Homeostasis of Dopamine
Nira Ben-Jonathan in Dopamine, 2020
MAOs catalyze the oxidative deamination of biogenic amines that include catecholamines, indoleamines, trace amines, and xenobiotics (Table 1.2). MAO action alone produces 3,4, dihydroxyphenylacetic acid (DOPAC) by oxidation from DA and 3,4, dihydroxymandelic acid by oxidation from NE and Epi. Humans have two types of MAO: MAO-A and MAO-B, which are the products of separate genes [19,20]. The MAO isoenzymes share high homology (~70%) and similar intracellular location and structural characteristics but differ in their pharmacological profiles, ontogeny, tissue distribution, and functional roles. MAO-A preferentially oxidizes serotonin (Ser; 5-HT) and NE, while MAO-B has the highest affinity for the trace amine β-phenylethylamine (PEA). DA is catabolized by both isoenzymes, with a species-specific different level of affinity for the two isoenzymes: DA is primarily a substrate for MAO-A in rodents but is a substrate for MAO-B in humans and other primates. Despite their physiological divergence, each isoenzyme contributes to the metabolism of non-preferred substrates in the absence of the other enzyme.
Neurobiological Changes as an Explanation of Benefits of Exercise
Henning Budde, Mirko Wegner in The Exercise Effect on Mental Health, 2018
Animal studies have also shown that acute exercise has little positive effect on whole brain concentrations of NA. Meeusen and colleagues (see Meeusen & De Meirleir 1995; Meeusen et al. 2001), in very thorough systematic reviews, found either a decrease in NA concentrations or no significant effect. However, research has shown increased DA concentrations, particularly in the brainstem and hypothalamus, during and immediately following acute exercise (see Meeusen et al. 2001; Meeusen & De Meirleir 1995, for reviews). Despite this limited support for acute exercise-induced increases in brain concentrations of NA, animal studies have shown increases in brain concentrations of the NA metabolite 3-methoxy 4-hydroxyphenylglycol (MHPG) in most brain regions (Meeusen et al. 2001). Similarly, increased concentrations of the DA metabolites 3, 4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy 3-methoxyphenylacetic acid, also known as homovanillic acid (HVA), have also been shown, particularly in the brainstem and hypothalamus (Meeusen et al. 1997). This is evidence of acute exercise-induced turnover of NA and DA in the brain.
Epilepsy
Divya Vohora in The Third Histamine Receptor, 2008
Presynaptic H3 receptors occur both on histaminergic neurons of the CNS (autoreceptors) and on nonhistaminergic neurons of the CNS and autonomic nervous system [72]. Thus, they regulate the release of not only histamine but also other important transmitters such as norepinephrine (NE) [73], dopamine (DA) [74], 5-hydroxytryptamine (5-HT)[75], acetylcholine (Ach)[76] and gamma amino butyric acid (GABA) [47] through heteroreceptors in the CNS. Such effects of H3 heteroreceptors have been most thoroughly investigated in the mouse brain cortex where they cause inhibition of NE release [77] and in the guinea pig small intestine causing inhibition of ACh release [78]. H3 receptor antagonists have been demonstrated to enhance whereas histamine and H3 receptor agonists have been shown to reduce the release of these transmitters in in vitro studies. All these transmitters are related in some or the other way to epilepsy and epileptic seizures [57]. Although THP, an H3 receptor antagonist, was found to increase the release of GABA from the rat hypothalamus [47], RAMH, a selective agonist, inhibited the release [79]. It is needless to emphasize the importance of GABA in seizures and epilepsy. The effect of these ligands on GABA release correlates well with their effects on modulation of seizure activity. A study by Arrang et al. [80], however, demonstrated no inhibition of ACh release from rat entorhinal cortex synaptosomes following H3 receptor activation. H3 receptor antagonists also provided protection against amygdala kindling in rats [22]. A reduction in DA and NE content occurs following amygdala kindling [13]. Thus, it is possible that the protection afforded by these agents involve an indirect action through the enhancement of release of these neurotransmitters in brain. However, the dose of THP employed in the study provided protection but did not affect the brain levels of DA, 3,4-dihydroxyphenylacetic acid, 5-HT, and 5-hydoxyindoleacetic acid [23]; thus, ruling out the possibility of involvement of these neurotransmitters in the protective effect. The role for NE, however, may not be overlooked, as H3 receptors regulating the release of NE are located in the catecholaminergic nerve terminals. However, the modulation of even catecholaminergic tone was also not confirmed by in vivo studies [61]. In view of all these observations, the heteroreceptor function seems to play a minor role in contrast with the modulation of histamine release by these receptors [81].
