Brexpiprazole prevents colitis-induced depressive-like behavior through myelination in the prefrontal cortex
Brexpiprazole prevents colitis-induced depressive-like behavior through myelination in the prefrontal cortex
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DOI：
10.1016/j.pnpbp.2022.110666
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发表时间：
2022-10
影响因子：
5.6
通讯作者：
Kohei Takahashi;L. Hong;K. Kurokawa;K. Miyagawa;Atsumi Mochida-Saito;H. Takeda;M. Tsuji
中科院分区：
文献类型：
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作者：
Kohei Takahashi;L. Hong;K. Kurokawa;K. Miyagawa;Atsumi Mochida-Saito;H. Takeda;M. Tsuji
患有炎症性肠病（IBD）的患者有更高的精神病理学发病率，包括抑郁症。葡聚糖硫酸钠（DSS）治疗的小鼠表现出IBD和抑郁样表型。肠道环境紊乱会导致血清素减少和大脑髓鞘形成异常，沿着啮齿类动物的抑郁样行为。然而，这些因素参与DSS诱导的小鼠抑郁样行为仍不清楚。在这项研究中，我们检查是否髓鞘蛋白在前额叶皮层（PFC）和海马中的DSS治疗的小鼠改变，沿着的变化，在PFC中的多巴胺能系统的蛋白质免疫印迹法和HPLC。采用悬尾试验评价了5-羟色胺调节剂布雷哌唑（Brx）对DSS诱导的抑郁样行为的影响。随后，我们研究了Brx的髓鞘，结蛋白，神经营养分子的PFC与蛋白质印迹的水平上的影响，并通过免疫组织化学检查改变节点的Ranvier形成。DSS治疗的小鼠表现出减少髓鞘和结蛋白，功能障碍的神经系统，并受损的节点的Ranvier在PFC的形成。Brx管理防止DSS诱导的抑郁样行为和脱髓鞘的PFC。然而，Brx介导的影响被抑制的选择性5-HT 1A拮抗剂，WAY 100635，或选择性TrkB拮抗剂，ANA-12。Brx降低DSS处理小鼠PFC中ERK、CREB和TrkB的磷酸化沿着BDNF的表达。WAY 100635可阻断Brx的作用。这些结果表明，髓鞘化的ERK 1/2-CREB-BDNF-TrkB通路的激活调节PFC中可能参与介导的Brx的抗抑郁作用。
Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mice exhibit IBD- and depressive-like phenotypes. A disturbed intestinal environment causes a decrease in serotonin and abnormal myelination in the brain, along with depressive-like behavior in rodents. However, the involvement of these factors in DSS-induced depressive-like behavior in mice remains unclear. In this study, we examined whether myelin proteins in the prefrontal cortex (PFC) and hippocampi were altered in DSS-treated mice, along with the changes in the serotonergic system in the PFC by western blotting and HPLC. The effects of brexpiprazole (Brx), a serotonin modulator, on DSS-induced depressive-like behavior using the tail-suspension test were evaluated. Subsequently, we investigated Brx's effects on the levels of myelin, nodal proteins, and neurotrophic molecules in the PFC with western blotting, and examined the altered node of Ranvier formation by immunohistochemistry. DSS-treated mice showed a reduction in myelin and nodal proteins, dysfunction of the serotonergic system, and impaired formation of the nodes of Ranvier in the PFC. Brx administration prevented the DSS-induced depressive-like behavior and demyelination in the PFC. However, the Brx-mediated effects were inhibited by the selective 5-HT1Aantagonist, WAY100635, or the selective TrkB antagonist, ANA-12. Brx decreased the phosphorylation of ERK, CREB, and TrkB along with the expression of BDNF in the PFC of DSS-treated mice. Moreover, the effects of Brx were blocked by WAY100635. These findings indicated that myelination regulated by the activation of the ERK1/2-CREB-BDNF-TrkB pathway in the PFC may be involved in mediating the antidepressant effects of Brx.