Repurposing of Cefotaxime for Its Therapeutic Potential in Alzheimer's Disease: An Explanation of the Possible Mechanism of Action.

Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive oxidative stress, neuroinflammation, and cognitive decline. Current pharmacological therapies are largely symptomatic, underscoring the need for new disease-modifying strategies. Drug repurposing provides an efficient approach to exploiting clinically approved compounds with established safety. Hence, in the current study, we investigated the neuroprotective potential of cefotaxime (CTX), a third-generation cephalosporin antibiotic, in an intracerebroventricular streptozotocin (ICV-STZ) rat model of AD. Adult male Sprague-Dawley rats were administered CTX (100-300 mg/kg, intraperitoneal, 28 days) and compared with donepezil (5 mg/kg). Behavioral performance was assessed using the Morris water maze, Y-maze, elevated plus maze, and open field tests. Biochemical assays (oxidative stress markers), histopathology, immunohistochemistry, ELISA, and RT-PCR were employed to examine molecular and cellular changes. CTX significantly ameliorated STZ-induced cognitive deficit, anxiety-like behaviors, oxidative stress, and neuroinflammation. While CTX reduced mRNA expression of β-amyloid and tau, it did not lower their protein levels as determined by ELISA, suggesting selective modulation at transcriptional rather than post-translational levels. Together, these findings suggest a potential role for CTX as a promising repurposed candidate for alleviating AD-related neurobehavioral deficits through the modulation of oxidative stress and inflammatory pathways.