Targeting Glial Glycolysis with EGCG Alleviates Parkinson's Disease in a PINK1 mutant Drosophila Model.

ETHNOPHARMACOLOGICAL RELEVANCE: Camellia sinensis (L.) Kuntze (Theaceae), commonly known as green tea, has been traditionally utilized in Traditional Chinese Medicine (TCM) as a neurotonic to clear the mind, alleviate fatigue, and counteract aging-related cognitive decline. Epigallocatechin-3-gallate (EGCG), its principal bioactive polyphenol, exhibits well-documented neuroprotective properties, providing a modern pharmacological rationale for its traditional botanical application in managing neurological disorders such as Parkinson's disease (PD). AIM OF THE STUDY: While the neuroprotective effects of EGCG against PD are known, whether its therapeutic efficacy involves the modulation of brain glucose metabolism remains largely unexplored. This study aimed to investigate the specific alterations of glucose metabolism in a PINK1 mutant Drosophila model of PD and to elucidate the role of EGCG in regulating glial glycolysis and subsequent neuroinflammation. MATERIALS AND METHODS: A Drosophila melanogaster model of PD carrying a PINK1 mutation was utilized. The metabolic shift in the brain was evaluated using quantitative PCR and biochemical assays. Pharmacological interventions (using EGCG, the glycolysis inhibitor oxamate, and exogenous lactate) and bidirectional genetic manipulations (glia-specific knockdown or overexpression of lactate dehydrogenase LDH via the Repo-GAL4 driver) were employed. Treatment outcomes were comprehensively assessed through behavioral assays (climbing and locomotor activity tracking), immunohistochemical quantification of dopaminergic neurons, and transcriptional analysis of inflammatory markers. RESULTS: We identified a prominent metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis in the PD Drosophila brain, accompanied by aberrant lactate accumulation. Pharmacological or genetic inhibition of this glial glycolysis alleviated both neuronal and behavioral deficits. Conversely, overactivation of the glial glycolytic pathway (LDH overexpression) exacerbated these phenotypes and triggered neuroinflammation. Crucially, pharmacological intervention with EGCG effectively downregulated the expression of key glycolytic enzymes, restored OXPHOS capacity, significantly suppressed glial-driven neuroinflammation, and attenuated a broad spectrum of PD-associated impairments. CONCLUSIONS: This study shows that EGCG, derived from Camellia sinensis (L.) Kuntze, alleviates PD disease symptoms by modulating glial glucose metabolism and inhibiting the glycolysis-lactate-neuroinflammation axis. These findings provide a novel mechanistic basis for the neuroprotective properties of tea polyphenols. Ultimately, this work provides modern pharmacological validation for the traditional use of green tea in mitigating age-related neurological decline, highlighting glial metabolic modulation by EGCG as a promising therapeutic strategy for neurodegenerative disorders.