Skip to main content

AN OVERVIEW OF HISTAMINE RECEPTOR H3 AS A DRUG TARGET IN CNS THERAPEUTICS

 

Clinical courses

About Authors:
Emanual Michael Patelia*, Rakesh Thakur, Jayesh Patel
Department of Pharmaceutical analysis and chemistry (Gujarat technical university)
Department of Pharmacology (University of Bedfordshire)
ricky.emanual@gmail.com

Abstract:
With the help of Jean michel and Jean charles schwatz team was founded histamine H3 receptor. H3 receptor antagonists discover, they have also therapeutic role in obesity and in different central nervous system disorders. After the discovery of H3 receptor, suddendly research of histamine receptor increase. In the nearly 1999, find H4 receptor, they show some therapeautic role in the treatment of asthma and inflammation. Histamine release from different cells like mast cell, enterochromaffine like cells, neurons. The h3 receptor capable of controlling the some neurotransmitters,like serotonin,acetylcholine, norepinephrine, dopamine. Generally, h3 receptor located in the CNS, like in basal ganglia, cerebral cortex, hypothalamus. H3 receptor has therapeutic action on some disorder like alzheimers disease, sleep disorder, pain and obesity.

REFERENCE ID: PHARMATUTOR-ART-1880

Introduction:
Before some year ago, information regarding the histamine is less.(Maria Beatrice Passani, 2000 Patrizio Blandina, 2006)Generally histamine has been shown two type of role, one in the different allergic disorders and second in the control of control of gastric acid secretion. (Maria Beatrice Passani, 2000 Patrizio Blandina, 2006)Further studies and systhesis on histamine, some selective agonists and antagonist has developed as a histamine receptor one, two, three and four. H1 receptor antagonists developed for such allergic condition like rhinitis and fever, which developed in the 1940.(Parsons et al., 2006) After in 1970 and 1980, they discover H2 receptor antagonist , which have therapeutically action to peptic ulcer and other gastric acid related disease treatment. In the 1987.(Parsons et al., 2006)  (Gemkow et al., 2003). H3 receptor identify as a promising G protein coupled receptor target in the CNS. (Bongers Gerold., 2007)20 isoforms of H3 receptor founded and some H3 receptor isoform founded in rat, guinea pig and mouse.(Bongers Gerold., 2007)  H1 receptor, H2 receptor, H3 receptor and H4 receptor all four subtype of histamine have very important therapeutic action on central nervous system (Tilgada Ekaterini., 2005).


Therapeutic potential:
1) Sleep disorder : histaminergic neurons shown more firing rate at the time of waking than during sleep. Arousal at the time of activation increasing histamine levels through h3 receptor blockade such as thioperamide and ciproxifan. Same as h3 receptor antagonists increase wakefulness and decrease rapid eye movement and slow wave sleep at the time of sleeping in normal animal. (Gemkow et al., 2003)

2) Obesity : kim et al. experimented with help of h1 receptor to knock out mouse, that this weight increase is mediated via h1 receptor linked activation of hypothalamic AMP kinase , this shown that because of feeding, increase the histamine level in the hypothalamus. Because of this suppression of food intake. H3 receptor help to reduced food intake. (Gemkow et al., 2003)


3) Pain : histamine is one of the inflammatory mediators, it involve in peripheral and central nociceptive processes. Wheneven histamine released at peripheral sites, they release various pain related molecules from primary afferent fibres. In CNS, histamine affect pain process in the thalamus and cerebral cortex. H3 receptor antagonist useful for pain stimuli and h3 receptor agonist may be help in some type of pain stimuli(Gemkow et al., 2003).with the help of virally rat models of neuropathic pain, it is discovered that H3 receptor antagonists/inverse agonists are effective(GSK 334429). (Tilgada Ekaterini., 2005).

4) Cognitive dysfunction : some neurotransmitter system, like acetylcholine, serotonin, glutamate, dopamine affected to specific cognition. H3 receptor antagonist an attractive drug target for cognitive disorder. It increase release of histamine, norepinephrine, dopamine and aetycholine. H3 receptor antagonist/inverse agonist can effect on level of neurotransmitters in the brain. The therapeutics restore impaired neurotransmitter system involved in disease, without leading to imbalance of normal brain function. (Gemkow et al., 2003)

Molecular mechanism :
Generraly histamine is prsent in the brain but after some research and studies on histamine, found that it is a neurotransmitter, which have therapeutic effect on the CNS. (Jin et al., 2009).

Inhibit adenylyl cyclase-cAMP-PKA pathway
Histamine 3 receptor activates inhibition of Gi/Go protein and adenylyl cyclase. H3R also participate in the activation of mitogen-activated protein kinase(MAPK) pathway. Intracellular cAMP and protein kinase are depend on adenylyl cyclase. H3R responsible for inhibition of adenylyl cyclase so indirectly H3R  responsible for reduction of intracellular cAMP and protein kinase activity. Protein kinase take parts in many pathway. (Bongers Gerold., 2007)

H3R activation decreases nor epinephrine exocytosis and reduces intraneuronal ca+2 responces. adenylyl cyclase, cAMP, protein kinase activity are also responsible for nor epinephrine exocytosis. Inhibition of NE exocytosis causes by inhibition of adenylyl cyclase, cAMP, Formation and PKA. Diminished PKA causes reduce phosphorylation of voltage operated ca2+ channels which reflects ca+2 current.(Levi Roberto., 2007)

H3 receptor stimulates phospholipase A2 via GALPHA1 subunit. H3R couple to MAPK cascade which contributes to PLA phosphorylation and stimulates its catalytic activity. PLA2 activation initiates the arachidonic acid with various eicosanoids including PGE2. PGE2 activates EP3 receptor which inhibit NE release. H3R inhibits NE exocytosis result from decrease adenylyl cyclase-cAMP-PKA functions, activation of MAPK and PLA2 and formation of arachidonate metabolites with anti exocytotics PGE2

Histamine H1R, H2R, H3R and H4R are present in the brain.(Jin et al., 2009). With the help of histidine decarboxylase enzyme, histamine produce from 1-histidine. Generally histamine production done in the part of the histaminergic neurons of tuberomamillary nucleus of the posterior hypothalamus. (Tilgada Ekaterini., 2005). Because histamine are not cross the blood brain barrier. (Tilgada Ekaterini., 2005).

References
1. Bongers, G., Bakker, R. A. and Leurs, R. (2007). Molecular aspects of the histamine H3 receptor. Biochem. Pharmacol. 73, 1195-1204.
2. Gemkow, M. J., Davenport, A. J., Harich, S., Ellenbroek, B. A., Cesura, A. and Hallett, D. Review: The histamine H3 receptor as a therapeutic drug target for CNS disorders. Drug Discov. Today 14, 509-515.
3. Jin, C. Y., Anichtchik, O. and Panula, P. (2009). Altered histamine H3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases. Br. J. Pharmacol. 157, 118-129.
4. Levi, R., Seyedi,N., Schaefer,U.,Estephan,R.,Mackins,C.J.,(2007) Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R.Biochemical Pharmacology 73,1146-1156.
5.  Maria Beatrice Passani, Patrizio Blandina. Histamine receptors in the CNS as targets for therapeutic intervention.
6. Parson, M.K.,Ganellin, C.R.(2006).British Journal of Pharmacology 147,s127-s137.
7. Tilgada Ekaterini, K. K. Histamine pharmacology and new CNS drug targets.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE