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

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.