Hormone Histamine

Histamine, found within granules of basophils and mast cells (>90% of body stores) is a biogenic amine and an organic nitrogen compound that occurs to various degrees in many foods such as cherries to about 0.17-13.46 ng/g, bananas and grapes, rice and cereals, herbs, olive oil, wine, beer, etc.. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity(a). the hormone, as a neurotransmitter is involved in regulating physiological function in the gut and immune response to foreign pathogens.

1. Histamine regulation in glucose and lipid metabolism via histamine receptors
In the study to to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet, showed that severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose(1).


2. Histamine intolerance
According to the study of University of Bonn, Bonn, diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines(2). 

3. The role of histamine H1 and H4 receptors in allergic inflammation
Antihistamines are inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists, researchers at the Johnson & Johnson Pharmaceutical Research & Development, L.L.C. San Diego, suggested that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions(3).


4. Oral provocation with liquid histamine
75 mg of pure liquid oral histamine--a dose found in normal meals--can provoke immediate as well as delayed symptoms in 50% of healthy females without a history of food intolerance. In a randomized, double-blind, placebo-controlled cross-over study in 10 healthy females (age range 22-36 years, mean 29.1 +/- 5.4) who were hospitalized and challenged on two consecutive days with placebo (peppermint tea) or 75 mg of pure histamine (equaling 124 mg histamine dihydrochloride, dissolved in peppermint tea), researchers found that after histamine challenge, 5 of 10 subjects showed no reaction. One individual experienced tachycardia, mild hypotension after 20 minutes, sneezing, itching of the nose, and rhinorrhea after 60 minutes. Four subjects experienced delayed symptoms like diarrhea (4x), flatulence (3x), headache (3x), pruritus (2x) and ocular symptoms (1x) starting 3 to 24 hours after provocation. No subject reacted to placebo. No changes were observed in histamine and DAO levels within the first 80 minutes in non-reactors as well as reactors. There was no difference in challenge with histamine versus challenge with placebo(4).

5. Atopic Dermatitis with a Low-histamine Diet
In a study to evaluate a six-year-old Korean boy with AD admitted to the hospital for evaluation of the possibility of food, particularly pork, as a triggering factor in his skin disease, found that in an oral food challenge test, he showed a positive result after eating 200 g of pork, but did not show a positive result after eating 60 g of pork. After discharge, we attempted to keep him on a balanced diet that included various types of food and prohibited him from eating food that contains a high level of histamine. After keeping the patient on a balanced and low-histamine dietary regimen, his AD symptoms showed improvement and have not worsened for more than seven months. A low-histamine, balanced diet could be helpful for AD patients having symptoms that resemble histamine intolerance in which their AD symptoms worsened after intake of histamine-rich foods, but in which food allergy tests are negative(5).

6. Histamine H3 receptors and sleep-wake regulation
The histamine H(3) receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H(3) receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications, according to the study of Integrative Physiology of Brain Arousal Systems, Claude Bernard University(6).

7.  Histamine and neuropsychiatric disorders
Brain histamine is involved in a wide range of physiological functions such as regulation of sleep-wake cycle, arousal, appetite control, cognition, learning and memory mainly through the 4 receptor subtypes: H1, H2, H3 and H4, according to the study of Dr. Tashiro M, and Dr. Yanai K. at the Tohoku University Cyclotron and Radioisotope Centre, a series of clinical studies on histamine H1 antagonists, or antihistamines, have demonstrated that antihistamines can be classified into sedative, mildly-sedative and non-sedative drugs according to their blood-brain barrier (BBB) permeability, showing apparent clinical usefulness regarding QOL, work efficiency and traffic safety of allergic patients. PET has also been used for elucidation of aging effects and pathophysiological roles of histaminergic nervous system in various neuropsychiatric disorders such as Alzheimer's disease, schizophrenia and depression, where H1 receptor binding potentials were lower than age-matched healthy controls. It has been also demonstrated that brain histamine functions as an endogenous anti-epileptic. In addition, H3 receptors are located in the presynaptic sites of not only histaminergic nerves but also in other nervous systems such as serotonergic, cholinergic and dopaminergic systems, and to be regulating secretion of various neurotransmitters. Nowadays, H3 receptors have been thought to be a new target of drug treatment of various neuropsychiatric disorders(7). 

