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Physiological Reviews Jul 2008Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are... (Review)
Review
Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Active solely during waking, they maintain wakefulness and attention. Three of the four known histamine receptors and binding to glutamate NMDA receptors serve multiple functions in the brain, particularly control of excitability and plasticity. H1 and H2 receptor-mediated actions are mostly excitatory; H3 receptors act as inhibitory auto- and heteroreceptors. Mutual interactions with other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, learning, and memory in health and disease.
Topics: Animals; Brain; Histamine; Homeostasis; Humans; Hypothalamic Area, Lateral; Nervous System; Nervous System Diseases; Receptors, Histamine; Signal Transduction
PubMed: 18626069
DOI: 10.1152/physrev.00043.2007 -
Cancer Cell Jan 2022Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy...
Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.
Topics: Cell Line, Tumor; Histamine; Humans; Immune Tolerance; Immunotherapy; Macrophages; Neoplasms; Receptors, Histamine; Tumor Microenvironment
PubMed: 34822775
DOI: 10.1016/j.ccell.2021.11.002 -
Frontiers in Immunology 2018Histamine and its receptors (H1R-H4R) play a crucial and significant role in the development of various allergic diseases. Mast cells are multifunctional bone... (Review)
Review
Histamine and its receptors (H1R-H4R) play a crucial and significant role in the development of various allergic diseases. Mast cells are multifunctional bone marrow-derived tissue-dwelling cells that are the major producer of histamine in the body. H1R are expressed in many cells, including mast cells, and are involved in Type 1 hypersensitivity reactions. H2R are involved in Th1 lymphocyte cytokine production. H3R are mainly involved in blood-brain barrier function. H4R are highly expressed on mast cells where their stimulation exacerbates histamine and cytokine generation. Both H1R and H4R have important roles in the progression and modulation of histamine-mediated allergic diseases. Antihistamines that target H1R alone are not entirely effective in the treatment of acute pruritus, atopic dermatitis, allergic asthma, and other allergic diseases. However, antagonists that target H4R have shown promising effects in preclinical and clinical studies in the treatment of several allergic diseases. In the present review, we examine the accumulating evidence suggesting novel therapeutic approaches that explore both H1R and H4R as therapeutic targets for histamine-mediated allergic diseases.
Topics: Animals; Blood-Brain Barrier; Cytokines; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Humans; Hypersensitivity; Inflammation; Mast Cells; Molecular Targeted Therapy; Receptors, Histamine; Receptors, Histamine H4; Th1 Cells
PubMed: 30150993
DOI: 10.3389/fimmu.2018.01873 -
Inflammation Research : Official... Jan 2021Reports that the over-the-counter histamine H receptor antagonist famotidine could help treat the novel coronavirus disease (COVID-19) appeared from April 2020. We,...
OBJECTIVE
Reports that the over-the-counter histamine H receptor antagonist famotidine could help treat the novel coronavirus disease (COVID-19) appeared from April 2020. We, therefore, examined reports on interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and histamine receptor antagonists.
METHODS
A systematic literature search was performed by 19 September 2020, and updated on 28 October 2020, in PubMed, Scopus, Cochrane Library and Google Scholar using (COVID-19 OR coronavirus OR SARS-CoV-2) AND (histamine antagonist OR famotidine OR cimetidine). ClinicalTrials.gov was searched for COVID-19 and (famotidine or histamine).
RESULTS
Famotidine may be a useful addition in COVID-19 treatment, but the results from prospective randomized trials are as yet awaited. Bioinformatics/drug repurposing studies indicated that, among several medicines, H and H receptor antagonists may interact with key viral enzymes. However, in vitro studies have to date failed to show a direct inhibition of famotidine on SARS-CoV-2 replication.
CONCLUSIONS
Clinical research into the potential benefits of H receptor antagonists in managing COVID-19 inflammation began from a simple observation and now is being tested in multi-centre clinical trials. The positive effects of famotidine may be due to H receptor-mediated immunomodulatory actions on mast cell histamine-cytokine cross-talk, rather than a direct action on SARS-CoV-2.
Topics: COVID-19; Histamine Antagonists; Histamine H2 Antagonists; Humans; Receptors, Histamine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33206207
DOI: 10.1007/s00011-020-01422-1 -
Naunyn-Schmiedeberg's Archives of... Dec 2023In previous studies, we demonstrated the involvement of HR in inflammatory bowel disease (IBD) and IBD-associated colon cancer in mice and could ascribe HR-mediated...
