Glutamate in CNS disorders as a target for drug development: an update

Parsons, Chris G.; Danysz, Wojciech; Quack, G.

doi:10.1358/dnp.1998.11.9.863689

Cited by 380 publications

(264 citation statements)

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“…Antagonist of NMDA receptor subtype of glutamate receptor, protect against brain damage in neurological disorders (Danysz et al, 1995;Parsons et al, 1998;Krystal et al, 1999). However, in the previous studies it was observed that administration of NMDA receptor antagonists with high affinity or at high doses, can produce psychotomimetic effect in humans and neurotoxicity in specific neuronal subpopulations in the CNS of rodents, in particular neurons of the limbic cortex.…”

Section: Discussionmentioning

confidence: 99%

“…Glutamate receptor blockers with selective action on N-methyl-D-aspartate (NMDA) receptors have wide therapeutic potential in a variety of central nervous system (CNS) disorders ranging from the acute neurodegeneration (eg stroke and trauma), chronic neurodegeneration (eg Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD) (Danysz et al, 1995;Parsons et al, 1998;Krystal et al, 1999), to symptomatic treatment (eg epilepsy, PD, drug dependence, depression, anxiety, and chronic pain) (Meldrum, 1986;Danysz et al, 1995;Krystal et al, 1999;Skolnick, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…In these conditions, an excessive release of glutamate is thought to play a major role in triggering neuronal death via NMDA receptors (Choi, 1988;Danysz et al, 1995;Parsons et al, 1998). NMDA receptor channel blockers represent one group of pharmacologically active agents able to antagonize NMDA receptor activation by acting directly on the phencyclidine recognition site within the channel.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

Marvanová

Lakso

Wong

2004

Neuropsychopharmacol

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In this study, we monitored gene expression profiles using cDNA microarrays after an acute systemic administration of the high affinity N-methyl-D-aspartate (NMDA) uncompetitive antagonist MK-801 (1 mg/kg; 4 h), and the clinically used moderate affinity antagonist memantine (25 mg/kg; 4 h) in adult rat brains. From a microarray containing 1090 known genes, 13 genes were regulated by both treatments of which 12 were upregulated and one was downregulated. In addition, 28 and 34 genes were regulated (X1.5-or p0.67-fold change) by either memantine or MK-801, respectively. Genes commonly regulated by both treatments and not previously reported were confirmed by in situ hybridization (ISH) and include regenerating liver inhibitory factor-1 (RL/IF-1), GDP-dissociation inhibitor 1 (GDI-1), neural visinin Ca 2 þ -binding protein 2 (NVP-2), neuromedin B receptor, and Na þ /K þ transporting ATPase 2b. ISH with memantine (5-50 mg/kg) revealed regulation of these genes in other cortical and hippocampal regions. RL/IF-1 induction occurred at 1 h and returned to basal levels by 8 h, consistent with the profile of an immediate early gene. Western blot analysis showed increases (B30-65%) in GDI-1 protein present in both cytosolic and membrane fractions that were significant in the 84-kDa Rab bound form, suggesting that memantine influences Ras-like GTPase function. Genes regulated by a 5 mg/kg dose of memantine might be important in its therapeutic effects. These findings increase the number of known, differentially altered genes after treatment of uncompetitive NMDA receptor antagonists and suggest broader actions of these agents than previously realized.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

Marvanová

Lakso

Wong

2004

Neuropsychopharmacol

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“…Regardless, neurons under various conditions can become so over stimulated by Glu that it actually kills them through receptor-mediated depolarization and calcium (Ca ++ ) influx 49,50 . There are five main factors necessary for the transition of Glu and Asp from neurotransmitters to excitotoxins.…”

Section: Excitotoxicitymentioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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“…L-Glutamate plays important roles in many fields including bioprocess monitoring [1,2], biomedical application [3,4] and food processing [5]. As a functional amino acid, it is a crucial excitatory neurotransmitter in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%