Effects of prazosin on the blood-brain barrier during experimental autoimmune encephalomyelitis.
Alterations in normal function of the blood-brain barrier (BBB) are important in the pathophysiology of multiple sclerosis and its laboratory counterpart, experimental autoimmune encephalomyelitis (EAE). As part of studies on drugs that affect vascular tone in rats with EAE, we have shown previously that the specific alpha 1-adrenoreceptor antagonist, prazosin, suppressed clinical and pathologic disease. In the present study we used quantitative morphometric analysis of capillary endothelium and the tracer horseradish peroxidase (HRP) to define effects of this drug on vascular events associated with central nervous system edema. In prazosin-treated and saline-treated EAE rats, protein extravasation in the spinal cord correlated with clinical presentation. Consistent with our previous data, the results showed that increased edema was associated with increased vesicular content of capillary endothelium. In prazosin-treated rats with no clinical signs, vesicular content was comparable to that found in normal animals. With increasing severity of disease, vesicular content increased and mitochondrial content decreased. In both prazosin- and saline-treated rats, mitochondrial content was reduced even when clinical signs were slight, and sharply declined when clinical signs increased. These results suggest that damage to mitochondria may be associated with early pathological events. In prazosin-treated animals, HRP accumulated in pericytes, suggesting that these cells were a target for the action of prazosin and may restrict the extravasation of fluid into the perivascular parenchyma. Our results underscore the presence of capillary changes associated with inflammation of the central nervous system, in addition to the well-recognized cellular inflammation that is targeted to the venular bed. The extent of capillary changes was closely associated with extent of tracer leakage in the spinal cord and support the conclusion that transcytotic vesicles are involved in transport of edema fluid during EAE, and that high mitochondrial levels are important for the normal function of BBB endothelium.
Claudio
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Division of Environmental Medicine, Mount Sinai Medical Center, New York, NY 10029-6574.
Brosnan
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CF
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology / Q000503:physiopathology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects; D004679:Encephalomyelitis / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
D011224:Prazosin