Protecting the Cerebellum from Ketamine-Induced Injury: Neuroprotective Effects of N-Acetylcysteine in Rats

Addiction is a neuropsychiatric disorder characterised by compulsive substance use despite harmful consequences. Ketamine a dissociative anaesthetic increasingly misused among young people has become a global public health concern, necessitating the search for effective neuroprotective interventions. N-acetylcysteine (NAC) a glutathione precursor with antioxidant and anti inflammatory properties, has shown promise in mitigating substance-induced neurotoxicity. This study investigated the neuroprotective effects of NAC on ketamine induced cerebellar alterations in Wistar rats. Sixty adult Wistar rats (120–150 g) were randomly assigned to six groups. Group A received distilled water (control); Groups B and C received NAC (500 or 1000 mg/kg, orally) Group D received ketamine (15 mg/kg, intraperitoneally) while Groups E and F received ketamine followed by NAC (500 or 1000 mg/kg, respectively). Ketamine was administered for 10 days followed by NAC treatment from days 11 to 24. Behavioural assessments including open-field Y-maze, and catalepsy tests, were conducted on day 25. Animals were then euthanised for biochemical analyses of total antioxidant capacity (TAC) malondialdehyde (MDA), tumour necrosis factor-alpha (TNF-alpha), and interleukins IL-1 beta, IL-6, and IL-10. Cerebellar tissues were processed for histological evaluation. Ketamine exposure induced hyperlocomotion, increased rearing, working memory deficits, oxidative stress, and elevated pro-inflammatory cytokines, with a concomitant reduction in anti-inflammatory markers. NAC treatment at both doses significantly attenuated these behavioural and biochemical disturbances. Histological examination revealed marked cerebellar neurodegeneration, including Purkinje and granule cell loss, in ketamine-treated rats, whereas NAC particularly at 1000 mg/kg largely preserved cerebellar cytoarchitecture. In conclusion, NAC exerted significant neuroprotective effects against ketamine-induced behavioural, biochemical, and structural cerebellar damage in rats, supporting its potential therapeutic relevance in mitigating ketamine-related neurotoxicity.