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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brief periods of cerebral ischemia result in prolonged inhibition of protein synthesis. In CA1 sector of hippocampus inhibition is irreversible, leading to delayed death of pyramidal neurons. In order to study the possible role of gene transcription in this process, expression of four individual RNAs was investigated in the gerbil brain after 5 min of global cerebral ischemia by in situ hybridization with the following nucleic acid probes: plasmid pMr100 (ribosomal RNA sequences), plasma pAG82 (cytochrome c oxidase sequences), plasmid p629 (amyloid A4 precursor protein of Alzheimer's disease, pre-A4 protein), and plasmid pHF beta A-1 (beta-actin sequences). Cytochrome c oxidase mRNA and ribosomal RNA did not show any changes in expression up to 48 hr after ischemia. After longer recirculation times they gradually declined in the CA1 sector of hippocampus in parallel with the morphological manifestation of delayed neuronal death. The pre-A4 mRNA transiently decreased after 8 hr of recirculation of the CA1 sector but then recovered before it finally disappeared in parallel with delayed neuronal death. The beta-actin mRNA transiently appeared to increase after 8 hr of recirculation in the stratum radiatum of hippocampus but then also declined and disappeared when CA1 neurons began to disintegrate. The possible significance of these changes in the pathogenesis of ischemic neuronal damage is discussed.
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PMID:Determination of RNA content in postischemic gerbil brain by in situ hybridization. 248 Dec 24

Mitochondrial dysfunction may underlie both acute and delayed neuronal cell death resulting from cerebral ischemia. Specifically, postischemic release of mitochondrial constituents such as the pro-apoptotic respiratory chain component cytochrome c could contribute acutely to further mitochondrial dysfunction and to promote delayed neuronal death. Experiments reported here tested the hypothesis that ischemia or severe hypoxia results in release of cytochrome c from mitochondria. Cytochrome c was measured spectrophotometrically from either the cytosolic fraction of cortical brain homogenates after global ischemia plus reperfusion, or from brain slices subjected to severe hypoxia plus reoxygenation. Cytochrome c content in cytosol derived from cerebral cortex was increased after ischemia and reperfusion. In intact hippocampal slices, there was a loss of reducible cytochrome c after hypoxia/ reoxygenation, which is consistent with a decrease of this redox carrier in the mitochondrial pool. These results suggest that cytochrome c is lost to the cytosol after cerebral ischemia in a manner that may contribute to postischemic mitochondrial dysfunction and to delayed neuronal death.
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PMID:Cytochrome C is released from mitochondria into the cytosol after cerebral anoxia or ischemia. 988 53

Neurons that express neuronal nitric oxide synthase (nNOS) are selectively spared from nitric oxide (NO)-induced cytotoxicity in acute cerebral ischemia and neurodegenerative conditions but the mechanism of this resistance is unknown. To identify specific gene products which may mediate this resistance, we performed polymerase chain reaction (PCR)-based subtractive hybridization on a mouse macrophage cell line treated with either L-NG-nitroarginine methyl ester (L-NAME, 1 mM, 1 h), an inhibitor of NOS, or with diethylamine NONOate (DEA NONO, 200 microM, 1 h), an NO donor. NO-treated cultures showed an acute induction of mRNA (less than 1 h after treatment) and protein (15 min) for the mitochondrial enzyme cytochrome c oxidase (CcO) as shown by Northern or Western blot analysis, respectively. Cytochrome c oxidase activity assay showed constant activity in NO-treated cultures, as compared to L-NAME-treated cultures. NO directly inhibits CcO, the terminal electron acceptor in mitochondrial oxidative respiration. Up-regulation of this enzyme by NO, therefore, appears to maintain vital CcO activity and cellular energy stores, thus contributing to selective sparing of nNOS neurons.
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PMID:Nitric oxide mediated induction of cytochrome c oxidase mRNA and protein in a mouse macrophage cell line. 1087 72

Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly(ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pI) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands, thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at the periphery of the infarct core.
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PMID:Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. 1272 25

Although protective effects of heat shock protein 70 (HSP70) overproduction after ischemic injury have been shown both in vitro and in vivo in neurons, the mechanisms are not fully understood. The hypothesis of this study is that transgenic mice overexpressing HSP70 (HSP70 Tg) show reduced mitochondrial cytochrome c release into cytosol and diminished apoptotic cell death after permanent focal ischemia in comparison to wild-type (Wt) mice. Permanent middle cerebral artery occlusion (pMCAO) was produced by intraluminal suture cannulation in HSP70 Tg and Wt mice. DNA fragmentation was evaluated with DNA gel electrophoresis and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) 24 h after pMCAO. Mitochondrial cytochrome c release into cytosol was assessed with Western blotting and immunohistochemistry 4 h after pMCAO. Cytochrome c levels in the cytosolic fraction were significantly reduced and immunoreactivity of cytochrome c in both cortex and striatum was significantly less in HSP70 Tg mice compared with Wt mice after 4-h pMCAO. DNA laddering, which was clearly observed in Wt mice, was markedly attenuated in HSP70 Tg mice 24 h after pMCAO. The number of TUNEL-positive cells was significantly reduced in HSP70 Tg mice compared with Wt mice. Results are consistent with an association between overexpression of HSP70 and reduction of cytochrome c release with subsequent DNA fragmentation. This may contribute to the HSP70-mediated neuroprotective effect observed after cerebral ischemia.
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PMID:Overexpression of rat heat shock protein 70 is associated with reduction of early mitochondrial cytochrome C release and subsequent DNA fragmentation after permanent focal ischemia. 1279 20

