Mahmoud Abdelrahman M A, Helal Manar G, El-Sherbiny Mohamed, Said Eman, Nader Manar A, Shehatou George S G
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Eur J Pharmacol. 2025 Jul 15;999:177686. doi: 10.1016/j.ejphar.2025.177686. Epub 2025 Apr 26.
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 5 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.
多发性硬化症（MS）是一种神经退行性疾病，涉及影响疾病进展和治疗的多种途径。犬尿氨酸途径（KP）在MS研究中受到关注，它会导致脱髓鞘和疾病进展。本研究旨在探讨依达拉奉（EDV）对脱髓鞘的 cuprizone（CPZ）动物模型中胼胝体和脊髓的药理作用。雄性Wistar大鼠被随机分为对照组、CPZ组和CPZ-EDV组。通过口服灌胃给予CPZ（500mg/kg/天），持续8周，在第5周开始时，给予EDV（5mg/kg/天，腹腔注射），并持续4周。EDV改善了CPZ中毒大鼠的行为和运动缺陷，并通过激活OLIG2促进少突胶质细胞祖细胞的分化，增强再髓鞘化。有髓神经纤维和共表达髓鞘碱性蛋白（MBP）的OLIG2+细胞密度增加证明了这一点，表明少突胶质前体细胞分化和再髓鞘化增强。EDV还降低了炎症介质TNF-α和NF-κB，并减少了NLRP3炎性小体的激活，抑制了IL-1β的释放。此外，EDV降低了吲哚胺2,3-双加氧酶-1（IDO1）的mRNA表达和活性，以及犬尿氨酸3-单加氧酶（KMO）的蛋白水平，导致神经毒性代谢产物（喹啉酸和邻氨基苯甲酸）减少，同时提高了神经保护代谢产物犬尿烯酸（KYNA）。总之，EDV通过减轻炎症、抑制KP的神经毒性代谢产物以及通过激活OLIG2促进再髓鞘化发挥神经保护作用。这些作用可能归因于EDV对TNF-α/NF-κB/NLRP3信号通路和KP的作用。
