Nitric oxide and dopamine metabolism converge via mitochondrial dysfunction in the mechanisms of neurodegeneration in Parkinson's disease

The molecular mechanisms underlying the degeneration and neuronal death associated with Parkinson's disease (PD) are not clearly understood. Several pathways and models have been explored in an overwhelming number of studies. Overall, from these studies, mitochondrial dysfunction and nitroxidative stress have emerged as major contributors to degeneration of dopaminergic neurons in PD. In addition, an excessive or inappropriate production of nitric oxide (center dot NO) and an abnormal metabolism of dopamine have been independently implicated in both processes. However, the participation of center dot NO in reactions with dopamine relevant to neurotoxicity strongly suggests that dopamine or its metabolites may be potential targets for center dot NO, affecting the physiological chemistry of both, center dot NO and dopamine. In this short review, we provide a critical and integrative appraisal of the nitric oxide-dopamine pathway we have previously suggested and that might be operative in PD. This pathway emphasizes a connection between abnormal dopamine and center dot NO metabolism, which may potentially converge in an integrated mechanism with toxic cellular outcomes. In particular, it encompasses the synergistic interaction of center dot NO with 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, leading to dopaminergic cell death via mechanisms that involve mitochondrial dysfunction, gluthathione depletion and nitroxidative stress.