Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of selective, systemically active alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists over the last 4 years has enabled the role of this excitatory amino acid receptor subtype to be scrutinised in the different models of ischaemia. The animal models of cerebral ischaemia can be subdivided into two major categories: focal ischaemia, in which the resulting infarct resembles the clinical condition of stroke; and models of severe forebrain ischaemia, in which there is delayed neuronal degeneration of hippocampal CA1 neurones. The neuropathology in the latter models resembles the clinical condition seen following a cardiac arrest, for example. It is well established that N-methyl-D-aspartate (NMDA) antagonists such as MK-801, 3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonate (CPPene), DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849), and N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine hydrochloride (CNS 1102) are neuroprotective in animal models of focal ischaemia. However, in models of severe forebrain ischaemia NMDA antagonists produced only partial protection. The discovery of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX) as a systemically active AMPA receptor antagonist enabled the role of this receptor subtype in ischaemia to be investigated. NBQX was shown to be neuroprotective against delayed neuronal degeneration of hippocampal CA1 neurones in animal models of severe forebrain ischaemia. Recent studies have demonstrated that NBQX administration can be delayed by up to 12 h and amelioration of delayed neuronal degeneration of hippocampal CA1 neurones can still be seen. NBQX has also been shown to be neuroprotective in animal models of permanent and temporary middle cerebral artery occlusion. 1-(Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a systemically active noncompetitive AMPA/kainate antagonist, was neuroprotective against focal ischaemia but was unable to attenuate hippocampal CA1 neuronal degeneration. Whilst the newer compounds such as (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl )-ethyl]-1,2,3,4,4a,5,6,7,8a-decahydroisoquinoline-3-carboxylic acid (LY 215490) and 6-(1-imidazolyl)-7-nitroquinoxaline-2,3(1H,4H)-dione (YM900) have been demonstrated to be neuroprotective in focal ischaemia models, there is still a lack of information with regard to their efficacy in models of severe forebrain ischaemia. It appears from initial studies that AMPA/kainate antagonists have a better behavioural profile than NMDA antagonists in terms of a lack of phychostimulant and phychotomimetic effects. However, these antagonists have their own problems in that they cause severe depression of glucose utilisation in the central nervous system at neuroprotective doses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists and their role in cerebral ischaemia. 752 37

Local cerebral glucose utilization was examined using [14C]2-deoxyglucose autoradiography following systemic administration of the AMPA antagonists 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) and 6-(2-(1H-tetrazol-5-yl)ethyl)decahydroisoquinoline-3-carboxy lic acid (LY-293558) in conscious rats. Both NBQX (10, 30 and 100 mg/kg) and LY-293558 (10, 30 and 100 mg/kg) produced marked, anatomically widespread, dose-dependent reductions in glucose utilization throughout the brain. In none of the 50 regions investigated were elevations in glucose use observed at any dose of either agent. The reductions in glucose use were accompanied by sedation, suppression of spontaneous behaviour, and respiratory depression after NBQX (30 and 100 mg/kg) and LY-293558 (30 and 100 mg/kg) administration. The greatest reductions in glucose use after NBQX or LY-293558 occurred in primary auditory regions, limbic structures (particularly hippocampal regions and cingulate cortex), neocortex and some thalamic nuclei. However, a small number of regions were found to be insensitive to either NBQX or LY-293558, most notably the superior colliculus superficial layer which failed to display significant alterations in glucose use following any concentration of either AMPA antagonist. The anatomical pattern of altered glucose use was essentially similar following either agent although the cerebral cortex, thalamus and auditory regions were more sensitive to LY-293558 and subcortical regions more sensitive to NBQX. The anatomical pattern of glucose use alterations after AMPA receptor antagonists differs from that described previously for competitive and non-competitive NMDA receptor antagonists.
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PMID:AMPA receptor antagonists and local cerebral glucose utilization in the rat. 801 34

