Farjam Mojtaba, Beigi Zarandi Faegheh Baha'addini, Farjadian Shirin, Geramizadeh Bita, Nikseresht Ali Reza, Panjehshahin Mohammad Reza
Department of Medical Pharmacology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Iran J Pharm Res. 2014 Spring;13(2):695-705.
Neurodegeneration is the pathophysiological basis for permanent neurological disabilities in multiple sclerosis (MS); thus neuroprotection is emerging as a therapeutic approach in MS research. Modulation of excitotoxicity by inhibition of NMDARs has been suggested for neuroprotection, but selective antagonisation of the NR2B subtype of these receptors, a subtype believed to play a more pivotal role in neurodegeneration, has not been tested in MS. In this study inhibition of NR2B-containing NMDAR was evaluated on the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE induction was done using MOG in C57BL/6 mice. Therapeutic administration of different doses of highly selective NR2B-containing NMDAR inhibitor (RO25-6981) was compared with memantine (non-selective NMDAR antagonist) and vehicle. Neurological deficits in EAE animals were more efficiently decreased by selective inhibition of NR2B-containing NMDARs. Histological studies of the spinal cords also showed decreased inflammation, myelin degradation and neuro-axonal degeneration when RO25-6981was administered with higher doses. The effects were dose dependent. Regarding the role of NR2B-containing NMDARs in excitotoxicity, selective inhibition of these receptor subtypes seems to modulate the neurological disabilities and pathological changes in EAE. Further elucidation of the exact mechanism of action as well as more experimental studies can suggest NR2B-containing NMDAR inhibition as a potentially effective treatment strategy for slowing down the clinical deterioration of disability in MS.
神经退行性变是多发性硬化症（MS）永久性神经功能障碍的病理生理基础；因此，神经保护正成为MS研究中的一种治疗方法。有人提出通过抑制NMDARs来调节兴奋性毒性以实现神经保护，但这些受体的NR2B亚型（一种被认为在神经退行性变中起更关键作用的亚型）的选择性拮抗作用尚未在MS中进行测试。在本研究中，在MS的动物模型实验性自身免疫性脑脊髓炎（EAE）上评估了对含NR2B的NMDAR的抑制作用。使用髓鞘少突胶质细胞糖蛋白（MOG）在C57BL/6小鼠中诱导EAE。将不同剂量的高选择性含NR2B的NMDAR抑制剂（RO25-6981）与美金刚（非选择性NMDAR拮抗剂）和赋形剂的治疗给药进行比较。通过选择性抑制含NR2B的NMDARs，EAE动物的神经功能缺损更有效地减少。脊髓的组织学研究还显示，当给予较高剂量的RO25-6981时，炎症、髓鞘降解和神经轴突变性减少。这些作用是剂量依赖性的。关于含NR2B的NMDARs在兴奋性毒性中的作用，对这些受体亚型的选择性抑制似乎可调节EAE中的神经功能障碍和病理变化。进一步阐明确切的作用机制以及更多的实验研究可能提示抑制含NR2B的NMDAR作为一种潜在有效的治疗策略，可减缓MS中残疾的临床恶化。
