Iwai Takashi, Mishima Rei, Hirayama Shigeto, Nakajima Honoka, Oyama Misa, Watanabe Shun, Fujii Hideaki, Tanabe Mitsuo
Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Clin Med. 2024 Jan 21;13(2):608. doi: 10.3390/jcm13020608.
The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress.
δ阿片受体（DOR）反向激动剂已被证明可改善遭受束缚应激的小鼠的学习和记忆障碍。在此，我们研究了新型DOR反向激动剂SYK - 623对丙咪嗪治疗抵抗性抑郁症小鼠模型行为、免疫组织化学和生化异常的影响。雄性ddY小鼠每天接受促肾上腺皮质激素（ACTH）治疗并结合慢性轻度应激暴露（ACMS）。在ACMS之前，每天一次给予SYK - 623、丙咪嗪或赋形剂。三周后，ACMS小鼠在Y迷宫试验中表现出学习和记忆受损，在强迫游泳试验中不动时间增加。SYK - 623而非丙咪嗪显著抑制了ACMS引起的行为异常。基于海马体的荧光免疫组织化学分析，ACMS导致星形胶质细胞和新生神经元减少，类似于在抑郁症患者死后大脑中观察到的报道结果。此外，在神经发生中起关键作用的小白蛋白阳性GABA神经元数量在海马体中减少，蛋白质印迹分析显示谷氨酸脱羧酶蛋白水平降低。除星形胶质细胞减少外，这些变化均被SYK - 623抑制。因此，SYK - 623减轻了慢性应激引起的行为异常和神经发生紊乱。
