Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the expression of ionotropic glutamate receptors (GluR) contribute to neuronal loss after brain ischemia and epilepsy. In order to determine whether altered expression of GluR subunits might contribute to cell loss after spinal cord injury (SCI), we performed a time course study of subunit mRNA expression using quantitative in situ hybridization. Expression was studied in ventral horn motor neurons (VMN) and glia in adjacent ventral white matter at 15 min and 4, 8, and 24 h after SCI in tissue sections 4 mm rostral and caudal to the injury epicenter. We found that the AMPA subunit GluR2 was significantly down-regulated in VMN at 24 h, but not at the earlier times examined, although half the loss of VMN in these locations occurs by 8 h after injury. No changes in the normal expression of GluR2 or GluR4 were found in white matter where glial loss occurs after SCI. NMDA subunits NR1 and NR2A were significantly and rapidly up-regulated in VMN after SCI, but only caudal to the lesion site, while VMN loss is similar rostral and caudal to the epicenter. Thus, the temporal pattern of AMPA and the spatial pattern of NMDA subunit expression changes were distinct from the pattern of VMN loss after SCI. We conclude that altered GluR subunit expression after SCI is unlikely to be involved in secondary cell loss and instead may be involved with plasticity and reorganization of the injured spinal cord.
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PMID:Relationship of altered glutamate receptor subunit mRNA expression to acute cell loss after spinal cord contusion. 1125 16

Prostaglandins may influence cyclo-oxygenase (COX-2) and nitric oxide (NO) synthase activity, thus interfering with ischemia-induced neurotoxic processes. The prostaglandin synthetic derivative, latanoprost was tested in different in vivo and in vitro models of neuronal damage in order to study its influence on these processes. Ischemia was induced in rats by bilateral occlusion of the carotid arteries for 30 min. Latanoprost (0.01 mg x kg(-1)per die, i.p. for 3 days) or the ionotropic glutamate receptors antagonist, MK-801 (0.1 mg x kg(-1)per die, i.p. for 3 days) were equal in preventing lactate accumulation in retinal tissue of animals subjected to acute ischemia. Similar results were obtained in animals with retinal ischemia induced by increasing intraocular pressure to 120 mm Hg for 45 min. PGF2alpha, PGE2, latanoprost and acid of latanoprost (PhXA85) reduced the release of LDH from primary cultures of human retinal cells in vitro subjected to glutamate (10 microM) or hypoxia/re-oxygenation exposure. This effect was observed only at concentrations of 1-0.01 microM for PGF2alpha and PGE2, and of 0.1-0.001 microM for latanoprost (0.01 microM-0.1 nM for PhXA85). The COX-2 activity in cultured retinal cells exposed to glutamate was measured as PGE2 production when latanoprost was applied compared to arachidonic acid (AA) at different molar concentrations. The COX-2 activity was reduced by arachidonic acid (0.1-0.01 microM) as well as by latanoprost (0.1-0.001 microM) and PhXA85 (0.01-0.001 microM) in retinal cells exposed to glutamate. Inhibition of inducible NO synthase was also found with the same drug concentrations. These results suggest that latanoprost exerts a neuroprotective activity in vitro and in vivo. This effect seems to be present only at low concentrations of the drug. A negative feedback on neuronal COX-2 activity may be possibly involved.
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PMID:Latanoprost exerts neuroprotective activity in vitro and in vivo. 1127 75

