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Iran J Pharm Res. 2014 Spring;13(2):695-705.

Inhibition of NR2B-Containing N-methyl-D-Aspartate Receptors (NMDARs) in Experimental Autoimmune Encephalomyelitis, a Model of Multiple Sclerosis.

Author information

1
Department of Medical Pharmacology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
2
Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
3
Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
4
Transplant Research Center, Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran.
5
Department of Neurology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Abstract

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.

KEYWORDS:

Experimental autoimmune encephalomyelitis; NR2B-containing NMDAR; RO25-6981

PMID:
25237366
PMCID:
PMC4157046

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