Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States

Abstract

Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/Wv) mice. No significant difference was found in the basal amount of sleep/wake between W/Wv mice and their wild-type littermates (WT), although W/Wv mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/Wv mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/Wv mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/Wv mice. W/Wv mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP+)

“…Mast cells are co-localized adjacent to glial cells in the brain indicating the presence of interactions between these cells. Mast cells contribute to both normal cognition, emotionality, sleep and fundamental neurobehavioral functions, but also promote deleterious effects in the brain [40]. The number as well as activation/degranulation status of mast cells in the brain vary with species, age, external environment and the techniques to detect [39].…”

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

“…Mast cells are generally co-localized adjacent to glial cells in the brain during neuroinflammatory responses (Kim et al, 2010). Resident brain mast cells are present adjacent to blood vessels, glial cells and nerves in the central nervous system (CNS), and communicate with these cells in pathophysiological conditions (Chikahisa et al, 2013). Activated mast cells release several multifunctional proinflammatory mediators including interleukin-1beta (IL-1β), IL-6, IL-8, IL-17, IL-18, IL-33, tumor necrosis factor-alpha (TNF-α), granulocyte macrophage-colony stimulating factor (GM-CSF), chemokine (C-C motif) ligand 2 (CCL2), CCL5, matrix metalloproteinase-3 (MMP-3), substance P, histamine, tryptase, prostaglandins, reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO) during an inflammatory response (Mekori and Metcalfe, 2000; Kalesnikoff and Galli, 2008; Sismanopoulos et al, 2012; Theoharides et al, 2012; Kempuraj et al, 2013).…”

Interactions of the histamine and hypocretin systems in CNS disorders

“…[82][83][84][85][86][87] Histamine signalling also directly enhances the activity of type 1 T helper cells by binding to the H 1 R expressed on these cells. 88 Histamine activation triggers T cells, B cells, macrophages, microglia and mast cells to secrete histamine and cytokines and chemokines, such as IFN-γ, tumour necrosis factor, quinolinic acid, glutamate and radical oxygen intermediates (Figure 4b), 78,89,90 initiating a local inflammatory response (Figure 4c).…”

“…Moreover, histamine signalling enhances the activity of type 1 T helper cells through binding to histamine type 1 receptors located on these cells 88. c | T cells, B cells, macrophages, microglia and mast cells secrete histamine and other cytokines and chemokines,78,89,90,163 triggering a local inflammatory response that can damage the sensitive hypocretin neurons. Abbreviations: Aβ, amyloid-β; CSF, cerebrospinal fluid.…”