Abstract
Background/Objectives: Rotenone (RT)-induced neurotoxicity is widely used to model Parkinsonism-like nigrostriatal injury and recapitulates several PD-relevant pathological features, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and dopaminergic neurochemical disturbance. Loganin (LG), an iridoid glycoside isolated from Cornus officinalis, has been reported to possess antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties. However, its protective effects in a unilateral stereotaxic RT lesion model have not been fully elucidated. This study aimed to investigate the neuroprotective potential of LG against RT-induced Parkinsonism-like pathology in rats and to explore the possible involvement of antioxidant-related signaling mechanisms. Methods: Adult male Wistar rats were randomly assigned to twelve experimental groups (n = 8/group), including control, sham, RT, sham + LG, RT + LG, RT + trigonelline (TG) + LG, and RT + selegiline (SL). RT was stereotaxically injected once into the right substantia nigra pars compacta (SNpc) on Day 0 to induce unilateral nigrostriatal injury. LG was administered orally once daily from Day 1 to Day 21 at doses of 3, 10, and 30 mg/kg. TG was given intraperitoneally 30 min before LG treatment, while SL served as a reference antiparkinsonian drug. Behavioral assessments and biochemical analyses were conducted to evaluate motor dysfunction, oxidative and nitrosative stress, endogenous antioxidant status, mitochondrial dysfunction, inflammatory and apoptotic responses in the SNpc, and striatal catecholamine disturbances. Results: RT lesioning produced significant motor deficits, oxidative and nitrosative stress, depletion of endogenous antioxidant defenses, mitochondrial dysfunction, inflammatory and apoptotic activation in the SNpc, and abnormalities in striatal catecholamine levels. LG treatment significantly attenuated these pathological changes, with more pronounced protective effects observed at 10 and 30 mg/kg. Co-administration of TG partially weakened the beneficial effects of LG, suggesting the possible involvement of antioxidant defense-related signaling while not providing direct proof of a single pathway. SL also ameliorated RT-induced behavioral and biochemical abnormalities. Conclusions: These findings suggest that LG confers multi-target neuroprotective effects against RT-induced Parkinsonism-like features in rats. The protective actions of LG were associated with attenuation of oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and catecholaminergic disturbances. Because the pathway analysis remains pharmacological and indirect, additional studies using direct molecular validation are warranted before LG can be considered a disease-modifying candidate for PD-related neurodegeneration.
