Adult Life Phase-Specific Dopaminergic Neuroprotective Efficacy of Curcumin is through Variant Modulation of Brain Dopamine Metabolism: Insights from ALSS Drosophila Model of Parkinson’s Disease

Abstract

Epidemiological studies suggest a strong link between exposure to environmental toxins and onset of Parkinson’s disease (PD). Our laboratory has developed an adult life stage-specific (ALSS) Drosophila model of sporadic PD which is critical to screen small molecules and identify molecular targets of dopaminergic (DAergic) neuroprotection for late-onset neurodegenerative diseases (NDD) such as PD. Nutraceutical curcumin (CU) has been a time-tested ingredient in the Asian kitchen, traditional medicine and has been employed in 450 clinical trials. Exposure to Paraquat (PQ) induces mobility defects in the health stage (point of time when there is no natural diseases) and transition stage (time period wherein about 10% deaths occur) of adult Drosophila; whereas CU ameliorates the deficits only during early health span but fails during late health and transition phases. Probing the whole fly brain using anti-tyrosine hydroxylase (anti-TH) antibodies, for PQ-mediated dopamine (DA) neurodegeneration illustrates that it does not cause loss of DA neurons per se. However, it leads to DA “neuronal dysfunction” (diminished levels of rate-limiting enzyme in dopamine synthesis- TH) and CU rescues the neuronal dysfunction only during the early health span but fails to mitigate the DA neuronal pathology during the transition phase of adult life. Genotropic nutraceutical CU replenishes the diminished levels of brain-specific DA and its metabolites DOPAC and HVA during the adult health phase (HP) and fails to do so in the adult transition phase (TP), suggesting its life phase-specific dopaminergic neuroprotective efficacy is mediated through differential modulation of perturbations in brain dopamine metabolism. The present study suggests the limitation of CU as a therapeutic strategy for PD and emphasizes the necessity and importance of screening putative neuroprotective small molecules for late onset NDD such as PD in life phase matched animal models during which the disease sets in.