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)

The mitochondrial permeability transition (MPT) occurs in several forms of necrotic cell death induced by various insults, including oxidative stress, ischemia/reperfusion injury Ca(2+)-ionophore toxicity, and apoptosis. In fact, the release of an apoptogenic factor such as cytochrome c is often associated with the opening of the transition pore. The present study shows that Aroclor 1254, a mixture of polychlorinated biphenyls that was banned in the U.S. in 1977 but is still present in the environment, inhibits the MPT in a dose-dependent manner in a concentration range of 1 to 25 nmol/mg protein. The compound prevents key phenomena associated with the MPT, including colloid-osmotic swelling, the collapse of membrane potential, nonspecific bidirectional traffic of solutes through the transition pore, and the oxidation of pyridine nucleotides. In contrast, Aroclor 1254 does not inhibit uptake of Ca(2+) or P(i). The effects of Aroclor 1254 are evident both in sucrose-based media and in saline and are observed when the compound is added before the opening of the pore. Aroclor 1254 prevents MPT induction provoked by a variety of agents, including phosphate, menadione, tert-butylhydroperoxide, and atractyloside. Aroclor 1254 also inhibits the specific release of cytochrome c, a correlate of MPT induction. These effects reveal a possible toxicological mechanism of action of this compound. The possibility that its effect on mitochondrial function is linked to its action as a tumor promoter is discussed.
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PMID:Aroclor 1254 inhibits the mitochondrial permeability transition and release of cytochrome c: a possible mechanism for its in vivo toxicity. 1192 78

Previously, in monkeys undergoing 20 min whole brain ischemia we demonstrated that the activated calpain-induced lysosomal disruption with the resultant leakage of cathepsins B and L, causes neuronal death in the cornu Ammonis (CA) 1 sector on day 5. Selective cathepsin inhibitors significantly protected ischemic CA1 neurons from delayed necrosis. Recently, pyridoxal phosphate (PLP) and pyridoxal (hydrochloride) (PL) were demonstrated to inhibit cathepsins B and L in vitro, because the active aldehyde at position 4 of the pyridine ring has an affinity for the active site -SH of cysteine residues of cathepsins. Here, we studied whether PLP and PL can, in vivo, protect monkey CA1 neurons from ischemic insult. In monkeys undergoing 20 min whole brain ischemia, 15 mg/kg body weight/day of drugs were intravenously injected for 10 days before and after the ischemic insult. Histological analysis of the surviving CA1 neurons was done using the hippocampus resected on day 5 after ischemia. For PLP or PL, approximately 17% (P = 0.0639) or 54% (P < 0.0001) of the total population (100%) of control CA1 neurons were, respectively, saved from the ischemia-induced neuronal death, showing a remarkable contrast to the surviving neurons (approximately 3.9%) in non-treated monkeys. These data suggested that PL (perhaps PLP intracellularly) is useful as a novel neuroprotectant in primates.
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PMID:Neuroprotective effects of pyridoxal phosphate and pyridoxal against ischemia in monkeys. 1184 15

In order to investigate the involvement of mGlu1 and mGlu5 metabotropic glutamate receptors in the development of postischemic neuronal death, we examined the effects of selective agonists and antagonists in models of cerebral ischemia in vitro and in vivo. In murine cortical cell cultures and rat organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD), the mGlu1 antagonists 1-aminoindan-1,5-dicarboxylic acid (AIDA; 300 microM), (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG; 300 microM), 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt; 10-30 microM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385; 30-100 microM) reduced neuronal loss when added to the medium during OGD and the subsequent 24-h recovery period. On the contrary, the potent and selective mGlu5 antagonist methyl-6-(phenylethynyl)-pyridine (MPEP; 0.1-1 microM) did not exhibit neuroprotection in any of these in vitro models. Incubation with the nonselective mGlu1 and mGlu5 agonist 3,5-dihydroxyphenylglycine (3,5-DHPG; 300 microM) but not with the mGlu5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 1 mM) enhanced the severity of OGD-induced neuronal damage. In gerbils subjected to global ischemia, intracerebroventricular administration of AIDA (100 nmol two times) or CBPG (300 nmol, two times) afforded consistent protection against CA1 pyramidal cell death, whereas MPEP (10 pmol i.c.v two times and 10 mg/kg i.p two times) failed to reduce postischemic hippocampal damage. Our results suggest that activation of mGlu1 but not mGlu5 receptor contributes to postischemic neuronal injury.
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PMID:Activation of mGlu1 but not mGlu5 metabotropic glutamate receptors contributes to postischemic neuronal injury in vitro and in vivo. 1211 99

