Haj-Mirzaian Arya, Amiri Shayan, Amini-Khoei Hossein, Rahimi-Balaei Maryam, Kordjazy Nastaran, Olson Carl O, Rastegar Mojgan, Naserzadeh Parvaneh, Marzban Hassan, Dehpour Ahmad Reza, Hosseini Mir-Jamal, Samiei Elika, Mehr Shahram Ejtemaei
Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran; Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Brain Res Bull. 2016 Jun;124:150-63. doi: 10.1016/j.brainresbull.2016.04.018. Epub 2016 Apr 26.
Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of tropisetron (1mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex.
托烷司琼是一种广泛用作止吐药的5-羟色胺3（5-HT3）受体拮抗剂，据报道它对情绪障碍有积极作用。青春期是大脑发育的关键时期，在此期间遭受慢性应激与抑郁症的发生高度相关。在本研究中，我们发现4周的幼年社会隔离应激（SIS）会引发雄性小鼠的抑郁样行为，这与皮质区域线粒体功能紊乱和一氧化氮过量产生有关。在本研究中，托烷司琼（5毫克/千克）逆转了SIS对雄性小鼠的负面行为影响。我们发现托烷司琼的作用是通过减轻诱导型一氧化氮合酶（iNOS）对线粒体活性的负面作用来介导的。给予氨基胍（特异性iNOS抑制剂，20毫克/千克）增强了托烷司琼（1毫克/千克）对SIS的保护作用。此外，L-精氨酸（一氧化氮前体，100毫克/千克）消除了托烷司琼的积极作用。这些结果增加了我们对线粒体功能在抑郁症病理生理学中的关键作用的认识，并突出了5-HT3受体在青春期心理社会应激反应中的作用。最后，我们观察到托烷司琼通过降低大脑皮质中硝化系统的活性来减轻线粒体功能障碍。
