Dose-Dependent Effects of Genistein on Motor Function and Neurodegeneration in a 6-OHDA Rat Model of Hemi-Parkinsonism

Background: Dopaminergic neuronal depletion, Lewy body formation, mitochondrial dysfunction, increased oxidative stress, and decreased glutathione levels have been identified as primary causes of dopaminergic degeneration in Parkinson's disease (PD). Objectives: This study evaluates the dose-dependent effects of genistein on motor function, oxidative stress, and neuroinflammation in a 6-OHDA rat model of Parkinsonism. Methods: This experimental study used the 6-OHDA-induced rat model of Parkinsonism. Adult male Wistar rats (200 - 280 g; n = 32) were divided into four groups: Sham-operated, 6-OHDA-injected, 6-OHDA + genistein (50 mg/kg), and 6-OHDA + genistein (500 mg/kg). Rotational behavior was assessed following apomorphine injection. Neurodegeneration was evaluated using Nissl staining, and markers of oxidative stress (lipid peroxidation, superoxide dismutase) and inflammation (TNF-α) were measured spectrophotometrically. Results: Genistein at 50 mg/kg significantly attenuated turning behavior, neurodegeneration, and oxidative stress compared to the lesioned group (P < 0.0001). Superoxide dismutase activity increased to 4.5 ± 0.7 units/mg protein, and malondialdehyde levels decreased to 6.5 ± 0.4 nmol/mg in the 50 mg/kg group. Conversely, 500 mg/kg genistein exacerbated oxidative stress and neurotoxicity. TNF-α levels were reduced significantly in the 50 mg/kg group (P < 0.0001), while the higher dose failed to produce similar effects. Conclusions: Genistein at 50 mg/kg exhibits neuroprotective effects, mitigating oxidative stress and neuroinflammation. However, a higher dose (500 mg/kg) exacerbates neurotoxic effects. Dose optimization is crucial for therapeutic applications in neurodegenerative diseases.