并减少海马中的 Arc 和 PSD95 表达。相比之下，腹腔内注射 calpeptin 阻断了这些变化。此外，脑室注射钙蛋白酶抑制剂（PD150606）或 ERK 抑制剂可改善 LPS 诱导的抑郁样行为。calpeptin 的给药还改善了 CUMS 诱导的抑郁样行为、SCOP 的降解、星形胶质细胞的激活和突触蛋白表达水平的降低。最后，我们还表明，NMDA 受体拮抗剂美金刚阻断 LPS 诱导的 SCOP 降解。总之，我们的结果表明钙蛋白酶抑制可改善抑郁样行为，可能是通过减少炎症和促进海马中的突触蛋白表达。