The pathophysiology of brain ischemia and reperfusion injury involves perturbation of intraneuronal ion homeostasis. To identify relevant routes of ion flux, rat hippocampal slices were perfused with selective voltage- or ligand-gated ion channel blockers during experimental oxygen-glucose deprivation and subsequent reperfusion. Electron probe X-ray microanalysis was used to quantitate water content and concentrations of Na, K, Ca and other elements in morphological compartments (cytoplasm, mitochondria and nuclei) of individual CA1 pyramidal cell bodies. Blockade of voltage-gated channel-mediated Na+ entry with tetrodotoxin (1 microM) or lidocaine (200 microM) significantly reduced excess intraneuronal Na and Ca accumulation in all compartments and decreased respective K loss. Voltage-gated Ca2+ channel blockade with the L-type antagonist nitrendipine (10 microM) decreased Ca entry and modestly preserved CA1 cell elemental composition and water content. However, a lower concentration of nitrendipine (1 microM) and the N-, P-subtype Ca2+ channel blocker omega-conotoxin MVIIC (3 microM) were ineffective. Glutamate receptor blockade with the N-methyl-D-aspartate (NMDA) receptor-subtype antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP; 100 microM) or the alpha-amino-3-hydroxy-5-methyl-4-isoazole propionic acid (AMPA) receptor subtype blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM/100 microM glycine) completely prevented Na and Ca accumulation and partially preserved intraneuronal K concentrations. Finally, the increase in neuronal water content normally associated with oxygen-glucose deprivation/reperfusion was prevented by Na+ channel or glutamate receptor blockade. Results of the present study demonstrate that antagonism of either postsynaptic NMDA or AMPA glutaminergic receptor subtypes provided nearly complete protection against ion and water deregulation in nerve cells subjected to experimental ischemia followed by reperfusion. This suggests activation of ionophoric glutaminergic receptors is involved in loss of neuronal osmoregulation and ion homeostasis. Na+ channel blockade also effectively diminished neuronal ion and water derangement during oxygen-glucose deprivation and reperfusion. Prevention of elevated Nai+ levels is likely to provide neuroprotection by decreasing presynaptic glutamate release and by improving cellular osmoregulation, adenosine triphosphate utilization and Ca2+ clearance. Thus, we suggest that voltage-gated tetrodotoxin-sensitive Na+ channels and glutamate-gated ionotropic NMDA or AMPA receptors are important routes of ion flux during nerve cell injury induced by oxygen-glucose deprivation/reperfusion.
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PMID:Effects of ion channel blockade on the distribution of Na, K, Ca and other elements in oxygen-glucose deprived CA1 hippocampal neurons. 1130 Dec 5

Oxidative stress is thought to be the cause of nerve cell death in many CNS pathologies, including ischemia, trauma, and neurodegenerative disease. Glutamate kills nerve cells that lack ionotropic glutamate receptors via the inhibition of the cystine-glutamate antiporter x(c)(-), resulting in the inhibition of cystine uptake, the loss of glutathione, and the initiation of an oxidative stress cell death pathway. A number of catecholamines were found to block this pathway. Specifically, dopamine and related ligands inhibit glutamate-induced cell death in both clonal nerve cell lines and rat cortical neurons. The protective effects of dopamine, apomorphine, and apocodeine, but not epinephrine and norepinephrine, are antagonized by dopamine D4 antagonists. A dopamine D4 agonist also protects, and this protective effect is inhibited by U101958, a dopamine D4 antagonist. Although the protective effects of some of the catecholamines are correlated with their antioxidant activities, there is no correlation between the protective and antioxidant activities of several other ligands. Normally, glutamate causes an increase in reactive oxygen species (ROS) and intracellular Ca(2+). Apomorphine partially inhibits glutamate-induced ROS production and blocks the opening of cGMP-operated Ca(2+) channels that lead to Ca(2+) elevation in the late part of the cell death pathway. These data suggest that the protective effects of apomorphine on oxidative stress-induced cell death are, at least in part, mediated by dopamine D4 receptors via the regulation of cGMP-operated Ca(2+) channels.
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PMID:The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death. 1148 30

