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

Abstract

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 99 Tc 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 99 Tc 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/W v 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.

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

“…NT is also found in the gut (29,73) and increases permeability of the intestinal lumen (74). NT may enter the blood and reach the brain by stimulating perivascular mast cells (75,76), which disrupt both the gut-blood barrier (77,78) and the blood-brain barrier (BBB) (79)(80)(81) (Fig. 9B).…”

Signaling Pathways in the Activation of Mast Cells Cocultured with Astrocytes and Colocalization of Both Cells in Experimental Allergic Encephalomyelitis

“…The integrity of the BBB can be affected by arachidonic acid and eicosanoids, bradykinin, histamine, serotonin, TNF-a, and free radicals (42)(43)(44), and by brain mast cell activation via acute restraint stress and corticotropine-releasing hormone (9,10). Histamine levels are high in the cerebrospinal fluid of MS patients (38), as well as in the brain of EAE-induced rodents (8,45).…”

“…In acute MS or EAE, early disruption of the integrity of the BBB precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cell activation caused by acute restraint stress or corticotropine-releasing hormone (9)(10)(11), and the histamine antagonist (H1 receptor blocker), hydroxyzine, inhibits the progression and severity of EAE (12). Mast cell-deficient mice develop a milder form of EAE disease than wild-type mice (8,13).…”

Expression Profiling Identifies the CRH/CRH-R1 System as a Modulator of Neurovascular Gene Activity

“…The implication of CRH and related peptides in cardiovascular function is well established and may play an important role in cardiovascular adaptations to stress (Coste et al, 2002). Acute stress increases blood-brain barrier permeability, an effect involving CRH, which has been demonstrated to directly affect brain microvessel endothelial cells (Esposito et al, 2002). The expression of CRH receptors in the cerebral vasculature has not yet been studied in detail although the CRH receptor protein has been detected in bovine and rat brain microvascular endothelial cells by Western blot albeit using an antibody detecting both receptors (Esposito et al, 2003).…”