Nutritional Protection Against Antipsychotic-Related Brain Injury: Combined Omega-3 and Vitamin E Effects on the Cerebellum

Abstract

Haloperidol is a widely used typical antipsychotic for schizophrenia but is associated with neurotoxic effects mediated by oxidative stress, neuroinflammation, and neuronal disruption. Omega-3 fatty acids possess anti-inflammatory and neuroprotective properties, while vitamin E is a potent lipid-soluble antioxidant. Although each has shown protective effects individually, their combined efficacy against haloperidol-induced cerebellar toxicity remains poorly understood. This study investigated the neuroprotective effects of co-administered omega-3 fatty acids and vitamin E on haloperidol-induced behavioural, biochemical, and histological alterations in the rat cerebellum. Sixty male Wistar rats (80-100 g) were randomly assigned to six groups (n = 10). Control animals received a standard diet and olive oil, while treatment groups received omega-3 fatty acids (500 mg/kg of feed), vitamin E (10 IU/kg, orally), haloperidol (1 mg/kg, intraperitoneally), or their combinations for 28 days. Haloperidol-treated rats showed significant reductions in body weight, feed intake, locomotor activity, rearing, and spatial working memory, alongside increased grooming behaviour and catalepsy (p < 0.05). These behavioural deficits were markedly attenuated by omega-3 fatty acids and vitamin E, particularly when administered together. Haloperidol also increased malondialdehyde and pro-inflammatory cytokines (IL-1{beta}, IL-6, TNF-) while reducing total antioxidant capacity, indicating heightened oxidative stress and inflammation. Co-treatment with omega-3 fatty acids and vitamin E significantly reversed these biochemical alterations. Histological analysis revealed pronounced cerebellar neuronal degeneration in haloperidol-only rats, whereas cerebellar architecture was largely preserved in co-treated groups. Overall, combined omega-3 fatty acid and vitamin E supplementation provided significant neuroprotection against haloperidol-induced cerebellar toxicity and motor impairment, supporting their potential role as adjunct therapies in reducing antipsychotic-related neurodegeneration.