Persistent therapeutic effect of a novel α5-GABA receptor antagonist in rodent preclinical models of vascular cognitive impairment.

This study examined the potential of the selective extra-synaptic α5-GABA receptor inhibitor S44819 (Egis-13529) to improve cognitive performance in preclinical models of vascular cognitive impairment (VCI). Chronic hypoperfusion of the brain in mice was induced by permanent occlusion of the right common carotid artery (rUCO). rUCO induced impairments of cognitive function in the object recognition test (OR) and the rewarded T-maze (RTM).

Loop F of the GABA receptor alpha subunit governs GABA potency.

Gamma-amino butyric acid (GABA) is an abundant neurotransmitter in the CNS. GABAergic interneurons orchestrate pyramidal neurons in the cerebral cortex, and thus control learning and memory. Ionotropic receptors for GABA (GABAR) are heteropentameric complexes of α, β and γ integral membrane-protein subunits forming Cl -channels operated by GABA, which are vital for brain function and are important drug targets.

Behavioural pharmacology of the α5-GABA receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models.

Previous work has shown that S44819 is a novel GABAA receptor (GABAR) antagonist, which is selective for extrasynaptic GABARs incorporating the α5 subunit (α5-GABARs). The present study reports on the preclinical neuropsychopharmacological profile of S44819. Significantly, no sedative or pro-convulsive side effects of S44819 were found at doses up to 30 mg/kg i.

A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential.

Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test.

Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents.

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects.

Kynurenine diminishes the ischemia-induced histological and electrophysiological deficits in the rat hippocampus.

The neuroprotective effect of L-kynurenine sulfate (KYN), a precursor of kynurenic acid (KYNA, a selective N-methyl-D-aspartate receptor antagonist), was studied. KYN (300 mg/kg i.p.

Neuroprotection achieved in the ischaemic rat cortex with L-kynurenine sulphate.

L-kynurenine is a metabolic precursor of kynurenic acid, which is one of the few known endogenous N-methyl-D-aspartate receptor inhibitors. In contrast with kynurenic acid, L-kynurenine is transported across the blood-brain barrier, and it may therefore come into consideration as a therapeutic agent in certain neurobiological disorders, e.g.

Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils.

Excessive stimulation of N-methyl-D-aspartate (NMDA) receptors during ischemia contributes to apoptotic and excitotoxic nerve cell death. Kynurenic acid is a selective antagonist at the glycine co-agonist site of the NMDA receptor complex at low concentration, and it is a broad-spectrum excitatory amino acid receptor blocker at high concentration. Kynurenic acid provides neuroprotection in animal models of cerebral ischemia only at very high doses as it hardly crosses the blood-brain barrier.

Therapeutic time window of neuroprotection by non-competitive AMPA antagonists in transient and permanent focal cerebral ischemia in rats.

EGIS-8332 and GYKI 53405 are selective, non-competitive AMPA (2-amino-3[3-hydroxy-5-methyl-4-isoxazolyl] propionic acid) antagonists that effectively protected against tissue injury caused by global and focal cerebral ischemia in laboratory animals. This study evaluated the therapeutic time window of neuroprotection by EGIS-8332 and GYKI 53405 in permanent and transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. Infarct size was measured by TTC staining 48 h after permanent MCAO (electrocoagulation), and 24 h after reperfusion following a 1-h transient MCAO carried out using the intraluminal filament technique.

Use of TTC staining for the evaluation of tissue injury in the early phases of reperfusion after focal cerebral ischemia in rats.

Background And Purpose: 2,3,5-Triphenyltetrazolium chloride (TTC) staining measures tissue viability used to evaluate infarct size. The goal of this study was to compare viability of neuronal tissue during the early phases of ischemia-reperfusion assessed either by perfusion of the brain with TTC solution transcardially, in vivo, or by staining brain slices, in vitro.

Methods: The middle cerebral artery was occluded for 1 h in male SPRD rats and then reperfused for 0, 1, 4, 8, 16 and 24 h.

The effects of AMPA receptor antagonists in models of stroke and neurodegeneration.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists have been shown to have neuroprotective effects in stroke models and although clinical trials with some agents are still ongoing, published results have not been favourable. We therefore wished to compare the effects of GYKI 52466, GYKI 53405, EGIS-8332 and EGIS-10608, non-competitive AMPA receptor antagonists with homophthalazine chemical structures, in standard animal stroke models with effects in a neurodegenerative model--excitoxicity in newborn mice. All compounds inhibited the S-AMPA-induced spreading depression in the chicken retina, in vitro, and were potent anticonvulsants against maximal electroshock in mice, in vivo.

Reduction of cerebral infarct size by non-competitive AMPA antagonists in rats subjected to permanent and transient focal ischemia.

Antagonists of 2-amino-3(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) receptors can considerably reduce brain damage after cerebral ischemia, but effectiveness of selective AMPA antagonists has been questioned recently. Therefore, we evaluated the antiischemic efficacy of [+/-]-7-acetyl-5-[4-aminophenyl]-7,8-dihydro-8-cyano-8-methyl-9H-1,3-dioxolo-[4,5-h]-2,3-benzodiazepine (EGIS-8332) and GYKI 53405, two selective, non-competitive AMPA antagonists in two rat models of focal cerebral ischemia. Permanent focal ischemia was produced by electrocoagulation of the middle cerebral artery (MCA).

Comparison of the AMPA antagonist action of new 2,3-benzodiazepines in vitro and their neuroprotective effects in vivo.

Purpose: AMPA receptor-mediated excitotoxicity is thought to be a critical process in diseases accompanied by neuronal cell loss following a hypoxic/anoxic state of the central nervous system. It has been suggested that blockade of AMPA receptors might result in significant protection of neurons against cellular damage. For testing the hypothesis, in vitro efficacy and in vivo neuroprotective action of new 2,3-benzodiazepine (2,3BDZ) AMPA antagonists have been compared.