,8-IMINAZOLYLETHYLAMINE is the amine which is produced when carbon dioxide is split off from histidine. It was first prepared synthetically by Windaus and Vogt'. Recently Ackermann2 obtained a large yield of the base by submitting histidine to the action of putrefactive organisms. It has been shown that several of the amines thus related to amino-acids possess marked physiological activity. The activity of j8-iminazolylethylamine was discovered in the course of the investigation of ergot and its extracts by G. Barger and one of us3, who attributed this structure to a base which they obtained, and which in minute doses produced tonic contraction of the uterus. The synthetic substance, and the base produced by splitting off carbon dioxide from histidine by bacterial action or by chemical means, were found to have an identical action. Meanwhile Kutscher4 had simultaneously and independently described the isolation from ergot of a base having this action and presumably identical with that obtained by Barger and Dale. By its chemical properties this first ergot base of Kutscher was not distinguishable from 8-iminazolylethylamine; but certain apparent differences in the physiological action of the two bases, observed by Ackermann and Kutscber-5, led them to the conclusion that the ergot base, though closely related to 8-iminazolylethylamine, is not identical with it. The alleged difference in action, on the existence and cause of which our experiments throw light, was as follows: the

The physiological action of β-iminazolylethylamine

Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies.

Mast cells and their mediators have been implicated in the pathogenesis of asthma and allergy for decades. Allergic asthma is a complex chronic lung disease in which several different immune cells, genetic factors and environmental exposures influence the pathology. Mast cells are key players in the asthmatic response through secretion of a multitude of mediators with pro-inflammatory and airway-constrictive effects. Well-known mast cell mediators, such as histamine and bioactive lipids are responsible for many of the physiological effects observed in the acute phase of allergic reactions. The accumulation of mast cells at particular sites of the allergic lung is likely relevant to the asthma phenotype, severity and progression. Mast cells located in different compartments in the lung and airways have different characteristics and express different mediators. According to in vivo experiments in mice, lung mast cells develop from mast cell progenitors induced by inflammatory stimuli to migrate to the airways. Human mast cell progenitors have been identified in the blood circulation. A high frequency of circulating human mast cell progenitors may reflect ongoing pathological changes in the allergic lung. In allergic asthma, mast cells become activated mainly via IgE-mediated crosslinking of the high affinity receptor for IgE (FceRI) with allergens. However, mast cells can also be activated by numerous other stimuli e.g. toll-like receptors and MAS-related G protein-coupled receptor X2. In this review, we summarize research with implications on the role and development of mast cells and their progenitors in allergic asthma and cover selected activation pathways and mast cell mediators that have been implicated in the pathogenesis. The review places an emphasis on describing mechanisms identified using in vivo mouse models and data obtained by analysis of clinical samples.

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Mast Cells and Their Progenitors in Allergic Asthma.

Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory functions by activating four types of GPCRs, designated as H1-4 . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H1 antihistamines and H2 -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders respectively. Recently, a first-in-class H3 inverse agonist was approved for the treatment of narcolepsy, whereas H4 antagonists are under clinical evaluation for their potential therapeutic exploitation in immune-related diseases. This review critically presents the past successes and drawbacks in histamine research, complemented by the modern conceptual innovations in molecular and receptor pharmacology. It targets both young and experienced researchers in an ongoing effort to stimulate novel insights for the dissection of the translational potential of histamine pharmacology. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.14524

Histamine pharmacology: from Sir Henry Dale to the 21st century.

Histamine, acting via distinct histamine H1 , H2 , H3 , and H4 receptors, regulates various physiological and pathological processes, including pain. In the last two decades, there has been a particular increase in evidence to support the involvement of H3 receptor and H4 receptor in the modulation of neuropathic pain, which remains challenging in terms of management. However, recent data show contrasting effects on neuropathic pain due to multiple factors that determine the pharmacological responses of histamine receptors and their underlying signal transduction properties (e.g., localization on either the presynaptic or postsynaptic neuronal membranes). This review summarizes the most recent findings on the role of histamine and the effects mediated by the four histamine receptors in response to the various stimuli associated with and promoting neuropathic pain. We particularly focus on mechanisms underlying histamine-mediated analgesia, as we aim to clarify the analgesic potential of histamine receptor ligands in neuropathic pain. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.14696

Histamine, histamine receptors, and neuropathic pain relief.

Among the four G protein–coupled receptors (H1–H4) identified as mediators of the biologic effects of histamine, the H3 receptor (H3R) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as autoreceptor and heteroreceptor, and this enables H3Rs to modulate the histaminergic and other neurotransmitter systems. The cloning of the H3R cDNA in 1999 by Lovenberg et al. allowed for detailed studies of its molecular aspects. In this work, we review the characteristics of the H3R, namely, its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonists, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main presynaptic and postsynaptic effects resulting from its activation. The H3R has attracted interest as a potential drug target for the treatment of several important neurologic and psychiatric disorders, such as Alzheimer and Parkinson diseases, Gilles de la Tourette syndrome, and addiction.

https://molpharm.aspetjournals.org/content/molpharm/90/5/649.full.pdf

The Histamine H3 Receptor: Structure, Pharmacology, and Function.

