Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease

Abstract

Mast cell activation plays an important role in stress-mediated disease pathogenesis. Chronic stress cause or exacerbate aging and age-dependent neurodegenerative diseases. The severity of inflammatory diseases is worsened by the stress. Mast cell activation-dependent inflammatory mediators augment stress associated pain and neuroinflammation. Stress is the second most common trigger of headache due to mast cell activation. Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disease that affects more women than men and woman's increased susceptibility to chronic stress could increase the risk for AD. Modern life-related stress, social stress, isolation stress, restraint stress, early life stress are associated with an increased level of neurotoxic beta amyloid (Aβ) peptide. Stress increases cognitive dysfunction, generates amyloid precursor protein (APP), hyperphosphorylated tau, neurofibrillary tangles (NFTs), and amyloid plaques (APs) in the brain. Stress-induced Aβ persists for years and generates APs even several years after the stress exposure. Stress activates hypothalamic-pituitary adrenal (HPA) axis and releases corticotropin-releasing hormone (CRH) from hypothalamus and in peripheral system, which increases the formation of Aβ, tau hyperphosphorylation, and blood-brain barrier (BBB) disruption in the brain. Mast cells are implicated in nociception and pain. Mast cells are the source and target of CRH and other neuropeptides that mediate neuroinflammation. Microglia express receptor for CRH that mediate neurodegeneration in AD. However, the exact mechanisms of how stress-mediated mast cell activation contribute to the pathogenesis of AD remains elusive. This mini-review highlights the possible role of stress and mast cell activation in neuroinflammation, BBB, and tight junction disruption and AD pathogenesis.

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

“…Mast cells are essential in the wound healing process, including infected wounds and tissue repair mechanisms in the body [47,48]. Over and sustained mast cell activation can be deleterious and neurotoxic based upon the tissue and disease conditions [49]. Mast cell activation-mediated histamine and other mediators contribute to the common posttraumatic headache in TBI patients [49].…”

Mast cell‑mediated neuroinflammation may have a role in attention deficit hyperactivity disorder (Review)

“…MC activation and CRH release increase BBB permeability, leading to further brain damage and contributing to chronic neuroinflammation in the brain (60,101). Microglia express CRH receptors and activation of microglia by CRH leads to the release of harmful inflammatory mediators in psychiatric diseases, such as AD and pain (102,103). Human MCs synthesize and secrete CRH and express functional CRH receptors (CRHR1 and CRHR2) (104).…”

“…CRHR1 also mediates stress-induced MC degranulation (105). CRH release from activated MCs may also activate glial cells in neurodegenerative diseases such as AD (103,106). Stressful conditions, including trauma or hypoxia, also activate peripheral MCs, which in turn activate CRH and substance P pathways, leading to BBB leakage and glial activation, causing further neuroinflammation and neurodegeneration (107).…”

Chronic unpredictable stress-induced inflammation and quantitative analysis of neurons of distinct brain regions in Wistar rat model of comorbid depression

“…Translational research has been helped in gaining significant progress in the field of stress integrating basic information and clinical practice. The stress response activates the hypothalamic-pituitary-adrenal axis and neuroinflammatory response prompting the generation of neuroinflammatory agents [ 2 ]. Stress is a risk factor for various psychological disorders, including depression and anxiety [ 1 ].…”