Chronic exposure of homocysteine in mice contributes to dopamine loss by enhancing oxidative stress in nigrostriatum and produces behavioral phenotypes of Parkinson’s disease

Abstract

Increased homocysteine (Hcy) level has been implicated as an independent risk factor for various neurological disorders, including Parkinson’s disease (PD). Hcy has been reported to cause dopaminergic neuronal loss in rodents and causes the behavioral abnormalities. This study is an attempt to investigate molecular mechanisms underlying Hcy-induced dopaminergic neurotoxicity after its chronic systemic administration. Male Swiss albino mice were injected with different doses of Hcy (100 and 250 mg/kg; intraperitoneal) for 60 days. Animals subjected to higher doses of Hcy, but not the lower dose, produces motor behavioral abnormalities with significant dopamine depletion in the striatum. Significant inhibition of mitochondrial complex-I activity in nigra with enhanced activity of antioxidant enzymes in the nigrostriatum have highlighted the involvement of Hcy-induced oxidative stress. While, chronic exposure to Hcy neither significantly alters the nigrostriatal glutathione level nor it causes any visible change in tyrosine hydroxylase-immunoreactivity of dopaminergic neurons. The finding set us to hypothesize that the mild oxidative stress due to prolonged Hcy exposure to mice is conducive to striatal dopamine depletion leading to behavioral abnormalities similar to that observed in PD.

Highlights

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  Chronic intraperitoneal Hcy injection causes parkinsonian like motor abnormalities.

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  Hcy injection caused complex-I inhibition in nigra and striatal dopamine depletion.

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  Hcy injection caused enhanced activity of antioxidant enzymes in nigrostriatum.

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  Hcy-induced mild oxidative stress is not sufficient to alter GSH and TH.