Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China.
Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.
J Neuroinflammation. 2023 Aug 20;20(1):191. doi: 10.1186/s12974-023-02873-z.
Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.
抑郁症是一种常见的心境障碍，其特征为一系列临床症状，包括长时间的情绪低落和兴趣减退。尽管许多临床和动物研究为抑郁症的病理生理学提供了重要的见解，但目前的治疗策略不足以治疗这种疾病。有人提出，连接蛋白（Cx）基半通道通过调节神经炎症状态，可能成为干预抑郁症的候选目标。在这项研究中，我们研究了一种最近发现的选择性 Cx 半通道抑制剂，一种名为 D4 的小分子有机化合物，对抑郁症的治疗作用。我们首先表明，D4 可降低 LPS 注射后全身炎症后的半通道活性。接下来，我们发现 D4 治疗可预防 LPS 诱导的炎症反应和抑郁样行为。这些行为效应伴随着反复给予小剂量 LPS 挑战诱导的抑郁样小鼠中星形胶质细胞激活和半通道活性的降低。D4 治疗还可逆转慢性束缚应激（CRS）小鼠的抑郁样症状。为了测试 D4 是否广泛影响神经活动，我们测量了与抑郁相关的脑区中的 c-Fos 表达，发现不同脑区的 c-Fos 细胞减少。D4 可显著使 CRS 诱导的多个脑区（包括海马体、内嗅皮层和外侧隔区）的低激活正常化。总之，这些结果表明，使用 D4 阻断 Cx 半通道可以通过减少神经炎症使神经元活动正常化并减轻小鼠的抑郁样症状。我们的工作为 D4 的抗抑郁样作用提供了证据，并支持胶质 Cx 半通道作为抑郁症的潜在治疗靶点。
