Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakansemaru, Ohtawara, Tochigi, 324-8501, Japan.
Department of Pharmacology, School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan.
Neurochem Int. 2021 Dec;151:105213. doi: 10.1016/j.neuint.2021.105213. Epub 2021 Oct 18.
We previously reported that abnormal emotionality in stress-maladaptive mice was ameliorated by chronic treatment with flesinoxan, a 5-HT receptor agonist. Furthermore, the maintenance of hippocampal myelination appeared to contribute to the development of stress adaptation in mice. However, the effects of 5-HT receptor activation on myelination under the stress-maladaptive situations and the underlying mechanisms remain unknown. In the present study, we examined using flesinoxan whether activation of 5-HT receptor can reduce an abnormal emotional response by acting on oligodendrocytes to preserve myelin proteins in stress-maladaptive mice. Mice were exposed to repeated restraint stress for 4 h/day for 14 days as a stress-maladaptive model. Flesinoxan was given intraperitoneally immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated by the hole-board test. The expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-cAMP response element-binding protein (p-CREB), myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and oligodendrocyte transcription factor 2 (olig2) in the hippocampus was assessed by western blotting. Hippocampal oligodendrogenesis were examined by immunohistochemistry. Chronic treatment with flesinoxan suppressed the decrease in head-dipping behaviors in stress-maladaptive mice in the hole-board test. Under this condition, the decreases in MAG and MBP in the hippocampus recovered with increase in BDNF, p-ERK, p-CREB, and olig2. Furthermore, hippocampal oligodendrogenesis in stress-maladaptive mice was promoted by chronic treatment with flesinoxan. These findings suggest that 5-HT receptor activation may promote oligodendrogenesis and myelination via an ERK/CREB/BDNF signaling pathway in the hippocampus and reduces abnormal emotionality due to maladaptation to excessive stress.
我们之前的研究报道称，5-HT 受体激动剂 flesinoxan 可改善应激适应不良小鼠的异常情绪，此外，海马髓鞘的维持似乎有助于小鼠的应激适应。然而，5-HT 受体激活在应激适应不良情况下对髓鞘形成的影响及其潜在机制尚不清楚。在本研究中，我们使用 flesinoxan 来研究 5-HT 受体的激活是否可以通过作用于少突胶质细胞来保护应激适应不良小鼠的髓鞘蛋白，从而减轻异常的情绪反应。将小鼠暴露于重复的束缚应激中，每天 4 小时，持续 14 天作为应激适应不良模型。在每天暴露于束缚应激后，立即通过腹膜内给予 flesinoxan。在最后一次暴露于束缚应激后，通过洞板试验评估小鼠的情绪。通过 Western blot 评估海马中的脑源性神经营养因子（BDNF）、磷酸化细胞外信号调节激酶（p-ERK）、磷酸化 cAMP 反应元件结合蛋白（p-CREB）、髓鞘相关糖蛋白（MAG）、髓鞘碱性蛋白（MBP）和少突胶质细胞转录因子 2（olig2）的表达水平。通过免疫组织化学检查海马中的少突胶质细胞发生。慢性 flesinoxan 治疗抑制了洞板试验中应激适应不良小鼠头探入行为的减少。在这种情况下，海马中 MAG 和 MBP 的减少随着 BDNF、p-ERK、p-CREB 和 olig2 的增加而恢复。此外，慢性 flesinoxan 治疗促进了应激适应不良小鼠的海马少突胶质细胞发生。这些发现表明，5-HT 受体的激活可能通过 ERK/CREB/BDNF 信号通路促进海马中的少突胶质细胞发生和髓鞘形成，并减少过度应激适应不良引起的异常情绪。
