Aegeline-rich Aegle marmelos Leaf Extract Mitigates Parkinson’s Disease Pathology associated with Mitochondrial ROS generation and α-SynucleinPhosphorylation

Introduction: Aegle marmelos is a medicinal plant used in traditional South Asian medicine. It is known to be a rich source of bioactive compounds exhibiting various therapeutic properties. Aegeline is one of the major active constituents with reported neuroprotective activity. Herein, we evaluated the efficacy of aegeline-rich A. marmelos extract for its efficacy in a cellular model of Parkinsonism. Methods: Sequential extraction of A. marmelos leaves was performed to obtain aegeline-rich extract (AMCE), which was characterized using RP-HPLC. Antioxidant and iron-chelation activities of AMCE were assessed using FRAP and hydroxyl radical scavenging assays. Cytotoxicity, mitochondrial ROS levels, and protective effects against MPP⁷ and rotenone-induced toxicity were studied using differentiated SH-SY5Y neuronal cells. The effects of AMCE and aegeline on α-synuclein phosphorylation were evaluated in wild-type and A53T mutant α-synucleinoverexpressing SH-SY5Y neuronal cells. Results: AMCE exhibited concentration-dependent antioxidant and iron-chelating activities, which were significantly higher than pure aegeline. Both AMCE and aegeline were non-toxic up to 5 μg/mL. They also showed significant neuroprotective effects upto 82%. AMCE completely inhibited mitochondrial ROS production at 10 μg/mL, while aegeline showed partial inhibition. Pretreatment with either AMCE or aegeline significantly reduced α-synuclein phosphorylation in both wild-type and A53T mutants. Discussion: The findings of the present study suggest that both aegeline and AMCE are promising candidates for therapeutic development against Parkinson’s disease. However, AMCE showed superior activity compared to aegeline alone, presumably due to the synergistic effect of other phytochemicals present in it. These in vitro findings should be further validated in animal models of Parkinson’s disease. Conclusion: Aegeline-rich extract, AMCE, exhibits multifunctional neuroprotective effects, including antioxidant activity, iron-chelating ability, and inhibition of α-synuclein phosphorylation.