Activation of kainate receptors depresses excitatory synaptic transmission in the hippocampus. In the present study, we have utilised a GluR5 selective agonist, ATPA [(RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid], and a GluR5 selective antagonist, LY294486 [(3SR,4aRS,6SR,8aRS)-6-([[(1H-tetrazol-5-y l)methyl]oxy]methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3 -carboxylic acid], to determine whether GluR5 subunits are involved in this effect. ATPA mimicked the presynaptic depressant effects of kainate in the CA1 region of the hippocampus. It depressed reversibly AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor-mediated field excitatory postsynaptic potentials (field EPSPs) with an IC50 value of approximately 0.60 microM. The dual-component excitatory postsynaptic current (EPSC) and the pharmacologically isolated NMDA (N-methyl-D-aspartate) receptor-mediated EPSC were depressed to a similar extent by 2 microM ATPA (61 +/- 7% and 58 +/- 6%, respectively). Depressions were associated with an increase in the paired-pulse facilitation ratio suggesting a presynaptic locus of action. LY294486 (20 microM) blocked the effects of 2 microM ATPA on NMDA receptor-mediated EPSCs in a reversible manner. In area CA3, 1 microM ATPA depressed reversibly mossy fibre-evoked synaptic transmission (by 82 +/- 10%). The effects of ATPA were not accompanied by any changes in the passive properties of CA1 or CA3 neurones. However, in experiments where K+, rather than Cs+, containing electrodes were used, a small outward current was observed. These results show that GluR5 subunits comprise or contribute to a kainate receptor that regulates excitatory synaptic transmission in both the CA1 and CA3 regions of the hippocampus.
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PMID:The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus. 984 64

Kainate receptors are implicated in a variety of physiological and pathological processes in the CNS. Previously we demonstrated that (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA), a selective agonist for the GLU(K5) subtype of kainate receptor, depresses monosynaptically evoked inhibitory postsynaptic potentials (IPSPs) in the CA1 region of the rat hippocampus. In the current study, we provide a more detailed characterisation of this effect. Firstly, our data demonstrate a rank order of potency of domoate>kainate>ATPA>alpha-amino-3-(3-hydroxy-5-methyl-4-isoxalolyl)propionic acid Secondly, we confirm that the effects of ATPA are not mediated indirectly via the activation of gamma-aminobutyric acid receptors (i.e. either GABA(A) or GABA(B)). Thirdly, we show that the small increase in conductance induced by ATPA is insufficient to account for the depression of monosynaptic inhibition. Fourthly, we show that the effects of ATPA on IPSPs are antagonised by the GLU(K5)-selective antagonist (3S, 4aR, 6S, 8aR)-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). However, LY382884 is less potent as an antagonist of the effects of ATPA on IPSPs compared to its depressant effect on EPSPs.
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PMID:Characterisation of the effects of ATPA, a GLU(K5) kainate receptor agonist, on GABAergic synaptic transmission in the CA1 region of rat hippocampal slices. 1527 25

Although some physiological functions of kainate receptors (KARs) still remain unclear, recent advances have highlighted a role in synaptic physiology. In hippocampal slices, kainate depresses GABA-mediated synaptic inhibition and increases the firing rate of interneurons. However, the sensitivity to agonists of these responses differs, suggesting that the presynaptic and somatic KARs have a distinct molecular composition. Hippocampal interneurons express several distinct KAR subunits that can assemble into heteromeric receptors with a variety of pharmacological properties and that, in principle, could fulfill different roles. To address which receptor types mediate each of the effects of kainate in interneurons, we used new compounds and mice deficient for specific KAR subunits. In a recombinant assay, 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) acted exclusively on homomeric glutamate receptor subunit 5 (GluR5), whereas 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl) 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) antagonized homomeric GluR5 and any heteromeric combination containing GluR5 subunits. In hippocampal slices, LY382884, but not NS3763, was able to prevent kainate-induced depression of evoked IPSC. In contrast, neither prevented the concomitant increase in spontaneous IPSC frequency. The selectivity of these compounds was seen additionally in knock-out mice, such that they were inactive in GluR5-/- mice but completely effective in GluR6-/- mice. Our data indicate that in wild-type mice, CA1 interneurons express heteromeric GluR6 -KA2 receptors in their somatic compartments and GluR5-GluR6 or GluR5-KA2 at presynaptic terminals. However, functional compensation appears to take place in the null mutants, a new pharmacological profile emerging more compatible with the activity of homomeric receptors in both compartments: GluR5 in GluR6-/- mice and GluR6 in GluR5-/- mice.
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PMID:A mosaic of functional kainate receptors in hippocampal interneurons. 1548 17