Phenytoin or Spironolactone Intervention Counteracts 5-Fluorouracil–Induced Alopecia in Rats by Suppressing Oxidative Stress and Inflammation While Promoting Collagen Synthesis

Chemotherapy-induced alopecia (CIA) remains one of the most distressing side-effects of cancer therapy, and it often results from oxidative stress and follicular injury. This study investigated the potential mitigating effects of oral phenytoin and spironolactone on 5-fluorouracil (5-FU)–induced hair loss, oxidative stress, and systemic toxicity in a rodent model. A rodent model of chemotherapy-induced alopecia was established by administering 5-FU intraperitoneally, followed by oral treatment with phenytoin or spironolactone for 21 days. Feed intake, body weight, and hair regrowth were monitored throughout the experiment. At the end of treatment, animals were sacrificed, and blood and skin samples were collected for biochemical (lipid peroxidation and cytokine assays) and histological analyses (H&E and Van Gieson stains). Following 5-FU administration, rats exhibited significant reductions in feed intake and body weight, accompanied by visible alopecia, incomplete hair regrowth, and follicular dystrophy; consistent with chemotherapy-induced systemic and dermal toxicity. Treatment with phenytoin or spironolactone markedly reversed 5-FU–induced weight loss, restored appetite, and improved overall activity, suggesting recovery of metabolic and physiological functions. Both agents significantly attenuated oxidative stress, as evidenced by reduced plasma malondialdehyde (MDA) levels, and modulated inflammatory responses by decreasing TNF-α and IL-1β while restoring IL-10 levels. Histological analysis revealed that 5-FU caused dermal papilla distortion, follicular shrinkage, and loss of anagen follicles; while phenytoin and spironolactone restored follicular morphology, hair shaft integrity, and anagen activity. Phenytoin’s restorative effects are attributed to its anti-inflammatory, antioxidant, and angiogenic properties, while spironolactone’s efficacy may derive from its antiandrogenic and antifibrotic mechanisms. Notably, spironolactone produced a more pronounced improvement in hair regrowth and the skin collagen appear better organised. Collectively, these findings suggest that both phenytoin and spironolactone possess therapeutic potential in mitigating chemotherapy-induced alopecia and systemic toxicity, thereby enhancing post-treatment recovery and quality of life.