Edaravone protects against cuprizone-induced demyelination in rats by modulating TNF-α/NF-ĸB/NLRP3 signaling and the kynurenine pathway.

Multiple sclerosis (MS) is a neurodegenerative disorder involving various pathways that affect disease progression and treatment. The kynurenine pathway (KP) has gained attention in MS studies, contributing to demyelination and disease progression. This study aimed to explore the pharmacological effects of edaravone (EDV) on the corpus callosum and the spinal cord in the cuprizone (CPZ) animal model of demyelination. Male Wistar rats were randomly divided into the control, CPZ, and CPZ-EDV groups. CPZ (500 mg/kg/day) was administered via oral gavage for eight weeks, and at the start of the 5th week, EDV (5 mg/kg/day,I.P.) was initiated and continued for 4 weeks. EDV ameliorated behavioral and motor deficits in CPZ-intoxicated rats and promoted the differentiation of oligodendrocyte progenitor cells by activating OLIG2, enhancing re-myelination. This was demonstrated by increased density of myelinated nerve fibers and OLIG2+ cells co-expressing myelin basic protein (MBP), indicating enhanced OPC differentiation and remyelination. EDV also reduced the inflammatory mediators TNF-α and NF-ĸB, and diminished the activation of NLRP3 inflammasome, inhibiting the release of IL-1β. Furthermore, EDV decreased indoleamine 2,3-dioxygenase-1 (IDO1) mRNA expression and activity, as well as the protein levels of kynurenine 3-monooxygenase (KMO), leading to reduced neurotoxic metabolites (quinolinic and anthranilic acid) while elevating the neuroprotective metabolite kynurenic acid (KYNA). In conclusion, EDV exerted neuroprotective effects by reducing inflammation, inhibiting the KP's neurotoxic metabolites, and promoting remyelination through OLIG2 activation. These effects are possibly attributed to EDV's action on TNF-α/NF-ĸB/NLRP3 signaling and the KP.