We previously reported that the activation of histamine H3 receptors (H3Rs) selectively counteracts the facilitatory action of adenosine A2A receptors (A2ARs) on GABA release from rat globus pallidus (GP) isolated nerve terminals (synaptosomes). In this work, we examined the mechanisms likely to underlie this functional interaction. Three possibilities were explored: (a) changes in receptor affinity for agonists induced by physical A2AR/H3R interaction, (b) opposite actions of A2ARs and H3Rs on depolarization-induced Ca2+ entry, and (c) an A2AR/H3R interaction at the level of adenosine 3′,5′-cyclic monophosphate (cAMP) formation. In GP synaptosomal membranes, H3R activation with immepip reduced A2AR affinity for the agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680) (Ki control 4.53 nM; + immepip 9.32 nM), whereas A2AR activation increased H3R affinity for immepip (Ki control 0.63 nM; + CGS-21680 0.26 nM). Neither A2AR activation nor H3R stimulation modified calcium entry through voltage-gated calcium channels in GP synaptosomes, as evaluated by microfluorometry. A2AR-mediated facilitation of depolarization-evoked [2,3-3H]-γ-aminobutyric acid ([3H]-GABA) release from GP synaptosomes (130.4 ± 3.6% of control values) was prevented by the PKA inhibitor H-89 and mimicked by the adenylyl cyclase activator forskolin or by 8-Bromo-cAMP, a membrane permeant cAMP analogue (169.5 ± 17.3 and 149.5 ± 14.5% of controls). H3R activation failed to reduce the facilitation of [3H]-GABA release induced by 8-Bromo-cAMP. In GP slices, A2AR activation stimulated cAMP accumulation (290% of basal) and this effect was reduced (− 75%) by H3R activation. These results indicate that in striato-pallidal nerve terminals, A2ARs and H3Rs interact at the level of cAMP formation to modulate PKA activity and thus GABA release.

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Adenosine A 2A and histamine H 3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [ 3 H]-GABA release from rat striato-pallidal terminals

Among the four G-protein coupled receptors (H1-H4 ) identified as the mediators of the biological effects of histamine, the H3 receptor (H3R) distinguishes for its almost exclusive expression in the nervous system and its dual function as auto- and hetero-receptor that enables H3Rs to modulate the histaminergic and other neurotransmitter systems. The basal ganglia are neuronal nuclei that form a sub-cortical circuitry responsible for integrating motor and sensorial information originated in the cerebral cortex and the thalamus. The abundant presence of H3Rs in the basal ganglia confers these receptors a preferential and strategic position to modulate both the incoming and the outgoing synaptic information. In this chapter we review the control by H3Rs of the release of the neurotransmitters involved in the basal ganglia circuitry.

Modulation by Histamine H3 Receptors of Neurotransmitter Release in the Basal Ganglia

Abstract Alterations in dopaminergic transmission are associated with neurological disorders, such as depression, autism, and Parkinson’s disease. Exposure of rats to ambient fine (FP) or ultrafine (UFP) particles induces oxidative and inflammatory responses in the striatum, a neuronal nucleus with dense dopaminergic innervation and critically involved in the control of motor activity. Objectives: We used an ex vivo system to evaluate the effect of in vivo inhalation exposure to FP and UFP on motor activity and dopaminergic transmission. Materials and Methods: Male adult Wistar rats were exposed to FP, UFP, or filtered air for 8 weeks (subchronic exposure; 5 h/day, 5 days/week) in a particle concentrator. Motor activity was evaluated using the open-field test. Uptake and release of [3H]-dopamine were assessed in striatal synaptosomes, and dopamine D2 receptor (D2R) affinity for dopamine was evaluated by the displacement of [3H]-spiperone binding to striatal membranes. Results: Exposure to FP or UFP significantly reduced spontaneous motor activity (ambulatory distance: FP −25%, UFP −32%; ambulatory time: FP −24%, UFP −22%; ambulatory episodes: FP −22%, UFP −30%), decreased [3H]-dopamine uptake (FP −18%, UFP −24%), and increased, although not significantly, [3H]-dopamine release (113.3 ± 16.3 and 138.6 ± 17.3%). Neither FP nor UFP exposure affected D2R density or affinity for dopamine. Conclusions: These results indicate that exposure to ambient particulate matter reduces locomotion in rats, which could be related to altered striatal dopaminergic transmission: UFP was more potent than FP. Our results contribute to the evidence linking environmental factors to changes in brain function that could turn into neurological and psychiatric disorders. HIGHLIGHTS Young adult rats were exposed to fine (FP) or ultrafine (UFP) particles for 40 days. Exposure to FP or UFP reduced motor activity. Exposure to FP or UFP reduced dopamine uptake by striatal synaptosomes. Neither D2R density or affinity for dopamine was affected by FP or UFP. UFP was more potent than FP to exert the effects reported.

Guadalupe-Elide Morales-Figueroa

Papers

The Histamine H3 Receptor: Structure, Pharmacology, and Function.

Adenosine A 2A and histamine H 3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [ 3 H]-GABA release from rat striato-pallidal terminals

Modulation by Histamine H3 Receptors of Neurotransmitter Release in the Basal Ganglia

Effect of subchronic exposure to ambient fine and ultrafine particles on rat motor activity and ex vivo striatal dopaminergic transmission