Pelargonium graveolens Attenuates Rotenone-Induced Parkinson's Disease in a Rat Model: Role of MAO-B Inhibition and In Silico Study.

Abstract

Parkinson's disease (PD), the second most common neurodegenerative condition, is primarily characterized by motor dysfunctions due to dopaminergic neuronal loss in the Substantia Nigra (SN), with oxidative stress playing a significant role in its progression. This study investigates the neuroprotective potential of Pelargonium graveolens (Thunb.) L'Hér leaves in a rotenone-induced PD rat model. The total ethanolic extract and its fractions, obtained via Diaion HP-20 column chromatography, were evaluated for monoamine oxidase-B (MAO-B) inhibition in vitro. The 50% methanol fraction (PG50) demonstrated the highest MAO-B inhibition (IC₅₀ 5.26 ± 0.12 µg/ml) compared to the reference drug selegiline (IC₅₀ 0.021 ± 0.003 µg/ml). In a rotenone-induced PD rat model, PG50 (100 mg/kg, p.o.) alleviated motor deficits (assessed via the wire hanging test), and restored norepinephrine, dopamine, and serotonin levels. PG50 and L-dopa reduced α-synuclein levels by 367.60% and 377.48%, respectively. Oxidative balance was restored with increased glutathione (23.12%) and decreased malondialdehyde (164.19%) in brain tissues. PG50 significantly reduced serum TNF-α (572.79%) and IL-6 (70.84%) levels, and improved succinate dehydrogenase (14.47%) and lactate dehydrogenase (7.74%) activities in brain tissues. Histopathological alterations in the SN were also ceased. UPLC-MS/MS analysis identified 61 metabolites, including 32 flavonoids, 13 phenolic acids, 7 coumarins, 5 phenolic glycosides, and 4 dicarboxylic acids, with in silico docking showing strong MAO-B binding by methoxylated flavonoids like methoxyluteolin dimethyl ether (docking score: - 8.0625 kcal/mol), surpassing that of safinamide (- 8.2615 kcal/mol). These findings suggest that P. graveolens holds promise as a neuroprotective agent against rotenone-induced PD.