Seo Mi Kyoung, Lee Chan Hong, Cho Hye Yeon, Lee Jung Goo, Lee Bong Ju, Kim Ji Eun, Seol Wongi, Kim Young Hoon, Park Sung Woo
Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea.
Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea; Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Republic of Korea; Department of Health Science and Technology, Graduate School of Inje University, Busan, Republic of Korea.
Neuropharmacology. 2014 Apr;79:222-33. doi: 10.1016/j.neuropharm.2013.11.019. Epub 2013 Dec 1.
The alteration of hippocampal plasticity has been proposed to play a critical role in both the pathophysiology and treatment of depression. In this study, the ability of different classes of antidepressant drugs (escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine) to mediate the expression of synaptic proteins and dendritic outgrowth in rat hippocampal neurons was investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. Postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP) levels were evaluated using Western blot analyses. Additionally, dendritic outgrowth was examined to determine whether antidepressant drugs affect the dendritic morphology of hippocampal neurons in B27-deprived cultures. Escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine significantly prevented B27 deprivation-induced decreases in levels of PSD-95, BDNF, and SYP. Moreover, the independent application of fluoxetine, paroxetine, and sertraline significantly increased levels of BDNF under normal conditions. All antidepressant drugs significantly increased the total outgrowth of hippocampal dendrites under B27 deprivation. Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PKA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PKA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs.
海马可塑性的改变被认为在抑郁症的病理生理学和治疗中都起着关键作用。在本研究中，研究了不同类别的抗抑郁药物（艾司西酞普兰、氟西汀、帕罗西汀、舍曲林、丙咪嗪、反苯环丙胺和噻奈普汀）在由B27缺乏诱导的毒性条件下介导大鼠海马神经元中突触蛋白表达和树突生长的能力，B27缺乏会导致海马细胞死亡。使用蛋白质免疫印迹分析评估突触后密度蛋白95（PSD - 95）、脑源性神经营养因子（BDNF）和突触素（SYP）水平。此外，检查树突生长以确定抗抑郁药物是否影响B27缺乏培养物中海马神经元的树突形态。艾司西酞普兰、氟西汀、帕罗西汀、舍曲林、丙咪嗪、反苯环丙胺和噻奈普汀显著预防了B27缺乏诱导的PSD - 95、BDNF和SYP水平降低。此外，在正常条件下单独应用氟西汀、帕罗西汀和舍曲林显著增加了BDNF水平。所有抗抑郁药物在B27缺乏条件下均显著增加了海马树突的总生长。钙/钙调蛋白激酶II（CaMKII）的特异性抑制剂KN - 93、蛋白激酶A（PKA）的特异性抑制剂H - 89或磷脂酰肌醇3 -激酶（PI3K）的特异性抑制剂LY294002显著降低了抗抑郁药物对树突生长的影响，而仅噻奈普汀对PI3K抑制剂有此作用。综上所述，这些结果表明某些抗抑郁药物可以提高海马神经元中的突触蛋白水平并促进树突生长。此外，对树突生长的影响可能需要CaMKII、PKA或PI3K信号通路。观察到的效应可能归因于抗抑郁药物的长期治疗。
