Repurposing antimicrobial agents for neuroprotection: Mechanisms, clinical potential, and challenges

Abstract Antimicrobial agents, originally developed for infectious diseases, have become attractive candidates for repurposing in neurodegenerative and neuroinflammatory diseases owing to their anti‐inflammatory, antioxidant, immunomodulatory, and neuroprotective activities. In this review, we critically examine the therapeutic potential of selected antimicrobial classes, including tetracyclines (e.g., minocycline), macrolides (e.g., azithromycin), antimalarial agents (e.g., chloroquine/hydroxychloroquine), sulfones (e.g., dapsone), and antiparasitic agents (e.g., ivermectin), in non‐infectious neurological diseases. We performed a narrative review of pre‐clinical and clinical studies to investigate the effects of these agents on the main neuropathological mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired autophagy, and gut–brain axis dysregulation. The available evidence suggests that many of the antimicrobial agents have beneficial effects in a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and traumatic brain injury. These agents have been shown to modulate microglia activation, to inhibit production of pro‐inflammatory cytokines, and to alter intracellular signaling pathways, including nuclear factor kappa‐light‐chain‐enhancer of activated B cells. Furthermore, by reshaping the gut microbiota, antimicrobials modulate immune signaling, alter neurotransmitter levels, and compromise blood–brain barrier integrity—thereby positioning the gut–brain axis as central to their mechanism of action. Repurposing antimicrobial agents is a pragmatic and novel approach to treat complex neurological disorders with available approved drugs. Despite the encouraging evidence, we must carefully manage challenges such as antimicrobial resistance, off‐target effects, and regulatory considerations. Further well‐designed clinical trials are essential to validate their long‐term safety and efficacy in neurodegenerative and neuroinflammatory diseases.