Mice overexpressing bcl-2 in their neurons are resistant to myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)

Multiple sclerosis (MS) is an inflammatory disease of the central nervous s ystem (CNS) characterized by destruction of myelin. Recent studies have ind icated that axonal damage is involved in the pathogenesis of the progressiv e disability of this disease. To study the role of axonal damage in the pat hogenesis of MS-like disease induced by myelin oligodendrocyte glycoprotein (MOG), we compared experimental autoimmune encephalomyelitis (EAE) in wild -type (WT) and transgenic mice expressing the human bcl-2 gene exclusively in neurons under the control of the neuron-specific enolase (NSE) promoter. Our study shows that, following EAE induction with pMOG 35-55, the WT mice developed significant clinical manifestations with complete hind-limb para lysis. In contrast, most of the NSE-bcl-2 mice (16/27) were completely resi stant, whereas the others showed only mild clinical signs. Histological exa mination of CNS tissue sections showed multifocal areas of perivascular lym phohistiocytic inflammation with loss of myelin and axons in the WT mice, w hereas only focal inflammation and minimal axonal damage were demonstrated in NSE-bcl-2 mice. No difference could be detected in the immune potency as indicated by delayed-type hypersensitivity (DTH) and T-cell proliferative responses to MOG. We also demonstrated that purified synaptosomes from the NSE-bcl-2 mice produce significantly lower level of reactive oxygen species (ROS) following exposure to H2O2 and nitric oxide (NO) than WT mice. In co nclusion, we demonstrated that the expression of the antiapoptotic gene, bc l-2, reduces axonal damage and attenuates the severity of MOG-induced EAE. Our results emphasize the importance of developing neuroprotective therapie s, in addition to immune-specific approaches, for treatment of MS.