Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) cleaves pro-IL-1 beta to produce mature IL-beta, and is a member of a family of proteases implicated in apoptosis. Intracerebroventricular (i.c.v.) administration of an irreversible ICE inhibitor, z-VAD-DCB (1 pmol, 30 min before and 15 min, 2, 4, 6 and 8 h after surgery) markedly reduced (50 +/- 4%, p < 0.001) infarct volume measured 24 h after focal cerebral ischaemia (middle cerebral artery occlusion, MCAo) in the rat. Inhibition of damage was observed in the cortex (51 +/- 5% reduction) and striatum (42 +/- 6% reduction). These data implicate ICE in ischaemic neuronal death in vivo. Inhibition of ICE could reduce ischaemic damage either by preventing IL-1 beta synthesis or by inhibiting apoptosis or by both of these processes, and may provide a useful therapeutic approach to the inhibition of ischaemic brain damage.
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PMID:An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. 885 99

An increased concentration of extracellular glutamate is associated with neuronal damage induced by cerebral ischemia. We have demonstrated previously that exposure of cultured cerebellar granule neurons to L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a glutamate uptake inhibitor, increases extracellular glutamate levels but does not induce neuronal damage. Coincubation of PDC, however, with a subthreshold concentration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), results in severe damage to these neurons. We have investigated the time course of changes in mitochondrial reducing capacity and ATP levels in cerebellar granule cells after simultaneous exposure to 3-NP and PDC, and its relation to cell viability and nuclear condensation. Although individually, 3-NP and PDC treatments are not harmful to neurons, the simultaneous exposure to both compounds results in a progressive decline in mitochondrial reducing capacity during the first 4 hr, and a rapid decrease in ATP levels. At 4 hr, cells lose plasma membrane integrity and show condensed nuclei. In the presence of the energy substrates pyruvate and acetoacetate, the N-methyl-D-apartate (NMDA) receptor antagonist, MK-801, and the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN), the decline in mitochondrial activity and ATP levels is prevented, the number of condensed nuclei is reduced, and plasma membrane integrity is preserved. In contrast, the broad-spectrum caspase inhibitor Z-Asp-DCB (Z-Asp-CH2-DCB) prevents nuclear condensation but has no effect on mitochondrial reducing capacity or cell survival. Our results show that glutamate uptake impairment rapidly induces neuronal death during inhibition of succinate dehydrogenase by a mechanism involving mitochondrial dysfunction that, if not prevented, leads to cell death.
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PMID:Glutamate uptake inhibitor L-trans-pyrrolidine 2,4-dicarboxylate becomes neurotoxic in the presence of subthreshold concentrations of mitochondrial toxin 3-nitropropionate: involvement of mitochondrial reducing activity and ATP production. 1464 2