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Tanay, Véronique A.-M. I.; Parent, Marise B.; Wong, Janet; Paslawski, Teresa; Martin, Ian L.; Baker, Glen B.

doi:10.1023/a:1012697904299

Cited by 20 publications

(3 citation statements)

References 36 publications

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“…The increase of GABA brain levels observed upon acute and chronic phenelzine treatments is known to be caused by a sustained inhibition of another PLPdependent enzyme, GABA aminotransferase [123]. An investigation that examined the effect of phenelzine on several amino acids levels and AGXT activity indicated a moderate but dose-related inhibition of the enzyme, which is probably contributing to the observed increase in alanine brain levels [124]. The analysis of the amino acid concentrations indicated an increase only for alanine and GABA, ruling out a role of phenelzine as a general inhibitor of PLP-dependent aminotransferases.…”

Section: Alanine Aminotransferasementioning

confidence: 99%

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Amadasi¹,

Bertoldi²,

Contestabile³

et al. 2007

CMC

177

156

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The vitamin B(6)-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA decarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), serine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent enzymes for the selection of drug targets is discussed.

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Section: Alanine Aminotransferasementioning

confidence: 99%

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Amadasi¹,

Bertoldi²,

Contestabile³

et al. 2007

CMC

177

156

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“…Phenelzine is a non-selective monoamine oxidase inhibitor (MAOI) that is used as an antidepressant. Phenelzine is a derivative of hydrazine, which is a phenylethylamine-like moiety that is similar to normal substrates of MAO [4,5]. When MAO attempts to oxidize phenelzine, the hydrazine-moiety binds covalently to the enzyme, thereby irreversibly inactivating it.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profile analysis of genes in rat hippocampus from antidepressant treated rats using DNA microarray

Lee

Kim

et al. 2010

BMC Neurosci

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BackgroundThe molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis. However, the entire cascade of mechanisms responsible for the therapeutic effect of antidepressants has not yet been elucidated.ResultsWe used a genome-wide microarray system containing 30,000 clones to evaluate total RNA that had been isolated from the brains of treated rats to identify the genes involved in the therapeutic mechanisms of various antidepressants, a tricyclic antidepressant (imipramine). a selective serotonin reuptake inhibitor (fluoxetine), a monoamine oxidase inhibitor (phenelzine) and psychoactive herbal extracts of Nelumbinis Semen (NS). To confirm the differential expression of the identified genes, we analyzed the amount of mRNA that was isolated from the hippocampus of rats that had been treated with antidepressants by real-time RT-PCR using primers specific for selected genes of interest. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signaling, survival and protein metabolism, suggesting that the therapeutic effect of these antidepressants is very complex. Surprisingly, unlike other antidepressants, we found that the standardized herbal medicine, Nelumbinis Semen, is free of factors that can induce neurodegenerative diseases such as caspase 8, α-synuclein, and amyloid precursor protein. In addition, the production of the inflammatory cytokine, IFNγ, was significantly decreased in rat hippocampus in response to treatment with antidepressants, while the inhibitory cytokine, TGFβ, was significantly enhanced.ConclusionsThese results suggest that antidepressants function by regulating neurotransmission as well as suppressing immunoreactivity in the central nervous system.

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“…Recently, upregulation of glutamate transporters by polyphenol-rich Hibiscus sabdariffa extract was found to protect HT-22 cells from glutamate-induced neurodegeneration [ 43 ]. There are also reports that alanine is involved in the transport and storage of glutamate in astrocytes and glutamatergic neurons [ 44 ]. In this study, PCA had no effect on histidine levels, although postmortem examinations in healthy rats given PCA p.o.…”

Section: Discussionmentioning

confidence: 99%

Protocatechuic Acid Prevents Some of the Memory-Related Behavioural and Neurotransmitter Changes in a Pyrithiamine-Induced Thiamine Deficiency Model of Wernicke–Korsakoff Syndrome in Rats

et al. 2023

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The purpose of this research was to investigate the effects of protocatechuic acid (PCA) at doses of 50 and 100 mg/kg on the development of unfavourable changes in cognitive processes in a pyrithiamine-induced thiamine deficiency (PTD) model of the Wernicke–Korsakoff syndrome (WKS) in rats. The effects of PCA were assessed at the behavioural and biochemical levels. Behavioural analysis was conducted using the Foot Fault test (FF), Bar test, Open Field test, Novel Object Recognition test (NOR), Hole–Board test and Morris Water Maze test (MWM). Biochemical analysis consisting of determination of concentration and turnover of neurotransmitters in selected structures of the rat CNS was carried out using high-performance liquid chromatography. PTD caused catalepsy (Bar test) and significantly impaired motor functions, leading to increased ladder crossing time and multiplied errors due to foot misplacement (FF). Rats with experimentally induced WKS showed impaired consolidation and recall of spatial reference memory in the MWM test, while episodic memory related to object recognition in the NOR was unimpaired. Compared to the control group, rats with WKS showed reduced serotonin levels in the prefrontal cortex and changes in dopamine and/or norepinephrine metabolites in the prefrontal cortex, medulla oblongata and spinal cord. PTD was also found to affect alanine, serine, glutamate, and threonine levels in certain areas of the rat brain. PCA alleviated PTD-induced cataleptic symptoms in rats, also improving their performance in the Foot Fault test. In the MWM, PCA at 50 and 100 mg/kg b.w. improved memory consolidation and the ability to retrieve acquired information in rats, thereby preventing unfavourable changes caused by PTD. PCA at both tested doses was also shown to have a beneficial effect on normalising PTD-disrupted alanine and glutamate concentrations in the medulla oblongata. These findings demonstrate that certain cognitive deficits in spatial memory and abnormalities in neurotransmitter levels persist in rats that have experienced an acute episode of PTD, despite restoration of thiamine supply and long-term recovery. PCA supplementation largely had a preventive effect on the development of these deficits, to some extent also normalising neurotransmitter concentrations in the brain.

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Cited by 20 publications

References 36 publications

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Gene expression profile analysis of genes in rat hippocampus from antidepressant treated rats using DNA microarray

Protocatechuic Acid Prevents Some of the Memory-Related Behavioural and Neurotransmitter Changes in a Pyrithiamine-Induced Thiamine Deficiency Model of Wernicke–Korsakoff Syndrome in Rats

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