Role of Histamine and Its Receptors in Cerebral Ischemia

Abstract

Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy. However, important questions about the molecular aspects and pathophysiology of histamine and related agents in cerebral ischemia remain to be answered to form a solid scientific basis for therapeutic application.

Histamine Promotes Locomotion Recovery After Spinal Cord Hemisection via Inhibiting Astrocytic Scar Formation

“…Numerous studies have proved that histamine participated in ischemic brain pathology. The results both in vivo and in vitro showed that histamine exerts protective effect in brain ischemic pathology , probably involving targeting to astrocytes . In SCI, it has been reported that histamine level increases in the traumatized segment at 2 h after injury , which may contribute to the increase of the sensitivity of vessels to other vasoactive substances .…”

Carnosine protects brain microvascular endothelial cells against rotenone‐induced oxidative stress injury through histamine H1 and H2 receptors in vitro

“…21 Since the clinical application of histamine is limited because of its inability to penetrate the blood-brain barrier and its involvement in peripheral inflammation, carnosine, which may serve as a reservoir of histamine in the brain, can be considered as an ideal alternative to histamine therapy to protect microvascular endothelial cells via actions mediated by H 1 or H 2 receptors. 22 Interestingly, we have previously documented that the alleviation of Ab42-induced neurotoxicity by carnosine is independent of its conversion to histamine and that carnosine may act by regulating glutamate release and NMDA receptor trafficking. 23 In astrocytes, the carnosine-induced upregulation of GLT-1 expression under oxygen-glucose deprivation does not depend on its transformation into histamine either.…”

“…In a previous in vivo study, carnosine was found to protect against amygdaloid‐kindled seizures through the same carnosine–histidine–histamine pathway . Since the clinical application of histamine is limited because of its inability to penetrate the blood–brain barrier and its involvement in peripheral inflammation, carnosine, which may serve as a reservoir of histamine in the brain, can be considered as an ideal alternative to histamine therapy to protect microvascular endothelial cells via actions mediated by H 1 or H 2 receptors …”

Potential of carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion‐induced vascular dementia

“…Histamine is an autacoid with diverse central and peripheral actions, which are mediated via specific receptors distributed throughout the body. It is suggested to act as neuromodulator and neurotransmitter in CNS . Studies have reported significant protective role of histamine in various disorders such as ischemia ; stroke and many other disorders .…”

“…Histamine is an autacoid with diverse central and peripheral actions, which are mediated via specific receptors distributed throughout the body. It is suggested to act as neuromodulator and neurotransmitter in CNS [68,69].…”