Monday, November 28, 2005

Novel Histamine Therapy Undergoing Clinical Trials

by O’Rita M. Siddall

Alzheimer’s disease (AD) is a neurodegenerative disease that results in gradual decline in cognition and behavior. Since there is no cure, the ultimate outcome is fatal. There are approximately 15 million people worldwide affected with this disease and it is more common in women than in men. The average age of onset is greater than 65; however, cases have been reported as early as age 40. Economically, Alzheimer’s disease is the third most expensive illness in the US, with an estimated national cost of 100 billion annually. Currently, new treatment options are being developed that target specific histamine receptors found in the brain.

Histamine and the Brain

Histaminergic cell bodies are located exclusively in the tuberomammillary nucleus of the hypothalamus, and project to all major areas of the brain involved in the regulation of many brain functions, like the sleep/wake cycle and memory processing [5].

The H3 receptor was first identified in 1983 by Arrang and colleges [4]. They showed from examination of the rat brain that histamine inhibited its own release via an action mediated by a class of receptors (H3) pharmacologically distinct from the H1 and H2 receptors [4]. H3 receptors are involved in the presynaptic regulation of the release of acetylcholine, dopamine, GABA, glutamate, and many others. They also provide a negative feedback loop to restrict the synthesis and release of histamine [5].

The H3 receptor is known as a heteroreceptor because its expression is not confined to histaminergic neurons. This receptor can modulate various neurotransmitter systems in the brain. The H3 receptor can activate G proteins found in the brain to modulate cellular signaling [6]. When G proteins are activated, adenyl cyclase is inhibited, resulting in lower cAMP levels [6]. Other H3-G protein mediated pathways include: mitogen-activated protein kinase, phosphatidylinositol 3-kinase, phospholipase A2 (which will activate the release of arachidonic acid) [6].

Histamine and Brain Disease

Plaques and neurofibrillary tangles develop within brain neurons of Alzheimer’s patients, and contribute to the fatality of this disease. Histaminergic neurons display prominent degeneration and tangles [5]. Also, in the tuberomamillary nucleus of the hypothalamus, tangles also occur with the number of neurons decreasing as the disease progresses [5]. It has been shown that in the areas of the brain that is affected by Alzheimer’s, the levels of histamine decrease [5].

The cognitive decline seen in this disease is linked to dysfunctions in acetylcholine mediated neurotransmission. Studies have shown that histamine might moderate the activity of cholinergic neurons [3]. In microdialysis studies done on rats, it was shown that activation of H3 receptors by histamine agonists reduced the release of acetylcholine [5].

Novel Histamine (H3) Receptor Antagonist Therapy

Many pharmaceutical companies have invested in the development of H3 receptor antagonists. Abbott Laboratories, GlaxoSmithKline, and Johnson and Johnson are some of these companies [3]. These agents are undergoing pre-clinical and Phase I investigations for treatment of cognitive dysfunction.

Preclinical Studies

There have been many compounds developed that exhibit H3 receptor antagonistic specificity. They are grouped into two categories, imidazole and non-imidazole H3 receptor antagonist. Thioperamide was the first compound developed. It has been used as the prototype for the refinement and development of other compounds [7]. Its use has shown to provide a novel approach in treating cognitive decline [7]. The imidazole compounds interact with the cytochrome P450 enzyme system, which of course is undesirable, and has led to research into development of the non-imidazole class. Compounds ABT-239, and ABT-834 have entered Phase I studies for cognitive disorders, including Alzheimer’s disease [3]. Abbott Laboratories is the Sponsor for these agents. In preclinical studies, ABT-239 demonstrated specificity to the H3 receptor. Efficacy in cognition was demonstrated in animal models [7, 8]. Abbott Laboratories is also the Sponsor for ABT-834. Data for ABT-839 has not been disclosed.

Researchers at Johnson and Johnson have reported on the preclinical effects of their compound JNJ-10181457 [3]. Efficacy in memory was demonstrated in rats.


1. Dipiro, J. Pharmacotherapy. Alzheimer’s disease. McGraw-Hill, 1165-1182 2002.
2. Ahluwalia N, Vellas B. Immunologic and inflammatory mediators and cognitive decline in Alzheimer's disease. Immunol Allergy Clin North Am 2003 Feb;23(1):103-15.
3. Leurs R, Bakker RA, Timmerman H, de Esch IJ. The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 2005 Feb;4(2):107-20.
4. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983 Apr 28;302(5911):832-7.
5. Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 2003 Feb;4(2):121-30.
6. Leurs R, Hoffmann M, Wieland K, Timmerman H. H3 receptor gene is cloned at last. Trends Pharmacol Sci 2000 Jan;21(1):11-2.
7. Esbenshade TA, Fox GB, Krueger KM, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Pan L, Wetter J, Marsh K, Bennani YL, Cowart MD, Sullivan JP, Hancock AA. Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and selective histamine H3 receptor antagonist with drug-like properties. J Pharmacol Exp Ther 2005 Apr;313(1):165-75. Epub 2004 Dec 17.
8. Cowart M, Faghih R, Curtis MP, Gfesser GA, Bennani YL, Black LA, Pan L, Marsh KC, Sullivan JP, Esbenshade TA, Fox GB, Hancock AA. 4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention. J Med Chem 2005 Jan 13;48(1):38-55.
10. DeLaGarza VW. Pharmacologic treatment of Alzheimer's disease: an update. Am Fam Physician 2003 Oct 1;68(7):1365-72.
This information has been published by the International Biopharmaceutical Association . Please note this information does not give any medical advice.

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