Asiaticoside alleviates migraine-induced cognitive impairment via TLR4-Mediated apoptosis regulation

Migraine, a prevalent neurological disorder, is often accompanied by cognitive impairment that significantly reduces patients' quality of life. This study explored the therapeutic potential of Asiaticoside, a neuroprotective compound derived from Centella asiatica, in alleviating migraine-associated cognitive deficits. Using network pharmacology, we identified putative molecular targets of Asiaticoside and cross-referenced them with migraine- and cognitive impairment-related targets from GeneCards and OMIM databases. Protein-protein interaction networks were constructed, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. In vivo validation was conducted using a nitroglycerin (NTG)-induced migraine mouse model, incorporating behavioral assessments alongside biochemical and molecular analyses. Network analysis highlighted the TLR4 signaling pathway and apoptosis as key mechanisms underlying Asiaticoside's therapeutic effects. Consistently, Asiaticoside dose-dependently alleviated NTG-induced nociceptive hypersensitivity and cognitive impairments. Mechanistically, Asiaticoside markedly inhibited the TLR4-MyD88-NF-κB signaling cascade and reduced the expression of pro-inflammatory cytokines and CGRP in the spinal trigeminal nucleus caudalis, prefrontal cortex, and hippocampus. Additionally, Asiaticoside attenuated neuronal apoptosis by modulating the balance of BCL-2 family proteins and suppressing Caspase-3 activation. Co-administration of the TLR4 inhibitor TAK-242 further enhanced Asiaticoside's protective effects. These findings collectively support that Asiaticoside alleviates migraine-induced cognitive impairments by modulating TLR4-mediated neuroinflammation and apoptosis, highlighting its promise as a potential therapeutic agent for migraine and its associated cognitive impairment.