Platelet-activating factor in multiple sclerosis: From peripheral inflammation to central neurodegeneration.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease in which peripheral immune activation, blood-brain barrier (BBB) dysfunction, and central nervous system (CNS) injury are closely interconnected. Platelet-activating factor (PAF) is a potent phospholipid mediator involved in inflammation, platelet activation, oxidative stress, and neuronal signaling. Increased PAF levels in the plasma and cerebrospinal fluid (CSF) of patients with MS suggest its involvement in both peripheral and central disease processes. Clinical and experimental evidence supports a working model in which peripheral platelet and neurovascular activation may interact with central PAF/PAF receptor (PAF-R) signaling, where microglial-neuronal communication, glutamate/NMDA-mediated excitotoxicity, synaptic injury, and demyelination may contribute to neural damage. Altered regulation of PAF activity may further enhance these processes. However, several mechanistic links remain derived from experimental models, and some detrimental effects of PAF appear to occur independently of PAF-R. This review integrates the evidence supporting a peripheral-to-central PAF framework in MS and critically evaluates direct PAF-R antagonists, indirect PAF modulators, and exploratory PAF-related candidates. Overall, PAF/PAF-R targeting remains a mechanistically promising but clinically unestablished therapeutic approach requiring further translational investigation.