The mitochondrial permeability transition pore (PTP) may operate as a physiological Ca2+ release mechanism and also contribute to mitochondrial deenergization and release of proapoptotic proteins after pathological stress, e.g. ischemia/reperfusion. Brain mitochondria exhibit unique PTP characteristics, including relative resistance to inhibition by cyclosporin A. In this study, we report that 2-aminoethoxydiphenyl borate blocks Ca2+-induced Ca2+ release in isolated, non-synaptosomal rat brain mitochondria in the presence of physiological concentrations of ATP and Mg2+. Ca2+ release was not mediated by the mitochondrial Na+/Ca2+ exchanger or by reversal of the uniporter responsible for energy-dependent Ca2+ uptake. Loss of mitochondrial Ca2+ was accompanied by release of cytochrome c and pyridine nucleotides, indicating an increase in permeability of both the inner and outer mitochondrial membranes. Under these conditions, Ca2+-induced opening of the PTP was not blocked by cyclosporin A, antioxidants, or inhibitors of phospholipase A2 or nitric-oxide synthase but was abolished by pretreatment with bongkrekic acid. These findings indicate that in the presence of adenine nucleotides and Mg2+,Ca2+-induced PTP in non-synaptosomal brain mitochondria exhibits a unique pattern of sensitivity to inhibitors and is particularly responsive to 2-aminoethoxydiphenyl borate.
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PMID:Cyclosporin A-insensitive permeability transition in brain mitochondria: inhibition by 2-aminoethoxydiphenyl borate. 1275 Mar 71

The Na(+)/H(+) exchanger (NHE) is involved in intracellular pH homeostasis of many mammalian cell types. To date seven NHE isoforms (NHE1-NHE7) have been identified. NHE1 is the most predominant isoform expressed in heart where it contributes to cardiomyocyte pH homeostasis. Although the NHE activation is essential for the restoration of physiological pH, hyperactivation of NHE1 during ischemia-reperfusion episodes disrupts the intracellular ion balance, leading to cardiac dysfunction and damage. Beside its ability to inhibit a conductive Na(+) channel and the Na(+)/Ca(++) exchanger, amiloride was the first drug described as NHE inhibitor. Double substitution of the nitrogen of the 5-amino group of amiloride gave DMA, EIPA, MIBA and HMA. Later, several acylguanidines were prepared to selectively inhibit NHE1. The replacement of the pyrazine ring of amiloride by a pyridine ring or by a phenyl increased the potency and the NHE selectivity. The simultaneous replacement of the pyrazine ring by a phenyl, of the 6-chloro by a sulfomethyl led to drugs such as HOE-694, cariporide, eniporide and BIIB-513 which also selectively inhibited NHE1. In the last decade several bicyclic guanidines were prepared: zoniporide, MS-31038, SM-20220, SM-20550, SMP-300, KB-R9032, BMS-284640, T-162559, TY-12533, S-3226 or SL-591227. Extensive pre-clinical studies indicated that NHE inhibitors afford substantial protection in different animal models of myocardial ischemia (MI) and reperfusion, but the results of clinical trials involving eniporide and cariporide were mixed.
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PMID:An overview of inhibitors of Na(+)/H(+) exchanger. 1283 26