8. Histamine and men sexual arousal
In the study to evaluate the course of histamine plasma levels through different stages of sexual arousal in the systemic and cavernous blood of healthy male subjects of 34 healthy men, researchers at the Department of Urology & Urological Oncology, Hannover Medical School, showed that histamine slightly decreased in the cavernous blood when the penis became tumescent. During rigidity, histamine decreased further but remained unaltered in the phase of detumescence and after ejaculation. In the systemic circulation, no alterations were observed with the initiation or termination of penile erection, whereas a significant drop was registered following ejaculation. Results are not in favour of the hypothesis of an excitatory role of histamine in the control of penile erection. Nevertheless, the amine might mediate biological events during the post-ejaculatory period(8). 

9.The role of histamine on cognition
The specific participation of histamine in cognitive functions followed a slow and unclear pathway because the many different experimental learning models, pharmacologic approaches, systemic and localized applications of the histamine active compounds into the brain used by researchers showed facilitating or inhibitory effects on learning, generating an active issue that has extended up to present time. The specific histamine receptors and the compartmentalizing proprieties of the brain that might explain the apparent inconsistent effects of the imidazolamine in learning. In addition, a hypothetical physiologic role for histamine in memory is proposed under the standard theories of learning in experimental animals and humans.according to the study of Dr. Edgardo O. Alvarez at the Universidad Nacional de Cuyo, Laboratorio de Neuropsicofarmacología Experimenta(9).

10. Histamine and schizophrenia
In a study of a strong hyperactivity of histamine neurons induced in rodent brain by administration of methamphetamine or NMDA-receptor antagonists, Dr. Arrang JM. at the Unité de Neurobiologie et Pharmacologie Moléculaire, found that H3-receptor antagonists/inverse agonists display antipsychotic-like properties in animal models of the disease. Because of the limited predictability value of most animal models and the paucity of drugs affecting histaminergic transmission that were tried so far in human, the evidence remains therefore largely indirect, but supports a role of histamine neurons in schizophrenia(10).

11. Histamine and eating behavior
Interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity, researchers at the found that the appetitive phase requires a high and yet optimal arousal state, and the histaminergic system is crucial for sustaining a high degree of arousal during motivated behavior. Histamine H(1) receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity; however, from a therapeutic standpoint, no brain-penetrating H(1) receptor agonists have been identified that would have antiobesity effects. Despite conflicting preclinical data, insights are emerging into the potential role of histamine H(3) receptors as a target of antiobesity therapeutics(11)

12. Histamine and the effects on nasal mucous membrane
In the study to examine the reliability of suppression of the histamine wheal and flare reaction in the skin to predict an antihistamine's clinical efficacy in two common allergic diseases seasonal allergic rhinitis and chronic idiopathic urticaria, showed that although histamine is one mediator in the allergic response in the skin and nasal mucosa, many other agents are important modulators of the allergic response. In addition, the major structural and functional differences that exist between the nasal mucosa and the skin affect the type of local response. These manifest themselves as differences between the responses to antigen and histamine challenge in the skin and the nose. The allergic responses in these tissues are not simply the consequence of one chemical but are the result of a cascade of interactions among various cells and mediators. The clinical manifestations of these complex interactions obviously cannot be fully replicated by injection of one chemical mediator, histamine, into the outer layer of the skin. Studies with antihistamines have shown that certain drugs, such as cetirizine, are more suppressive than others (loratadine, terfenadine) in controlling the histamine-induced wheal and flare reaction in the skin. When the clinical efficacy of these medications is compared in clinical trials in seasonal allergic rhinitis and chronic idiopathic urticaria, all are equally efficacious in controlling symptoms(12).

13. Histamine and smooth muscle cells
Acoording to the study by The University of Tennessee, histamine markedly induces protein kinase D (PKD) activation in human aortic smooth muscle cells (HASMCs). PKD belongs to a family of serine/threonine protein kinases, and its function in vascular disease is largely unknown. Histamine-induced PKD phosphorylation is dependent on the activation of histamine receptor 1 (H1) and protein kinase C (PKC). PKD2 predominantly mediates histamine-induced TF expression via the p38 MAPK pathway, while PKD1 mediates histamine-induced TF expression through a p38 MAPK-independent pathway. PKD is a new component in histamine signaling in live cells and that PKD has a novel function in the histamine signaling pathway leading to gene expression, as evidenced by TF expression. Importantly, our data reveal a regulatory link from histamine to PKD and TF, providing new insights into the mechanisms of coagulation and the development of atherothrombosis(13).

14.  Histamine and variant angina and acute coronary syndromes
Histamine can induce coronary vasospasm, leading to variant angina and acute myocardial infarction, according to the study by Cardiovascular Research, Physiology Institute, University of Zurich, histamine induces expression of TF, but not TF pathway inhibitor, in vascular cells via activation of the H1, but not H2, receptor. This effect is mediated by the MAP kinases p38, ERK, and JNK. This observation may open novel perspectives in the treatment of variant angina and acute coronary syndromes(14).