In previous studies, we demonstrated the involvement of HR in inflammatory bowel disease (IBD) and IBD-associated colon cancer in mice and could ascribe HR-mediated histamine function to colon epithelial cells. The transferability of obtained data to humans is however lacking. Functional expression of HR on colon epithelial cells is a prerequisite to pursue the hypothesis of involvement of HR in carcinogenesis. Thus, we here compared the expression of histamine receptor subtypes in a series of cell lines. Out of these, three colon-derived cell lines displaying different combinations of HR and HR expression were submitted to functional analyses. Human hematopoietic HMC-1, HL-60, and U937, lung-derived A549 and Calu-3, and colorectal LoVo, SW 480, Caco-2, HT-29, and HCT116 cells were included in the study. mRNA expression was quantified by RT-qPCR. For functional analyses, Caco-2, HT-29, and HCT116 cells were treated by incubation with 1 - 10 µM histamine in the presence or absence of selective histamine receptor antagonists. Calcium mobilization, cAMP accumulation, and cell proliferation were measured by fluorimetry, mass spectrometry, and real-time bioimpedance measurements, respectively. Histamine receptor expression was heterogeneous in the cell lines tested. In most cell lines, we detected HR mRNA while HR mRNAs were found only occasionally. The colon-derived epithelial cell lines LoVo, SW480, and HT-29 expressed HR mRNA exclusively, while in HCT116 cells HR and HR mRNAs and in CaCo-2 HR mRNA were detectable. Subsequent functional analyses in HT29, Caco-2, and HCT116 cells, however, indicated that only HT-29 responded to histamine stimulation, by means of HR. For a detailed analysis of histamine receptor function, esp. that of HR and HR, in human colon-derived cell lines, the cell lines tested here are not fully convenient unless genetically modified.
Topics: Humans; Mice; Animals; Histamine; Receptors, Histamine H1; Receptors, Histamine H4; Caco-2 Cells; Receptors, Histamine; Colon; Inflammatory Bowel Diseases; RNA, Messenger
PubMed: 37300703
DOI: 10.1007/s00210-023-02565-8 -
British Journal of Pharmacology Feb 2020Histamine, acting via distinct histamine H , H , H , and H receptors, regulates various physiological and pathological processes, including pain. In the last two... (Review)
Review
Histamine, acting via distinct histamine H , H , H , and H receptors, regulates various physiological and pathological processes, including pain. In the last two decades, there has been a particular increase in evidence to support the involvement of H receptor and H receptor in the modulation of neuropathic pain, which remains challenging in terms of management. However, recent data show contrasting effects on neuropathic pain due to multiple factors that determine the pharmacological responses of histamine receptors and their underlying signal transduction properties (e.g., localization on either the presynaptic or postsynaptic neuronal membranes). This review summarizes the most recent findings on the role of histamine and the effects mediated by the four histamine receptors in response to the various stimuli associated with and promoting neuropathic pain. We particularly focus on mechanisms underlying histamine-mediated analgesia, as we aim to clarify the analgesic potential of histamine receptor ligands in neuropathic pain. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
Topics: Analgesics; Histamine; Humans; Neuralgia; Pain Management; Receptors, Histamine
PubMed: 31046146
DOI: 10.1111/bph.14696 -
Biomolecules Sep 2021Histamine does not only modulate the immune response and inflammation, but also acts as a neurotransmitter in the mammalian brain. The histaminergic system plays a... (Review)
Review
Histamine does not only modulate the immune response and inflammation, but also acts as a neurotransmitter in the mammalian brain. The histaminergic system plays a significant role in the maintenance of wakefulness, appetite regulation, cognition and arousal, which are severely affected in neuropsychiatric disorders. In this review, we first briefly describe the distribution of histaminergic neurons, histamine receptors and their intracellular pathways. Next, we comprehensively summarize recent experimental and clinical findings on the precise role of histaminergic system in neuropsychiatric disorders, including cell-type role and its circuit bases in narcolepsy, schizophrenia, Alzheimer's disease, Tourette's syndrome and Parkinson's disease. Finally, we provide some perspectives on future research to illustrate the curative role of the histaminergic system in neuropsychiatric disorders.
