Novel protective mechanisms of antidepressants against 3-nitropropionic acid induced Huntington's-like symptoms: a...

Huntington's disease (HD) is characterized by progressive degeneration of neurons in the striatum, cortex and other parts of the brain, causing motor and cognitive dysfunction. 3-Nitropropionic acid (3-NP) is a well-known mycotoxin that significantly induces motor dysfunction in animals. Studies suggested the involvement of oxidative stress and nitric oxide mechanisms in HD pathogenesis. Clinical reports have also indicated the neuroprotective potential of antidepressants. Therefore, the present study has been designed to elucidate and compare the mechanistic role of different antidepressants (sertraline, venlafaxine, imipramine and trazodone) and their interaction with nitric oxide modulators if any, against 3-NP-induced neurotoxicity. Systemic 3-NP (10 mg/kg) administration for 14 days significantly reduced locomotor activity, body weight, motor coordination, oxidative defense and impaired mitochondrial complex enzyme activities in the striatum. Sertraline, venlafaxine, imipramine and trazodone treatments significantly improved behavioral, oxidative defense and mitochondrial complex enzyme activities as compared with the 3-NP-treated group. Systemic L-arginine (50 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly attenuated their protective effect. Similarly, L-nitro-arginine methyl ester (L-NAME) (10 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly potentiated their protective effects which were significant as compared with their effect alone, respectively. The results of the present study suggest that a nitric oxide mechanism might be involved in their protective effect against 3-NP-induced neurotoxicity.