Role of the mitochondrial oxidative stress-inflammation-apoptosis-Sirtuin 1 integrative network in the brain of D-galactose-induced aging mice model: Multi-protection role of tropisetron

Background: Tropisetron is gaining attention of researchers for its neuroprotective properties in aging-related degenerative disorders. Due to tropisetron’s effect in reversing oxidative stress, inflammation and apoptosis processes, we performed the current study to evaluate the neuroprotective effect of tropisetron on D-galactose-induced aging mice model in brain. Materials and methods: Aging was induced by D-galactose (100 mg/kg/day) subcutaneously injected to male mice for 6 weeks. Tropisetron was simultaneously administered once a day intraperitoneally at three various doses (1, 3, 5 mg/kg). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide and pro-inflammatory cytokines levels including tumor necrosis factor-α and interleukin-6 were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and aging-related gene (Sirtuin 1) were determined by Real Time PCR method. In addition, assessment of histopathological alterations were conducted. Results: Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and inflammatory mediators overproduction induced by DG in the brain tissue. In addition, co-treatment with tropisetron suppressed DG-induced apoptosis via upregulation of Bcl-2 gene expression and Bax gene expression downregulation. Additionally, tropisetron was found to significantly elevate sirtuin 1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. Conclusion: In sum, tropisetron suppressed the aging process in brain via a combination of reversing oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and regulating the aging-related gene expression. Therefore, it can be a potential neuroprotective drug in neurodegenerative diseases occurring in aging process.

Keywords:

Aging , Tropisetron , D-galactose , Brain , Neurotoxicity , Sirtuin 1