Histamine function

Fernandez-Novoa, L., Cacabelos, R. (2001) Histamine function in brain disorders. Behav. Brain Res., 124, 213-233. 

Histamine in the Brain. There is evidence that histamine functions as a neurolransmiller or a neuromodululor in the brain. In the brain, histamine is related to functions such as the regulation of neuroendocrine and cardiovascular systems, thermoregulation, the circadian rhythm of sleep-wakefulness. behavior, vestibular function, cerebral vascular regulation, and anlinociccption and analgesia. 

Marchelli used the copper(II) complex of histamine-functionalized P-cy-clodextrin for chiral recognition and separation of amino acids [27]. The best results were obtained for aromatic amino acids (Trp). Enantioselective sensing of amino acids by copper(II) complexes of phenylalanine-based fluorescent P-cyclodextrin has been recently published by the same author [28, 29]. The host containing a metal-binding site and a dansyl fluorophore was shown to form copper(II) complexes with fluorescence quenching. Addition of d- or L-amino acids induced a switch on of the fluorescence, which was enantioselective for Pro, Phe, and Trp. This effect was used for the determination of the optical purity of proline. 

These observations suggest a relative decrease in histamine function in schizophrenia. Consistent with this hypothesis, one study that examined histamine receptor expression in postmortem brain found a decreased [3H]mepyramine binding to the HI receptor in the PFC (Nakai et al., 1991). Given the modulatory roles of the histamine receptors in the CNS, including direct effects on NMDA receptor activation and therapeutic effects in affected individuals, this receptor family warrants closer scrutiny in this illness (Brown et al., 2001). 

Histamine released from mast cells plays an important physiological role in immediate hypersensitivity and allergic responses. In addition, histamine functions as a neurotransmitter in the CNS and it is a potent stimulus for gastric acid secretion. These actions depend on the interaction of histamine with two types of receptors, Hi and H2. Hi and H2 receptors are coupled via G proteins to phospholipase C and adenylyl cyclase, respectively. The principal H3 receptor response is stimulation of gastric acid secretion, whereas other actions of histamine (e.g., smooth muscle contraction, vasodilation, increased capillary permeability, pain, and itching) are prunarily mediated by Hi receptors. 

Question Two scaffolds with histamine receptor antagonist activity were in the process of being optimized with a histamine functional assay see Figure 14.20. It was known that the assay was somewhat variable (i.e., histamine varies in potency from day to day), but it was... 

Following release, histamine binds to either HI or H2 histamine receptors causing a variety of effects (listed in Table 9.8). In addition to allergens, several other substances cause histamine release, including radiodiagnostic dyes, some antibiotics, kinins (chemicals released by immune cells) and some venoms. Several synthetic histamine agonists are available for laboratory studies of histamine functions, but there are virtually no clinical indications for histamine receptor agonists. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

FIGURE 4.5 The structures of some ammo acids that are not normally found in proteins but that perform other important biological functions. Epinephrine, histamine, and serotonin, although not amino acids, are derived from and closely related to amino acids. 

Histamine is a biogenic amine that is widely distributed in the body and functions as a major mediator of inflammation and allergic reactions, as a physiological regulator of gastric acid secretion in the stomach, as a neurotransmitter in the central nervous system (CNS) and may also have a role in tissue growth and repair. 

Hill SI (1990) Distribution, properties and functional characteristics of three classes of histamine receptor. Pharmacol Rev 42 45-83... 

TBT and TFT are membrane-active molecules, and their mechanism of action appears to be strongly dependent on organotin(IV) lipophilicity. They function as ionophores and produce hemolysis, release Ca(II) from sarcoplasmic reticulum, alter phosphatodylseiine-induced histamine release, alter mitochondrial membrane permeability and perturb membrane enzymes. Organotin(IV) compounds have been shown to affect cell signaling they activate protein kinase and increase free arachidonic acid through the activation of phospholipase... 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati 61 J, Huvar A, Jackson MR> Erlander MG Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol 1999 55 1101. 

Imamura M, Seyedi N, Lander HM, Levi R Functional identification of histamine H3-receptors in the human heart. Circ Res 1995 77 206. 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

In the preceding chapters, the synaptic pharmacology of those substances clearly established as NTs in the CNS, i.e. glutamate, GABA, ACh, NA, DA, 5-HT and certain peptides, has been discussed in some detail. There are other substances found in the CNS that could have a minor transmitter role, e.g. ATP, histamine and adrenaline, while still others that cannot claim such a property but clearly modify CNS function in some way, e.g. steroids, prostaglandins and nitric oxide. We will consider each of them in what we hope is appropriate detail. 

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