Histamine Signalling in Cerebral Malaria


mosquitoHistamine is a biogenic amine which acts as a mediator of immune responses as well as acting as a neurotransmitter in the CNS. Histamine plays a role in a variety of physiological processes including allergic reactions, gastric acid secretion, bronchoconstriction and neurotransmission. Four histamine receptors, termed H1, H2, H3, and H4, have been identified. The H1 receptor mediates most of the pro-inflammatory effects of histamine whereas the anti-inflammatory and immunosuppressive activities of histamine are mainly dependent on stimulation of the H2 receptor. The H4 receptor is expressed predominantly on haematopoietic cells and agonists of this receptor induce chemotaxis of mast cells and eosinophils as well as production of IL-16 by T-cells. H4 stimulation has also recently been shown to cause inhibition of airway resistance and inflammation in a murine model of allergic asthma. Unlike the other histamine receptors, H3 receptors are expressed mainly on neurons of the peripheral and central nervous system where they control the synthesis and release of histamine and also influence the release of other neurotransmitters including dopamine, γ-aminobutyric acid, noradrenaline, acetylcholine, serotonin and tachykinins.

In human infection with Plasmodium falciparum, as well as in murine models of malaria, increased levels of histamine have been shown to be associated with severity of infection. Histamine signalling through H1 and H2 receptors increases the susceptibility of mice to infection with lethal strains of Plasmodium berghei and mice genetically deficient in the histidine decarboxylase gene – and thus lacking histamine – are highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. A study recently published in the journal PLoS ONE has now investigated the role of the H3 receptor in the inflammatory response in the brain during P. berghei infection in mice. Compared with wild type mice, mice deficient in the H3 receptor showed an accelerated onset of cerebral malaria, increased brain pathology and more pronounced loss of blood brain barrier integrity associated with earlier death. H3 receptors tightly regulate release of histamine and other neurotransmitters and neuronal histamine activity was found to be significantly higher in naive knockout mice than in wild type mice.

cimetidine structureIn further studies, the H3 receptor agonist, (R)-alpha-methylhistamine, was found to be effective in reducing progression to cerebral malaria. In wild type mice, both the H1 receptor antagonist, levocetirizine, and the H2 receptor antagonist, cimetidine, were found to be effective in reducing clinical symptoms and mortality caused by cerebral malaria. This protection was attributed, in part at least, to down-regulation of inflammatory response-associated genes such as IFN-γ and TNF-α. The beneficial role of the H3 receptor in controlling histamine levels and limiting disease was demonstrated by the higher effectiveness of cimetidine and, to a lesser extent, levocetirizine in wild type compared with H3 receptor knockout mice. The authors propose that H1 or H2 receptor antagonists, either alone, or together with an H3 receptor agonist if one becomes available, might be used alongside anti-malaria medicines as preventative therapies against the development of cerebral malaria, especially in areas where malaria transmission is seasonal.

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