BIOCHEMICAL AND PATHOLOGICAL CORRELATES OF CLINICAL DISEASE IN EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS (DEMYELINATION, ADRENERGIC RECEPTOR, GLIOSIS, BLOOD BRAIN BARRIER, MYELIN)

Abstract

Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) that has been extensively studied as a model of multiple sclerosis (MS). This thesis had two major objectives using this model: (1) to test the hypothesis that EAE is mediated by a delayed-type hypersensitivity reaction in which vasoactive amines play a major role in the development of the lesion, and (2) to investigate reports of widespread changes in myelin composition in animals sensitized against certain adjuvants and CNS specific antigens. The results demonstrated an hitherto unrecognized role for catecholamines in the development of EAE, and failed to confirm that changes could be detected in myelin composition regardless of the clinical state of the animals or the encephalitogenic potential of the inoculum.;A role for the catecholamines was demonstrated by the data showing that prazosin, a specific alpha(,1)-adrenergic antagonist, could significantly suppress clinical signs of disease in both actively-induced and passively-transferred EAE. This effect appeared to be specific for the alpha(,1)-receptor since treatment with either antagonists of the beta (propranolol) of alpha(,2) (yohimbine) receptor exacerbated disease, whereas treatment with the mixed alpha(,1)/alpha(,2) antagonist, phenoxybenzamine, had some suppressive activity. Further studies showed that prazosin delayed histopathological expression of perivascular inflammation, delayed immunohistological expression of GFAP, and significantly reduced edema in the spinal cord. The enhanced staining of GFAP in EAE animals could not be attributed to either increased turnover or increased synthesis of GFAP. The results to date support the hypothesis that the extent of edema in the CNS is closely linked to clinical expression of EAE and that the primary site of action of prazosin is on the vascular alpha(,1)-adrenergic receptor.;Standard biochemical techniques were used to analyze myelin from sensitized animals. The results showed that there were no consistent differences in the yield, protein content, CNPase activity, 5'-nucleotidase activity of lipid values in any of the animals. These results do not support the conclusion that major biochemical changes occur in the CNS myelin sensitization, and thus are in agreement with the histopathological findings.