15. Histamine and endumetrium
In the study to investigate whether histamine was taken up by perivascular adrenergic nerves and released by periarterial nerve stimulation (PNS) to induce vascular responses, showed that histamine treatment for 20 min induced PNS-induced vasoconstriction followed by vasodilation without affecting CGRP-induced vasodilation. Chlorpheniramine, guanethidine, combination of histamine and desipramine, and endothelium-removal abolished PNS-induced vasodilation in histamine-treated preparations. These results suggest that histamine taken up by and released from adrenergic nerves by PNS causes endothelium-dependent vasodilation in rat mesenteric arteries(15).

16. Histamine H4 receptor and CNS
Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. According to the Immunobiology Program, University of Vermont, H(4)R plays a role in determining the frequency of T regulatory (T(R)) cells in secondary lymphoid tissues, and regulates T(R) cell chemotaxis and suppressor activity. Moreover, the lack of H(4)R leads to an impairment of an anti-inflammatory response due to fewer T(R) cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells(16).

17. Histamine-induced vasodilation and vasoconstriction 
In the study to examine the vascular response to histamine in rat perfused mesenteric vascular beds with active tone, suggested that histamine induced endothelium-dependent vasodilation via endothelium histamine H(1) receptors and endothelium-independent vasodilation via smooth muscle histamine H(2) receptors. It is also suggested that the histamine-induced endothelium-independent vasoconstriction and vasodilation are mediated by histamine H(1) receptors and perivascular nerves(17).

18. Histamine on Monocyte Adhesion to Vascular Endothelial Cells
The histamine level is high during allergic attacks, and patients with allergy may have chronic inflammatory conditions at which tumor necrosis factor (TNF)-α is extensively released by macrophages. In the study  in vitro static and microfluidic flow assays conducted to investigate the combined influence of histamine and TNF-α on adhesion of monocytic THP-1 cells to human umbilical vein endothelial cells (HUVEC), showed that  the number of crawling and firmly adherent THP-1 cells was higher on TNF-α + histamine activated HUVEC than on HUVEC activated by TNF-α alone. This synergistic effect of histamine and TNF-α is caused by the increased endothelial surface expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Since the exposure of TNF-α-activated endothelium to histamine favors monocyte recruitment, it may be a serious risk factor for atherosclerosis and other inflammatory disorders(18).

19. Histamine and IgE-mediated diseases
Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01-0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare)(19).

20. Role of histamine in motion sickness
In the study to elucidate the role of histamine in motion sickness, researchers at the Faculty of Pharmaceutical Sciences, University of Tokyo, found that shaking the animals for 2 min increased HA contents in telencephalon and diencephalon without significantly changing the t-MH levels. alpha-Fluoromethylhistidine (alpha-FMH), which is presumed to deplete the neuronal HA, tended to raise the HA levels. alpha-FMH slightly alleviated the vomiting response to motion stimulus and suppressed the HA increase in diencephalon caused by shaking. Compound 48/80, which releases HA from mast cells, did not alter the control HA levels, but effectively prevented the motion sickness and completely suppressed the motion-induced rises in HA levels. These results provide further evidence that brain HA plays an important role in the development of motion sickness(20).

21. Histamine and motivation
Brain histamine may affect a variety of different behavioral and physiological functions; however, its role in promoting wakefulness has overshadowed its other important functions. Evidence indicated that brain histamine plays a central role in motivation and emphasize its differential involvement in the appetitive and consummatory phases of motivated behaviors(21).

22. Histamine in addiction and addiction-related behaviors
Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors(22).

23. Low cerebrospinal fluid (CSF) histamine levels and  hypersomnia
Researchers at the Akita University School of Medicine confirmed that reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin(23)

24. Histamine and stimulate gastric acid secretion
Ghrelin, a novel growth hormone-releasing peptide, is present in the rat and human stomach and is known to stimulate acid secretion and stomach motility. In the stidy to  to elucidate the role of histamine in ghrelin-induced acid secretion in rat stomach. Intravenous administration of ghrelin at 0.8 to 20 microg/kg dose dependently increased gastric acid secretion, as measured by the gastric lumen perfusion method. The maximum response was almost equal to that of gastrin (20 microg/kg), showed that ghrelin increased histidine decarboxylase (HDC) messenger RNA (mRNA) levels, as measured by real-time reverse transcription-polymerase chain reaction using LightCycler. The action of ghrelin on HDC mRNA was abolished by vagotomy. Ghrelin did not affect histamine release from isolated vascularly perfused rat stomach. Taken together, these results suggest that ghrelin stimulates gastric acid secretion via a mechanism involving activation of vagal efferent nerve and histamine release from gastric enterochromaffin-like cells(24).

