Cuprizone-induced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System which is characterized by multifocal demyelinated lesions dispersed throughout the brain. Although white matter lesions have been the most extensively studied, cortical demyelinaton lesions are also detected in MS brains.Cuprizone (CPZ)-induced demyelination in rodents has been widely used as a model for MS. Most of these studies focus on oligodendrocyte-rich structures, such as the corpus callosum (CC) and the cerebellar peduncles. However, it has been recently described that CPZ administration in mice also produces cortical demyelination, resembling some of the lesions found in MS patients. In this work we used CPZ-demyelinating model in Wistar rats to study demyelination in cortical forebrain areas. At the ultrastructural level, demyelination in the cortex was observed before detectable myelin loss in the subcortical white matter. During the course of CPZ intoxication Myelin Basic Protein immunodetection was decreased in cortical layers I-III due to a reduction in the number of cortical oligodendrocytes (OL). Oligodendroglial loss in CPZ-intoxicated rats correlated with an increase in the number of Glial Fibrillary Acidic Protein positive astrocytes and a shift in the location of Carbonic Anhydrase II from OL to astrocytes. After removal of CPZ from the diet, we evaluate intranasal Thyroid hormone (TH) effects on the progression of cortical lesions. As previously reported in the CC, TH treatment also accelerates remyelination rate in the cortex compared to rats undergoing spontaneous remyelination. Our results suggest that manipulation of TH levels could be considered as a strategy to promote remyelination process in the cortex and to prevent neuronal irreversible damage in patients suffering from MS.

► Cuprizone intoxication in rats produces white and gray matter demyelination. ► During cortical demyelination astrogliosis correlates with areas of oligodendrocyte depletion. ► Cortical remyelination is enhanced by thyroid hormone intranasal instillation treatment.