Perinatal brain injury following trauma, hypoxia, and/or ischemia represents a substantial cause of pediatric disabilities including mental retardation. Such injuries lead to neuronal cell death through either necrosis or apoptosis. Numerous in vivo and in vitro studies implicate ionotropic (iGluRs) and metabotropic (mGluRs) glutamate receptors in the modulation of such cell death. Expression of glutamate receptors changes as a function of developmental age, with substantial implications for understanding mechanisms of post-injury cell death and its potential treatment. Recent findings suggest that the developing brain is more susceptible to apoptosis after injury and that such caspase mediated cell death may be exacerbated by treatment with N-methyl-D-aspartate receptor antagonists. Moreover, group I metabotropic glutamate receptors appear to have opposite effects on necrotic and apoptotic cell death. Understanding the relative roles of glutamate receptors in post-traumatic or post-ischemic cell death as a function of developmental age may lead to novel targeted approaches to the treatment of pediatric brain injury.
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PMID:Traumatic brain injury: developmental differences in glutamate receptor response and the impact on treatment. 1175 17

Recent studies suggest that nuclear factor NF-kappaB may be involved in excitotoxin-induced cell apopotosis. To analyze the variation of NF-kappaB, levels of NF-kappaB were measured after the rats were subjected to 30 min of four-vessel occlusion and sacrificed in selected reperfusion time points. Induction of NF-kappaB consisting mainly of p65 and p50 subunits was detected by Western blot with anti p65, p50 antibodies, respectively. DNA binding activity of NF-kappaB was performed by electrophoretic mobility-shift analysis. Our studies indicate that ischemia-induced NF-kappaB nuclear translocation is time-dependent. Inductions or binding activity of NF-kappaB in nucleus increased about 10-fold from 6 to 12 h as compared with that of the control group, then gradually declined in the following 24, 72 h. To further analyze the regulation by ionotropic glutamate receptor and L-type voltage-gated Ca(2+) channel (L-VGCC) in vivo, N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3 (1H,4H)-dione and L-VGCC antagonist nifedipine were given 20 min prior to 30 min of ischemia. The NF-kappaB nuclear translocation was completely blocked by these three antagonists in a dose-dependent manner after ischemia/reperfusion 6 h. Increased phosphorylation of the NF-kappaB regulatory unit IkappaB-alpha was detected by Western blot. Decrement of IkappaB-alpha was found after 3 h reperfusion in the cytoplasm following global ischemia, which was also blocked by such three antagonists. These results illustrate that glutamate-gated ionotropic NMDA or non-NMDA receptors and voltage-gated Ca(2+) channels are important routes to mediate NF-kappaB activation during brain ischemic injury. Active NF-kappaB may attend the excitotoxin-induced cell death in turn. Our studies also suggest that IkappaB-alpha is an important regulatory unit that controls the activation of NF-kappaB after its phosphorylation and degradation and resynthesis in rat hippocampus following global ischemia.
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PMID:Nuclear factor kappaB activation is mediated by NMDA and non-NMDA receptor and L-type voltage-gated Ca(2+) channel following severe global ischemia in rat hippocampus. 1192 32

We examined the pharmacological properties of 3-methyl-aminothiophene dicarboxylic acid (3-MATIDA) by measuring second messenger responses in baby hamster kidney cells stably transfected with mGlu1a, mGlu2, mGlu4a or mGlu5a receptors and ionotropic glutamate receptor agonist-induced depolarizations in mouse cortical wedges. 3-MATIDA was a potent (IC(50)=6.3 microM, 95% confidence limits 3-15) and relatively selective mGlu1 receptor antagonist. When tested on mGlu2, mGlu4 or mGlu5 receptors its IC(50) was >300 microM. When tested in cortical wedges, however, 3-MATIDA was also able to antagonize AMPA or NMDA responses with an IC(50) of 250 microM. When present in the incubation medium of cultured murine cortical cells, 3-MATIDA (1-100 microM) significantly reduced the death of neurons induced by 60 min of oxygen and glucose deprivation (OGD), even when added up to 60 min after OGD. A similar neuroprotective activity was observed when 3-MATIDA was present at 10-100 microM in the medium of rat organotypic hippocampal slice cultures exposed to 30 min OGD. Systemic administration of 3-MATIDA (3-10 mg/kg, immediately and 1 h after the onset of ischemia) reduced the volume of brain infarcts following permanent middle cerebral artery occlusion in rats. Our results show that 3-MATIDA is a potent and possibly selective mGlu 1 receptor antagonist that may be considered as a novel prototype neuroprotective agent.
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PMID:The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death. 1201