Topics: Animals; Brain; Clinical Trials as Topic; Histamine; Humans; Mental Disorders; Receptors, Histamine; Signal Transduction
PubMed: 34572558
DOI: 10.3390/biom11091345 -
Biomedicine & Pharmacotherapy =... Jun 2022Human histamine H3 receptor (H3R) was initially described in the brain of rat in 1983 and cloned in 1999. It can be found in the human brain and functions as a regulator... (Review)
Review
Human histamine H3 receptor (H3R) was initially described in the brain of rat in 1983 and cloned in 1999. It can be found in the human brain and functions as a regulator of histamine synthesis and release. H3 receptors are predominantly resident in the presynaptic region of neurons containing histamine, where they modulate the synthesis and release of histamine (autoreceptor) or other neurotransmitters such as dopamine, norepinephrine, gamma-aminobutyric acid (GABA), glutamate, acetylcholine and serotonin (all heteroreceptors). The human histamine H3 receptor has twenty isoforms of which eight are functional. H3 receptor expression is seen in the cerebral cortex, neurons of the basal ganglia and hippocampus, which are important for process of cognition, sleep and homoeostatic regulation. In addition, histamine H3R antagonists stimulate insulin release, through inducing the release of acetylcholine and cause significant reduction in total body weight and triglycerides in obese subjects by causing a feeling of satiety in the hypothalamus. The ability of histamine H3R antagonist to reduce diabetes-induced hyperglycaemia is comparable to that of metformin. It is reasonable therefore, to claim that H3 receptor antagonists may play an important role in the therapy of disorders of cognition, the ability to sleep, oxidative stress, inflammation and anomaly of glucose homoeostasis. A large number of H3R antagonists are being developed by pharmaceutical companies and university research centres. As examples of these new drugs, this review will discuss a number of drugs, including the first histamine H3R receptor antagonist produced.
Topics: Acetylcholine; Animals; Diabetes Mellitus; Histamine; Histamine Antagonists; Histamine H3 Antagonists; Humans; Rats; Receptors, Histamine H3
PubMed: 35447544
DOI: 10.1016/j.biopha.2022.112947 -
British Journal of Pharmacology Jan 2022Epilepsy is a common neurological disorder characterized by repeated and spontaneous epileptic seizures and is not well controlled by current medication. Traditional... (Review)
Review
Epilepsy is a common neurological disorder characterized by repeated and spontaneous epileptic seizures and is not well controlled by current medication. Traditional theory suggests that epilepsy results from an imbalance of excitatory glutamate neurons and inhibitory GABAergic neurons. However, new evidence from clinical and preclinical research suggests that histamine in the CNS plays an important role in the modulation of neural excitability and in the pathogenesis of epilepsy. Many histamine receptor ligands have achieved curative effects in animal epilepsy models, among which the histamine H receptor antagonist pitolisant has shown anti-epileptic effects in clinical trials. Recent studies, therefore, have focused on the potential action of histamine receptors to control and treat epilepsy. In this review, we summarize the findings from animal and clinical epilepsy research on the role of brain histamine and its receptors. We also identify current gaps in the research and suggest where further studies are most needed.
Topics: Animals; Anticonvulsants; Brain; Epilepsy; Histamine; Histamine Antagonists; Receptors, Histamine H3
PubMed: 34599508
DOI: 10.1111/bph.15692 -
Neuropharmacology Jul 2016Histamine modulates several aspects of energy homeostasis. By activating histamine receptors in the hypothalamus the bioamine influences thermoregulation, its circadian... (Review)
Review
Histamine modulates several aspects of energy homeostasis. By activating histamine receptors in the hypothalamus the bioamine influences thermoregulation, its circadian rhythm, energy expenditure and feeding. These actions are brought about by activation of different histamine receptors and/or the recruitment of distinct neural pathways. In this review we describe the signaling mechanisms activated by histamine in the hypothalamus, the evidence for its role in modulating energy homeostasis as well as recent advances in the understanding of the cellular and neural network mechanisms involved. This article is part of the Special Issue entitled 'Histamine Receptors'.
Topics: Animals; Body Temperature Regulation; Brain; Energy Metabolism; Feeding Behavior; Histamine; Homeostasis; Humans; Receptors, Histamine
PubMed: 26107117
DOI: 10.1016/j.neuropharm.2015.04.011