Human-dose equivalent 5-fluorouracil induces graded neurobehavioural, neuromorphological and immunohistochemical changes in the cerebral cortex of Wistar rats

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. Behavioral assessments were conducted and animals were sacrificed 24 hours after the final test. Cortical tissues were analyzed 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 behavioral 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.