Sequestration of oxidative is necessary but not sufficient enough to conclude dopaminergic neuroprotective efficacy of curcumin: Insights from ALSS Drosophila Parkinson disease model

Turmeric is a centuries-old ethnomedicine in Asia. Previously our laboratory demonstrated in the adult life stage-specific (ALSS) Drosophila model of Parkinsons disease (PD) that Curcumin (K)-mediated dopaminergic (DAergic) neuroprotection is absent in the transition stage of adult life during which late-onset neurodegenerative disorders like PD sets-in, suggesting its limitation as a therapeutic agent. The present study demonstrates that K can sequester the enhanced levels of brain oxidative stress (OS) during both adult life phases i.e. health and transition stages but confers neuroprotection only during the health phase. However, literature reviews illustrate that efficacy of supposed therapeutic agents was asserted by their ability to sequester OS in only young PD animal models. In this context, it is important to point out that despite encouraging results in animal models, therapeutic efforts to target the general state of OS failed to retard PD progression. To understand this paradigm, we further investigated ALSS regulation of molecular players in the brain of the ALSS fly PD model and discovered that K-mediated differential modulation of adaptive stress response through dFOXO contributes to health phase-specific neuroprotection. These observations suggest that apart from the study of OS markers; it is essential to understand the ALSS regulation of molecular players. The synergistic influence of OS and the ALSS dysfunctional molecular networks could be responsible for the DAergic neurodegeneration in PD. The insights suggest that sequestration of OS by a therapeutic agent is necessary, but inadequate to conclude its neuroprotective efficacy and push it to the next phase of preclinical/clinical evaluation.