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    • In conclusion we demonstrate for the first time that histami

    2021-11-29

    In conclusion, we demonstrate, for the first time, that histamine plays a key role in regulating astrocyte function and gliotransmitter release, and we now must re-consider the roles of monoamine neurotransmitters in brain function in the context of astrocyte signalling. Further in vivo studies will reveal new possibilities in drug design for the treatment of different neurological disorders.
    Conflict of interest
    Acknowledgements We acknowledge the support of the Biomedical Research Core of Tohoku University Graduate School of Medicine and the Biomedical Research Unit of Tohoku University Hospital. This work was supported by a Grant-in-Aid for Scientific Research (A) (26253016) from the Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Young Scientists (B) (16K18389) from JSPS, and a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan. We also acknowledge the support of the Tohoku University Division for Interdisciplinary Advanced Research and Education, and the Nishinomiya Basic Research Fund, Japan.
    Introduction Histamine (2-[4-imidazolyl]ethylamine) is a bioactive amine discovered in 1910 by Dale and Laidlaw [1] which is synthesized by decarboxylation of the amino AS8351 histidine, using pyridoxal phosphate (vitamin B6) as cofactor. It is mainly produced in mast cells, basophils, platelets, histaminergic neurons and enterochromaffin cells; where it is stored intracellularly in vesicles until its release upon stimulation. Histamine (HA) is involved in the regulation of different physiological functions such as the secretion of gastric juice, cell growth and cellular differentiation, the day-night rhythm, neurotransmission and immunomodulation [2], [3]. Two metabolic pathways for HA are known in humans. Histamine-N-methyltransferase (HNMT) is the enzyme responsible for the ring methylation of HA and is mainly located in the liver and kidney and it carries out the conversion of HA to 1-methylhistamine (MHA), which will be finally converted to N-methylimidazoleacetic acid. As a cytosolic protein, HNMT metabolizes HA only in the intracellular space of cells [4], [5], [6]. On the other hand, diamine oxidase (DAO) is an enzyme of mainly intestinal location that performs the oxidative deamination of HA producing imidazole acetaldehyde, which will later be converted to imidazoleacetic acid and finally combined with ribose for its urinary excretion. As a secretory protein, DAO is responsible for scavenging extracellular HA after mediator release, being the main enzyme for the metabolism of intestinal HA [4], [5], [6]. Histamine intolerance (HIT) is a disorder in the homeostasis of HA due to a reduced intestinal degradation of this amine resulting in its accumulation in plasma and the appearance of multifaceted clinical symptoms, mainly headaches, flatulence, diarrhea, abdominal pain, sneezing, rhinorrhea, hypotonia, arrhythmias, idiopathic urticaria and pruritus [2], [3], [7]. An enzymatic deficiency of DAO, key enzyme in the intestinal degradation of histamine, can occur based on genetic predisposition, in inflammatory and degenerative intestinal disorders or by pharmacological blockade [3], [8], [9]. The incidence of HIT has been estimated to be 1% of the population although this percentage may increase as a consequence of a better knowledge and diagnostic of this enzymatic deficiency. Current therapy for HIT is the limitation of foods containing HA, which may be complemented with encapsulated DAO enzyme to contribute to the degradation of intestinal HA [3], [10]. Currently, the identification of individuals with HIT is based on plasmatic DAO activity through a biochemical assay that measures the amount of HA that can be degraded by this enzyme [11]. An alternative for the diagnosis of HIT by DAO deficiency could be the determination of HA and its metabolites in urine, considering that individuals with insufficient DAO activity would have a distribution profile of these compounds significantly different from healthy individuals. In fact, individuals with symptoms associated with HIT would show a higher urinary content of HA and its major metabolite produced by the HNMT metabolic pathway (MHA) than healthy population.