A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination

Abstract

Recent studies have revealed widespread demyelination in the cortex of patients with chronic multiple sclerosis. In contrast to white matter lesions, cortical multiple sclerosis lesions are accompanied by only minor inflammation. Research into the pathogenesis of cortical lesion formation has been hampered by the fact that the conventional rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), does not regularly affect the cortex. To overcome this limitation we developed a new rat model of cortical multiple sclerosis. Lesions were stereotactically targeted to the cerebral cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with myelin oligodendrocyte glycoprotein (MOG). We thus generated highly reproducible demyelinated lesions in the neocortex with remarkable histological similarities to cortical multiple sclerosis lesions. The focal cortical EAE model led to the typical pattern of intracortical and subpial demyelination, infiltration with inflammatory cells, complement deposition, acute axonal damage and neuronal cell death. Surprisingly, extensive cortical inflammation largely resolved within 2 weeks. Furthermore, cortical demyelination was readily compensated by rapid remyelination. Our data thus suggest that cortical inflammation is a transient phenomenon, and that remyelination of cortical inflammatory-demyelinating lesions may occur rapidly.