We investigated the effects of serotonin (5-HT), SL65.0472 (7-fluoro-2-oxo-4-[2-[4-thieno[3,2-c]pyridine-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide, a 5-HT(1B)/5-HT(2A) receptor antagonist) and ketanserin (a 5-HT(2A) receptor antagonist) during exercise-induced cardiac ischemia in conscious dogs. Dogs were administered a hypercholesterolemic diet and an inhibitor of nitric oxide synthetase to produce chronic endothelial dysfunction. Myocardial ischemia was induced by a treadmill exercise test associated with limitation of left anterior descending coronary blood flow. Infusion of serotonin during exercise produced dose-related cardiovascular changes (after 10 microg/kg/min; heart rate +27+/-6 bpm, systolic blood pressure +18+/-3 mm Hg, left circumflex coronary blood flow +64+/-8 ml/min, myocardial segment length shortening in the ischemic zone -5.9+/-1.9%, P<0.05). SL65.0472 blocked serotonin-induced increases in blood pressure, rate pressure product and circumflex coronary artery flow (100 microg/kg i.v., P<0.05) and reduced serotonin-induced ischemic myocardial segment length shortening (300 microg/kg i.v., P<0.05). Ketanserin (30-300 microg/kg i.v.) had no significant effect on any serotonin-induced changes during exercise. Thus, SL65.0472 opposes serotonin-induced myocardial dysfunction in a dog model of exercise-induced ischemia.
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PMID:Serotonin aggravates exercise-induced cardiac ischemia in the dog: effect of serotonin receptor antagonists. 1532 35

Dopamine (DA), released from the lateral olivocochlear efferent fibers, is suggested to be neuroprotective against ischemia and noise exposure in the mammalian cochlea because it can reduce the postsynaptic excitotoxic effect of glutamate on the dendrite of the afferent auditory neuron. Using in vitro microvolume superfusion method on isolated guinea pig cochlea preparation, we found that the selective mGluR2/3 agonist (2R,4R)-aminopyrrolidine-2,4-dicarboxylic acid (2R,4R-APDC) significantly increased the release of DA in a dose-dependent manner. Other mGluR agonists, acting on groups I and III receptors (3,5-dihydroxyphenylglycine, amino-4-phosphonobutyric acid) and antagonists (2-methyl-6-(phenylethynyl)pyridine), (2S)-2-amino-2-(1S,2S-2-carboxycyclopronan-1-yl-3-(xanth9-yl)propanoic acid, alpha-methylserine-O-phosphate), were ineffective. The GABA(A) antagonist bicuculline (10microM) could antagonize the effect of 2R,4R-APDC suggesting that the mGluR-mediated enhancement of DA release was most likely attributable to a disinhibitory mechanism involving local GABAergic fibers. Bicuculline alone could also elevate the DA outflow indicating that cochlear GABA controls local DA release tonically. Our findings expand the view on the local effects of glutamate in the cochlea by showing the ability of the excitatory neurotransmitter to alleviate its own action on type I afferents via mGluRs and initiate a neuroprotective mechanism.
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PMID:Cochlear dopamine release is modulated by group II metabotropic glutamate receptors via GABAergic neurotransmission. 1592 69

