Oleanolic Acid as a Therapeutic Agent in Drosophila melanogaster Model of Lead-induced Alpha-synucleinopathies

Alpha-synucleinopathy, characterized by the abnormal clumping of alpha-synuclein, is associated with neurodegenerative conditions like Parkinson's disease. Lead, a widespread environmental contaminant, intensifies oxidative stress and promotes alpha-synuclein aggregation. Oleanolic acid (OA), a biologically active triterpenoid, is recognized for its antioxidant and anti-inflammatory qualities, yet its effectiveness against lead-induced neurotoxicity remains largely unexplored. This research investigated the protective capacity of oleanolic acid against lead-triggered alpha-synucleinopathies within a Drosophila melanogaster model. Drosophila melanogaster (Harwich strain, 1 -3 days old) were initially subjected to oral exposure of lead nitrate (10, 20, and 30 ppm) and oleanolic acid (50, 100, and 200 µM) under controlled conditions for 14-day survival assessments. Subsequently, oleanolic acid (100 µM) was selected to evaluate its therapeutic impact on lead (10 ppm)-induced alpha-synucleinopathies in D. melanogaster following 7 days of oral administration. Neurobehavioral tests, including crawling, climbing, and reproductive rates, were used to assess impairments in locomotion and development. Biochemical analyses quantified oxidative stress markers, enzyme activities, and antioxidant levels. Histological and immunohistochemical examinations were conducted to evaluate brain morphology and alpha-synuclein aggregation. The findings indicated that lead exposure significantly diminished survival, locomotor activity, and reproductive success. Biochemical indicators revealed elevated oxidative stress, decreased antioxidant levels, and increased enzymatic dysfunction. Histological studies demonstrated extensive neurodegeneration, while immunostaining confirmed alpha-synuclein aggregation. Conversely, OA treatment alleviated lead-induced effects, leading to improved survival, enhanced motor functions, and better reproduction. OA also re-established oxidative balance, reduced alpha-synuclein aggregation, and maintained brain histology. Oleanolic acid exhibits neuroprotective attributes by mitigating lead-induced alpha-synucleinopathies.

Key Words: alpha-synucleinopathies, oleanolic acid, neuronal dysfunction, Drosophila melanogaster, Lewy bodies