Vitamin D3 attenuates methamphetamine-induced oxidative stress, neurochemical alterations, and neuronal damage in male Wistar rats

Background/Objective Methamphetamine is a potent psychostimulant associated with severe neurotoxicity mediated by oxidative stress, neuroinflammation, metabolic dysfunction, and neuronal apoptosis. Vitamin D₃ has been reported to possess antioxidant and anti-inflammatory properties that may provide neuroprotective effects. This study evaluated the potential protective effects of vitamin D₃ against methamphetamine-induced neurotoxicity in rat brain tissue. Methods Twenty male Wistar rats were randomly divided into four groups (n = 5): control, methamphetamine-treated (10 mg/kg), vitamin D₃-treated (0.1 μg/kg), and methamphetamine plus vitamin D₃. Treatments were administered orally for 56 days. At the end of the experimental period, brain tissues were harvested for biochemical analyses, including oxidative stress markers, antioxidant defense parameters, neurotransmitter levels, metabolic enzymes, inflammatory markers, apoptotic indicators, and histopathological examination. Results Methamphetamine administration significantly increased oxidative stress markers and inflammatory mediators while reducing antioxidant defenses, neurotransmitter levels, and metabolic enzyme activities in brain homogenates. Caspase-3 activity was significantly elevated, indicating enhanced apoptotic signaling. Histopathological examination revealed vascular congestion and structural alterations in methamphetamine-treated animals. Co-administration of vitamin D₃ attenuated several of these biochemical alterations by reducing oxidative stress and inflammatory responses and improving antioxidant status and neurotransmitter levels, although some histological changes persisted. Conclusions Methamphetamine induces neurotoxicity through mechanisms involving oxidative stress, neuroinflammation, metabolic disruption, and apoptosis in brain tissue. Vitamin D₃ supplementation partially mitigates these adverse effects, suggesting its potential role as a neuroprotective agent against methamphetamine-induced neuronal damage.