The preclinical discovery and development of cariprazine for the treatment of schizophrenia
Published in Expert Opinion on Drug Discovery, 2018
Anna Wesołowska, Anna Partyka, Magdalena Jastrzębska-Więsek, Marcin Kołaczkowski
Atypical antipsychotics are able to preferentially increase extracellular concentrations of monoamines and acetylcholine in cortical and limbic brain regions [21–24]. In vivo studies with cariprazine focused primarily on dopaminergic and serotonergic neuronal activity [12]. Cariprazine enhanced the turnover and biosynthesis of dopamine in mouse brain, preferentially in olfactory tubercles (i.e. limbic region) compared to the striatum. Moreover, this compound potently and dose-dependently, but only partially, reduced the dopamine biosynthesis in the striatum of reserpinized mice and normalized a metabolite of dopamine (3,4-dihydroxyphenylacetic acid) accumulation to the control levels, reaching a plateau at the highest dose used. Cariprazine showed lower potential in inhibiting dopamine neurotransmission in the striatum relative to the limbic area, which suggests that it has low propensity toward causing extrapyramidal symptoms [12]. In addition, cariprazine moderately but significantly reduced serotonin turnover in all three regions studied: olfactory tubercles, striatum, and frontal cortex [12].
Insights into the intestinal bacterial metabolism of flavonoids and the bioactivities of their microbe-derived ring cleavage metabolites
Published in Drug Metabolism Reviews, 2018
Xinchi Feng, Yang Li, Mahmood Brobbey Oppong, Feng Qiu
Flavonols, flavones, flavanones, and chalcones undergo similar intestinal bacterial metabolic pathways. In 1956, Booth et al. provided evidence that quercetin could be metabolized into phenolic compounds (Booth et al. 1956). Four metabolites in the ether extracts of the urine of rabbits were found after the oral ingestion of rutin or its aglycone quercetin. Three of the metabolites were identified to be 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3-hydroxyphenylacetic acid (3-HPAA), and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA), respectively, by using both paper chromatographic and X-ray diffraction analyses. Additionally, the evidence that these phenolic compounds could not be detected in germ-free rats indicated that intestinal bacteria were responsible for their formation (Griffiths and Barrow 1972). Several other bacterial metabolites of flavonoids have been identified and it has been demonstrated that the degradation of quercetin was accompanied by the transient formation of two intermediates, taxifolin and alphitonin (Figure 2) (Gross et al. 1996; Braune et al. 2001; Rechner et al. 2002; Labib et al. 2004; Rechner et al. 2004; Serra et al. 2012; Weidmann 2012).
Aldehyde dehydrogenase-2 as a therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2019
Mitsuru Kimura, Akira Yokoyama, Susumu Higuchi
ALDH2 also plays an important role in eliminating toxic compounds produced due to the metabolism of lipids and neurotransmitters in the central nervous system. In addition to the neurotoxic effect of 4-HNE and MDA, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycoaldehyde (DOPGAL) produced from dopamine and norepinephrine, respectively by monoamine oxidase (MAO) are known to be associated with neurodegeneration due to their neurotoxicity. ALDH2 is widely expressed in the glial cells and neurons in the brain, which include the frontal and temporal cortexes, hippocampus, mid-brain, basal ganglia and cerebellum [85]. ALDH2 oxidizes DOPAL and DOPGAL into the nontoxic metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxymandelic acid (DOMA), respectively. Therefore, ALDH2 is considered to have neuroprotective effects against neurodegenerative diseases.
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