25. Histamine and neurotransmitter release
In the study to investigate the effect of histamine-3 (H(3)) receptors, expressed in the tuberomammillary nucleus (TMN) of the hypothalamus and in the prefrontal cortex (PFC), on histamine neurotransmission in the rat brain, showed that systemic administration of the selective H(3)-agonist, immepip, decreases, and the reverse H(3) /H(4)-agonist, thioperamide, increases the firing activity of histamine neurons in the TMN and the release of histamine in TMN and PFC. Local perfusion of immepip into the TMN increased, and thioperamide decreased, histamine levels in the TMN but not in the PFC. Local perfusion of immepip into the PFC, however, decreased extracellular histamine levels in both TMN and PFC. It can be concluded that brain H(3) receptors, and especially those expressed in the PFC, play an important role in the autoregulation of histamine neurotransmission(25)

26. Histamine and noradrenaline and acetylcholine
In the study the effects of different histamine concentrations (1 X 10(-6) to 1 X 10(-4)M) on the contractile effects of noradrenaline and acetylcholine on isolated smooth-muscle preparations from rats, showed that histamine increases 2.6 to 16.2 times the noradrenaline concentrations needed for inducing 50 per cent of the maximum contractile response of the anococcygeal muscle. The interaction between noradrenaline and histamine on this smooth-muscle preparation is not competitive. Histamine in the concentrations applied does not influence the contractile effects of noradrenaline on vas deferens and of acetylcholine on tracheal smooth-muscle preparation. In rat anococcygeal muscle histamine most probably influences the contractile effects of noradrenaline and acetylcholine through allosteric interaction with their receptors(26).

27. The role of histamine H4 receptor in immune and inflammatory disorders
In the study the efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples, showed that  the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders(27).

28. The role of histamine H1 and H4 receptors in allergic inflammation
In the study to the effect of histamine  in allergic inflammatory conditions, showed that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions(28).






Sources
(a) http://www.ncbi.nlm.nih.gov/pubmed/17490952
(1) http://www.ncbi.nlm.nih.gov/pubmed/20566747
(2) http://www.ncbi.nlm.nih.gov/pubmed/18172439 
(3) http://www.ncbi.nlm.nih.gov/pubmed/17490952
(4) http://www.ncbi.nlm.nih.gov/pubmed/15603203 
(5) http://www.ncbi.nlm.nih.gov/pubmed/22028584  
(6) http://www.ncbi.nlm.nih.gov/pubmed/20864502
(7) http://www.ncbi.nlm.nih.gov/pubmed/17370648
(8) http://www.ncbi.nlm.nih.gov/pubmed/21950740 
(9) http://www.sciencedirect.com/science/article/pii/S016643280800675X
(10) http://www.ncbi.nlm.nih.gov/pubmed/17349864 
(11) http://www.ncbi.nlm.nih.gov/pubmed/20864503
(12) http://www.ncbi.nlm.nih.gov/pubmed/9042073 
(13) http://www.ncbi.nlm.nih.gov/pubmed/23001835
(14) http://www.ncbi.nlm.nih.gov/pubmed/16009787 
(15) http://www.ncbi.nlm.nih.gov/pubmed/22510969
(16) http://www.ncbi.nlm.nih.gov/pubmed/22147765 
(17) http://www.ncbi.nlm.nih.gov/pubmed/16337938 
(18) http://www.ncbi.nlm.nih.gov/pubmed/23053728
(19) http://www.ncbi.nlm.nih.gov/pubmed/22794675
(20) http://www.ncbi.nlm.nih.gov/pubmed/1741719 
(21) http://www.ncbi.nlm.nih.gov/pubmed/22783171
(22) http://www.ncbi.nlm.nih.gov/pubmed/20638439 
(23) http://www.ncbi.nlm.nih.gov/pubmed/19238805
(24) http://www.ncbi.nlm.nih.gov/pubmed/16838121 
(25) http://www.ncbi.nlm.nih.gov/pubmed/22050612
(26) http://www.ncbi.nlm.nih.gov/pubmed/7315388 
(27) http://www.ncbi.nlm.nih.gov/pubmed/19309354
(28) http://www.ncbi.nlm.nih.gov/pubmed/18172439