Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) that has been used extensively as a model for multiple sclerosis (MS). Clinical signs of paralysis depend on the sensitization of T-lymphocytes to myelin basic protein (MBP) and correlate with the extent of edema in the CNS. Treatment with the alpha-1-adrenergic receptor antagonist prazosin, has been found to significantly suppress clinical signs of EAE in the Lewis rat. This effect appears to be specific for the alpha-1 receptor. In both actively and passively-induced EAE treatment with prazosin delays and reduces perivascular inflammation, significantly suppresses leakage of serum proteins into the CNS, and delays onset of increased GFAP staining of astrocytes. Catecholamines modulate a diverse array of cellular functions and whether prazosin acts on the vasculature, or the immune response, or both, remains to be determined. It is the object of this proposal to explore in greater depth the effect of prazosin, and other adrenergic ligands, in various models of EAE. Since perivascular inflammation and edema are features of the early lesion in MS, these results suggest that prazosin may have some clinical efficacy for patients with MS. However, two questions need to be addressed before such an undertaking can be considered: (1) How universal is the suppressive effect of prazosin for EAE in other species? and, (2) What is the mechanism of action? Experiments in the mouse and the guinea pig will determine the effect of prazosin on other models of EAE. Experiments in the rat will explore the mechanism of action of prazosin. In examining the effect on the vasculature, special emphasis will be placed on the quantitation of edema and cellular infiltration. Immunocytochemical techniques will be used to determine the pattern of leakage of serum proteins into the CNS, and to examine the distribution of T-cell subsets at various stages of the disease. Studies on the immune response will determine if prazosin alters the response of lymphocytes to antigens and mitogens, and affects the release of soluble mediators. Prazosin (Minipress) has recently achieved widespread use as an anti-hypertensive agent. The relative lack of toxicity that has been detected with the use of prazosin, persuades us that these promising results in the rat are worth pursuing further.
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