We used pharmacological agents and genetic methods to determine whether the potent A(3) adenosine receptor (AR) agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/reperfusion injury in mice via the A(3)AR or via interactions with other AR subtypes. Pretreating wild-type (WT) mice with Cl-IB-MECA reduced myocardial infarct size induced by 30 min of coronary occlusion and 24 h of reperfusion at doses (30 and 100 mug/kg) that concomitantly reduced blood pressure and stimulated systemic histamine release. The A(3)AR-selective antagonist MRS 1523 [3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine-carboxylate], but not the A(2A)AR antagonist ZM 241385 [4-{2-7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol], blocked the reduction in infarct size provided by Cl-IB-MECA, suggesting a mechanism involving the A(3)AR. To further examine the selectivity of Cl-IB-MECA, we assessed its cardioprotective effectiveness in A(3)AR gene "knock-out" (A(3)KO) mice. Cl-IB-MECA did not reduce myocardial infarct size in A(3)KO mice in vivo and did not protect isolated perfused hearts obtained from A(3)KO mice from injury induced by global ischemia and reperfusion. Additional studies using WT mice treated with compound 48/80 [condensation product of p-methoxyphenethyl methylamine with formaldehyde] to deplete mast cell contents excluded the possibility that Cl-IB-MECA was cardioprotective by releasing mediators from mast cells. These data demonstrate that Cl-IB-MECA protects against myocardial ischemia/reperfusion injury in mice principally by activating the A(3)AR.
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PMID:Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. 1698 66

Calpain-mediated proteolysis has been involved in neuronal cell death of retinal neurological degeneration. An aldehyde-based calpain inhibitor, SJA6017 (1), was effective following oral administration in a rat retinal ischemia model but had low oral bioavailability. The aim of this study was to identify calpain inhibitors with good retinal penetration after oral dosing. The orally bioavailable inhibitors, hemiacetal 3 (SNJ-1715), amphipathic ketoamide 5 (SNJ-1945), and pyridine ketoamide 6 (SNJ-2008), were evaluated for their retinal pharmacokinetic (PK) profiles. The retinal drug exposure of these inhibitors was more than tenfold higher than 1. Among these compounds, 5 exhibited the most favorable retinal PK properties, such as good penetration and long half-life. Comparisons of 5 and the structurally related ketoamide 6 suggested that the presence of a methoxy diethylene glycol moiety resulted in the inhibitor with high penetration into the retina and the sustained high retinal levels. Ketoamide 5 was selected as the development candidate for the treatment of retinal diseases.
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PMID:Retinal penetration of calpain inhibitors in rats after oral administration. 1723 7

The role of adenosine A3 receptors in synaptic transmission under severe (7 min) and shorter (2-5 min) ischemic conditions, obtained by oxygen and glucose deprivation (OGD), was investigated in rat hippocampal slices. The effects of selective A3 agonists or antagonists were examined on field excitatory postsynaptic potentials (fEPSPs) extracellularly recorded at the dendritic level of the CA1 pyramidal region. The novel, selective A3 antagonist LJ1251 ((2R,3R,4S)-2-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol, 0.1-10 nM) protected hippocampal slices from irreversible fEPSP depression induced by severe OGD and prevented or delayed the appearance of anoxic depolarization. Similar results were obtained when severe OGD was carried out with a long, receptor-desensitizing exposure to various selective A3 agonists: 5'-N-methylcarboxamidoadenosine derivatives Cl-IB-MECA (N6-(3-iodobenzyl)-2-chloro), VT72 (N6-methoxy-2-phenylethynyl), VT158 (N6-methoxy-2-phenylethynyl), VT160 (N6-methoxy-2-(2-pyridinyl)-ethynyl), and VT163 (N6-methoxy-2-p-acetylphenylethynyl) and AR132 (N6-methyl-2-phenylethynyladenosine). The selective A3 antagonist MRS1523 (3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine carboxylate, 100 nM) reduced fEPSP depression evoked by 2-min OGD and induced a faster recovery of fEPSP amplitude after 5-min OGD. Similar results were obtained for 2- or 5-min OGD applied in the presence of each of the A3 agonists tested. Shorter exposure to A3 agonists significantly delayed the recovery of fEPSP amplitude after 5-min OGD. This indicates that A3 receptors, stimulated by selective A3 agonists, undergo desensitization during OGD. It is inferred that CA1 hippocampal A3 receptors stimulated by adenosine released during brief ischemia (2 and 5 min) might exert A1-like protective effects on neurotransmission. Severe ischemia would transform the A3 receptor-mediated effects from protective to injurious.
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PMID:Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen-glucose deprivation episodes of different duration. 1762 85


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