Age specific neuroprotection of curcumin is through differential modulation of brain dopamine metabolism: Insights from Drosophila model of Parkinson’s disease

Abstract Epidemiological studies suggest a strong linkage between exposure to environmental toxins and onset of Parkinson’s disease (PD). Rotenone is a widely used pesticide and known inhibitor of mitochondrial complex I, that has been shown to induce Parkinsonian phenotypes in various animal models. Our laboratory has developed a rotenone mediated ALSS Drosophila model of PD which is critical to screen small molecules and identify molecular targets of dopaminergic neuroprotection for late-onset neurodegenerative diseases such as PD. Using negative geotaxis assay, qualitative and quantitative analysis of dopaminergic neurons by fluorescence microscopy and further quantifying the levels of dopamine and its metabolites by HPLC, we have assessed the neurodegeneration under PD induced conditions and neuroprotection by employing curcumin in Drosophila model of PD. Exposure to rotenone induces mobility defects in health and transition phase of adult Drosophila; whereas curcumin ameliorates the deficits only during early health phase but fail during late health and transition phases. Probing the whole fly brain using anti-tyrosine hydroxylase antibodies, for rotenone mediated dopamine neurodegeneration illustrates that it does not cause loss of dopaminergic neurons per se. However, it leads to dopaminergic “neuronal dysfunction” (diminished levels of rate limiting enzyme of dopamine synthesis) and curcumin rescues the neuronal dysfunction only during the early health phase but fails to mitigate the dopamine neuronal pathology during the transition phase of adult life. Genotropic nutraceutical curcumin replenishes the diminished levels of brain specific dopamine and its metabolites DOPAC and HVA during adult early health phase and fails to do so in adult transition phase, suggesting that the life phase-specific dopaminergic neuroprotective efficacy is mediated through differential modulation of perturbations in brain dopamine metabolism. Present study suggests the limitation of curcumin as a therapeutic agent for PD and emphasizes the necessity of screening putative neuroprotective small molecules for late onset neurodegenerative diseases such as PD in life phase matched animal models during which the disease sets in.