Human-dose equivalent 5-fluorouracil triggers a pathophysiological cascade of neuroinflammation, cortical remodeling, and behavioural disruption in Wistar rats

 Anthony Tope Olofinnade¹, Joshua Aduragbemi Ajao², Akinsanmi Festus Akinsehinwa³, Olakunle James Onaolapo^4*, Adejoke Yetunde Onaolapo^5*

1. Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Clinical Sciences, College of Medicine, Lagos State University, Ikeja, Lagos State. anthony.olofinnade@lasucom.edu.ng 
2. Department of Pharmacology and Therapeutics, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria 
3. Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria 
4. 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 
5. Behavioural Neuroscience and Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria, ORCID: 0000-0001-7126-705, ayonaolapo@lautech.edu.ng

ABSTRACT 

5-Fluorouracil (5-FU) is an antimetabolite widely used in cancer chemotherapy. Despite its central role in many anticancer regimens information on its potential effects on the central nervous system (CNS) remains limited. This study investigated the effects of human dose equivalent 5-FU on the cerebral cortex of rats. Fifty male rats were randomly assigned into five groups (n=10). The control group received intraperitoneal (i.p) saline, while four experimental groups received i.p 5-FU at 12.5 25 50 or 100 mg/kg body weight. Saline or 5-FU was administered for four consecutive days, followed by alternate-day dosing until day 12. Behavioural assessments were conducted and animals were sacrificed 24 hours after the final test. Cortical tissues were analysed using biochemical assays histology and immunohistochemistry. 5-FU administration caused dose-dependent decreases in body weight food intake and locomotor activity. Treated rats also showed impaired spatial working memory and reduced time spent in the open arms of the elevated plus maze. Biochemically 5-FU significantly increased cortical malondialdehyde and tumor necrosis factor-alpha levels while total antioxidant capacity and interleukin-10 levels decreased. Histological analysis revealed progressive disruption of cortical cytoarchitecture with increasing doses. 5-FU induces dose-dependent neurotoxicity in the rat cerebral cortex characterized by behavioural deficits, oxidative stress neuroinflammation and
histomorphological alterations. These findings highlight the need to better understand and mitigate CNS toxicity associated with 5-FU–based chemotherapy. 

KEYWORDS: Antimetabolite, Anxiety, Memory loss, Neurotoxicity, Neurodegeneration, Neuroinflammation