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    • Levodopa br Introduction br The histaminergic system in

    2021-11-29


    Introduction
    The histaminergic system in the central nervous system The Levodopa is continually processing information through aminergic systems present in the mammalian CNS such as the serotonergic, dopaminergic, noradrenergic and histaminergic systems which function by projecting signals throughout the brain and spinal cord (Brown et al., 2001). Histamine has become progressively more apparent as one of the major neurotransmitters and is involved in a wide range of physiological functions such as cognition, emotion, feeding behaviour and sleep-wake cycle (Parsons and Ganellin, 2006, Passani and Blandina, 2011). Lately, post mortem studies have revealed alterations in the histaminergic systems in neurological and psychiatric diseases. Brain histamine levels are noticeably reduced in Alzheimer's disease patients whereas higher histamine concentrations are found in the brain of Parkinson's disease and schizophrenic patients. Low histamine levels are associated with convulsions and seizures. Neuronal histamine is also involved in pain perception, and ligands that cause an increase in the brain and spinal histamine concentrations have antinociceptive properties (Nuutinen and Panula, 2010). The histaminergic system seems to also give a contribution in the aetiology of Tourette syndrome, where a recent study highlights the involvement of histamine pathways (mainly H1 and H2 receptor) to copy number variants identified in pedigree Tourettes and autism spectrum disorder (Fernandez et al., 2012). Due to the importance of maintaining healthy levels of histamine for normal cognitive function, genetic variations of its receptors have been extensively studied; Table 2 summarizes these findings.
    The histaminergic system in inflammatory conditions Besides the central role histamine plays in allergies and autoimmune diseases, it was shown by various research studies that histamine can strongly influence in immune response (Banu and Watanabe, 1999, Idzko et al., 2002, Jutel et al., 2001). Histamine is stored in specialised granules in mast cells and basophils, and the level of histamine is principally controlled by two enzymes; diamine oxidase and histamine N-methyltransferase (HNMT) (Jutel et al., 2002). Different receptor affinities to histamine and different cell types expressing the receptor trigger distinct biological responses leading to numerous inflammatory disorders. Histamine levels have been studied in various inflammatory diseases suggesting an association of these conditions to histamine receptors. Histamine levels are found to be elevated in bronchoalveolar fluids extracted from asthma patients, in the skin and plasma of patients with atopic dermatitis, in chronic urticaria biopsies, in both plasma and synovial fluid of patients with rheumatoid arthritis and in the plasma of patients with psoriatic arthritis (Pino-Ángeles et al., 2012). The major receptors shown to be linked to inflammation and immune response are H1, H2 and H4 receptors (Yu et al., 2010b). Activation of H1 receptors increases histamine release and the release of other mediators, while also augmenting the pro-inflammatory activity of the immune system by promoting migration to the area of inflammation. On the other hand, H2 receptors work by suppressing inflammation by decreasing eosinophil and neutrophil chemotaxis; decreasing IL-12 by dendritic cells; increasing IL-10 and inducing the development of Th2 or tolerance-inducing dendritic cells. The H4 receptor promotes the accumulation of inflammatory cells at sites of allergic inflammation by increasing calcium flux in human eosinophils; increasing eosinophil chemotaxis; and increasing IL-16 production (Akdis and Simons, 2006, Jutel et al., 2002).
    The histaminergic system in cancer Histamine has also been shown to be a contributing factor to cancer. Histamine seems to play a role in cell proliferation in malignant cells, where high histamine biosynthesis was reported in different human neoplasias (Medina et al., 2011, Rivera et al., 2000). It has been shown that H1 and H2 receptors are expressed in normal and malignant cell lines, and that H3 and H4 receptors are expressed in cell lines of human mammary gland (Medina et al., 2011). Studies focusing on the latter pair of receptors also demonstrated the presence in human mammary tissue with 67% for H3 receptor being detected in benign lesions and in all carcinomas, while 14% for H4 receptor being detected in benign lesions and 44% in carcinomas (Medina et al., 2008). The same research group also investigated the effect of H4 receptor agonists have on triple negative human breast cancer, and they showed that the agonists can significantly increase survival rate and tumour cell apoptosis (Martinel Lamas et al., 2013). These findings suggest that H3 and H4 receptors could be potential molecular therapeutic targets.