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Vol. 303, Issue 3, 1061-1066, December 2002

Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrier Permeability Induced by Acute Stress

Pamela Esposito, Nathan Chandler, Kristiana Kandere, Subimal Basu, Stanley Jacobson, Raymond Connolly, David Tutor and Theoharis C. Theoharides

Department of Pharmacology and Experimental Therapeutics (P.E., N.C., K.K., S.B., D.T., T.C.T), Department of Surgical Research (R.C.), Department of Anatomy and Cell Biology (S.J.), and Department of Internal Medicine (T.C.T.), Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts

Stress activates the hypothalamic-pituitary-adrenal axis through release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down-regulate immune responses. Acute stress, however, also has proinflammatory effects that seem to be mediated through the activation of mast cells. Stress and mast cells have been implicated in the pathophysiology of various inflammatory conditions, including some in the central nervous system, such as multiple sclerosis in which disruption of the blood-brain barrier (BBB) precedes clinical symptoms. We previously showed that acute restraint stress increases rat BBB permeability to intravenous 99Tc gluceptate and that administration of the "mast cell stabilizer" disodium cromoglycate (cromolyn) inhibits this effect. In this study, we show that the CRH-receptor antagonist Antalarmin blocks stress-induced 99Tc extravasation, whereas site-specific injection of CRH in the paraventricular nucleus (PVN) of the hypothalamus mimics acute stress. This latter effect is blocked by pretreatment of the PVN with cromolyn; moreover, restraint stress cannot disrupt the BBB in the diencephalon and cerebellum of W/Wv mast cell-deficient mice. These results demonstrate that CRH and mast cells are involved in regulating BBB permeability and, possibly, brain inflammatory disorders exacerbated by acute stress.

0022-3565/02/3033-1061$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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