Yenisetti, S. C. | Search bioRxiv

bioRxiv2025

Differential regulation of brain-specific molecular pathways is the reason for curcumin adult life-phase specific DAergic neuroprotection: Insights from ALSS Drosophila model of Parkinson disease

AbstractCurcumin (CU), a bioactive compound of turmeric, has been put forward as a "golden molecule" due to its anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, and anti-cancer ability, as proven by research conducted over the decade and more. Our laboratory, developed an adult life stage specific (ALSS) Drosophila model of sporadic Parkinsons disease (PD), and for first time demonstrated that dopaminergic (DAergic) neuroprotective efficacy of curcumin is limited to health phase viz. adult-young life stage and is absent during transition phase viz. adult senior life stages when PD set in. This observation suggests the limitation of curcumin as a therapeutic agent for late-onset disorders like PD. Further, our laboratory also demonstrated that despite curcumins ability to sequester oxidative stress during both the adult life stages, neuroprotection and brain dopamine replenishment is granted only in health stages but not in a vulnerable transition stage, which prompted to put forward the hypothesis that the molecular target(s) of CU, may be absent or inadequate in the transition stage of aging brain. With this insight, the current study was implemented to analyse the life stage-specific differential regulation of multiple molecular players of neuro-integral pathways in brain of ALSS Drosophila model of PD with curcumin intervention. It is discovered that curcumin-mediated health phase-specific neuroprotection underlies the correction of an altered expression of 1. dFOXO, GADD45, Puc of Bsk-dFOXO stress response pathway, 2. Mfn2 of Mitochondrial dynamics 3. CncC, GCLC, Prx 2540 -1,2, Jafrac1, Prx3 of Phase II antioxidant defense system pathway. Further, it is discovered that significant aging-associated naturally altered expression of certain molecular targets exists, that may contribute to the limitation of curcumins DAergic neuroprotective efficacy during the adult-transition stage. This knowledge will help in developing altered therapeutic strategies for PD as molecular targets of curcumin are conserved among fly, mice and human.

neuroscience↗

bioRxiv2024

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.

neuroscience↗