Cerebellar Neurotoxicity from Ketamine Exposure: Protective Impact of N-Acetylcysteine in a Rodent Model

Samson Oluwamuyiwa Alade¹, Abiodun Moses Arojojoye ¹, Joshua Aduragbemi Ajao², Akinsanmi Festus Akinsehinwa¹, Opeyemi Ojo Famuyide¹, Olakunle James Onaolapo³, Adejoke Yetunde Onaolapo⁴

1. Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria 
2. Department of Pharmacology and Therapeutics, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria 
3. Behavioural Neuroscience and Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria, ORCID: 0000-​0003-2142-6046 ojonaolapo@lautech.edu.ng  
4. Behavioural Neuroscience and Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria, ORCID: 0000-0001-7126-7050, ayonaolapo@lautech.edu.ng 

 ABSTRACT 

Addiction is a neuropsychiatric disorder characterized by the compulsive use of illicit substances, including ketamine, despite harmful consequences. Ketamine, an anaesthetic increasingly misused among youths, has become a global concern, prompting the search for protective interventions such as N-acetylcysteine (NAC). This study investigated the potential neuroprotective effects of NAC on ketamine-induced cerebellar alterations in Wistar rats. Sixty adult Wistar rats (120–150 g) were divided into six groups. Group A received distilled water (control); groups B and C received NAC (500 and 1000 mg/kg orally); group D received ketamine (15 mg/kg, i.p.); while groups E and F received ketamine (15 mg/kg, i.p.) with NAC (500 and 1000 mg/kg, respectively). Ketamine was administered for 10 days, followed by NAC from days 11–24. Behavioural assessments (open field, Y maze and catalepsy tests) were conducted on day 25, after which animals were euthanised for biochemical analyses, including Total Antioxidant Capacity (TAC), Malondialdehyde (MDA), Tumour Necrosis Factor-α (TNF-α), and Interleukin (IL)-6, -10, and -1β. The Cerebellum was processed for general histology and microscopic evaluation. Ketamine exposure caused hyperlocomotion, increased rearing, memory deficits, oxidative stress, and elevated pro-inflammatory cytokines, with a concurrent reduction in anti-inflammatory markers. NAC at both doses ameliorated these effects. Histological examination showed neuronal degeneration and loss of Purkinje and granule cells in ketamine-treated rats, while NAC, particularly at 1000 mg/kg preserved cerebellar cytoarchitecture. In conclusion, NAC exhibited significant neuroprotective effects against ketamine-induced behavioural, biochemical, and structural cerebellar damage in rats. Further research is warranted to explore its therapeutic relevance in humans. 

KEYWORDS: Antioxidant, Neuroinflammation, Neuroprotection, N-methyl-D-aspartate Antagonist