Trigeminal afferent neurons express ionotropic P2X receptors for extracellular ATP which are known to be sensitive to low interstitial pH. Both conditions - ATP release and tissue acidosis - may occur in the dura following the ischemia phase of migraine attacks. Aim of this study was to investigate whether and how ATP and protons may cooperate in exciting meningeal afferents. After removal of the cerebral hemispheres hemisected scull cavities of adult Wistar rats were used as organ bath of their own lining, the dura mater. The dura was chemically stimulated and the amounts of immunoreactive calcitonin gene-related peptide (iCGRP) and prostaglandin E(2) (PGE(2)) released into incubation fluid were measured using enzyme immunoassays. Stimulation with ATP (10(-4) and 10(-3)M) augmented iPGE(2) release dose-dependently whereas iCGRP secretion was minimally enhanced only if the dura had previously been depleted of extracellular ATP using hexokinase. Acid buffer solutions (pH 5.9 and 5.4) resulted in pH-dependent increase of iCGRP release but reduced iPGE(2) release. Purines (ATP 10(-3)>UTP 10(-4)M>ATP 10(-4)M) and PGE(2) (10(-5)M) were found to facilitate the proton-induced increase in iCGRP release. The proton-reduction of PGE(2) release was overcome by adding ATP (10(-3)M). S(+)-flurbiprofen (10(-6)M) suppressed both the basal and stimulated iPGE(2) release and prevented the ATP(10(-4)M)-induced facilitation of the proton response. The facilitating effect of ATP was also blocked under suramin, a non-selective P2 antagonist, and under reactive blue, an non-selective P2Y-antagonist, but not under pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, a P2X-antagonist. The present results provide evidence that ATP has poor, if at all, direct excitatory effects on CGRP-containing trigeminal nerve endings in the isolated dura and its facilitatory action seems to depend on G-protein coupled P2Y receptors and secondary PGE(2) release. The UTP effect and the antagonist profile is indicative for the P2Y(2) receptor subtype.
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PMID:ATP can enhance the proton-induced CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat dura mater. 1204 22

Anoxia-tolerant neurons from several species of animals may offer unparalleled opportunities to identify strategies that might be employed to enhance the hypoxia or ischemia tolerance of vulnerable neurons. In this review, the authors describe how the response of hypoxia-tolerant neurons to limited oxygen supply involves a suite of mechanisms that reduce energy expenditure in concert with decreased energy availability. This response avoids energy depletion, excitotoxic neuronal death, and apoptosis. Suppression of ion channel functions, particularly those of the ionotropic glutamate receptors, is a response common in hypoxia-tolerant neurons. The depression of excitability thereby achieved is essential given that the fundamental response to oxygen lack in anoxia-tolerant cells is a throttling down of metabolism to "pilot-light" levels. Many different types of processes have been found to down-regulate ion channel function. These include phosphorylation control, interactions with intracellular and extracellular ions, removal of active receptors from the neurolemma, and the direct sensing of oxygen by Na+ and K+ channels. Changes in [Ca2+]i may initiate a protective down-regulation of many different pumps or channels. Transcriptional events leading to differential and/or decreased expression of receptors, proteins, and their subunits are probably very important but little studied.
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PMID:Molecular adaptations for survival during anoxia: lessons from lower vertebrates. 1206 3

DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.
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PMID:DOPA causes glutamate release and delayed neuron death by brain ischemia in rats. 1220 Jan 94


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