It has been reported that immunosuppressant FK506 inhibited ischemic neuronal injury in forebrain ischemia or transient focal cerebral ischemia, but the mechanisms of the neuroprotective effect have not been clarified. In permanent focal cerebral ischemia, we investigated whether FK506 caused remission of brain infarction, and how mechanism was concerned. Male Balb/c mice were subjected to permanent middle cerebral artery (MCA) occlusion. They were treated with 1.0 or 3.0 mg/kg FK506 or vehicle 30 min before ischemia. Infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) method after 24 h. Cytochrome c release from mitochondria was evaluated by Western blotting and immunocytochemistry after ischemia. Simultaneously, the immunoreactivity of total and phosphorylated BAD was also studied using immunocytochemistry. We demonstrated that pretreatment with 3.0 mg/kg FK506 salvaged the tissue damage in the infarct rim and significantly reduced infarct volume to 75.5% (P<0.05), and FK506 inhibited cytochrome c release on 6 h after ischemia for Western blot analysis (P<0.05). Immunocytochemical study showed that permanent MCA occlusion increased the amount of cytochrome c and total BAD in the cytosol, but not phosphorylated BAD, in the ischemic core and the infarct rim as early as 1 h after ischemia, and FK506 inhibited the increases in the infarct rim. The results suggest that FK506 may, at least in part, ameliorate tissue damage due to permanent focal cerebral ischemia in the infarct rim through maintaining BAD turnover and inhibiting cytochrome c release from mitochondria.
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PMID:FK506 reduces infarct volume due to permanent focal cerebral ischemia by maintaining BAD turnover and inhibiting cytochrome c release. 1497 53

Signaling cascades associated with apoptosis contribute to cell death after focal cerebral ischemia. Cytochrome c release from mitochondria and the subsequent activation of caspases 9 and 3 are critical steps. Recently, a novel mitochondrial protein, apoptosis-inducing factor (AIF), has been implicated in caspase-independent programmed cell death following its translocation to the nucleus. We, therefore, addressed the question whether AIF also plays a role in cell death after focal cerebral ischemia. We detected AIF relocation from mitochondria to nucleus in primary cultured rat neurons 4 and 8 hours after 4 hours of oxygen/glucose deprivation. In ischemic mouse brain, AIF was detected within the nucleus 1 hour after reperfusion after 45 minutes occlusion of the middle cerebral artery. AIF translocation preceded cell death, occurred before or at the time when cytochrome c was released from mitochondria, and was evident within cells showing apoptosis-related DNA fragmentation. From these findings, we infer that AIF may be involved in neuronal cell death after focal cerebral ischemia and that caspase-independent signaling pathways downstream of mitochondria may play a role in apoptotic-like cell death after experimental stroke.
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PMID:Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. 1508 15

Lidocaine is a local anesthetic and antiarrhythmic agent. Although clinical and experimental studies have shown that an antiarrhythmic dose of lidocaine can protect the brain from ischemic damage, the underlying mechanisms are unknown. In the present study, we examined whether lidocaine inhibits neuronal apoptosis in the penumbra in a rat model of transient focal cerebral ischemia. Male Wistar rats underwent a 90-min temporary occlusion of middle cerebral artery. Lidocaine was given as an i.v. bolus (1.5 mg/kg) followed by an i.v. infusion (2 mg/kg/h) for 180 min, starting 30 min before ischemia. Rats were killed and brain samples were collected at 4 and 24 h after ischemia. Apoptotic changes were evaluated by immunohistochemistry for cytochrome c release and caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) for DNA fragmentation. Cytochrome c release and caspase-3 activation were detected at 4 and 24 h after ischemia and DNA fragmentation was detected at 24 h. Double-labeling with NeuN, a neuronal marker, demonstrated that cytochrome c, caspase-3, and TUNEL were confined to neurons. Lidocaine reduced cytochrome c release and caspase-3 activation in the penumbra at 4 h and diminished DNA fragmentation in the penumbra at 24 h. Lidocaine treatment improved early electrophysiological recovery and reduced the size of the cortical infarct at 24 h, but had no significant effect on cerebral blood flow in either the penumbra or core during ischemia. These findings suggest that lidocaine attenuates apoptosis in the penumbra after transient focal cerebral ischemia. The infarct-reducing effects of lidocaine may be due, in part, to the inhibition of apoptotic cell death in the penumbra.
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PMID:Lidocaine attenuates apoptosis in the ischemic penumbra and reduces infarct size after transient focal cerebral ischemia in rats. 1509 83

Apoptosis plays a critical role in many neurologic diseases, including stroke. Cytochrome c release and activation of various caspases are known to occur after focal and global ischemia. However, recent reports indicate that caspase-independent pathways may also be involved in ischemic damage. Apoptosis-inducing factor (AIF) is a novel flavoprotein that helps mediate caspase-independent apoptotic cell death. AIF translocates from mitochondria to nuclei where it induces caspase-independent DNA fragmentation. Bcl-2, a mitochondrial membrane protein, protects against apoptotic and necrotic death induced by different insults, including cerebral ischemia. In the present study, Western blots confirmed that AIF was normally confined to mitochondria but translocated to nuclei or cytosol 8, 24, and 48 hours after onset of ischemia. Overall, AIF protein levels also increased after stroke. Confocal microscopy further demonstrated that nuclear AIF translocation occurred in the peri-infarct region but not in the ischemic core where only some cytosolic AIF release was observed. Our data also suggest that AIF translocated into nuclei after cytochrome c was released into the cytosol. Bcl-2 transfection in the peri-infarct region blocked nuclear AIF translocation and improved cortical neuron survival.
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PMID:Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor translocation after focal ischemia in the rat. 1518 76

Cytochrome c-initiated activation of apoptotic protease activating factor-1 (Apaf-1) is a key step in the mitochondrial-signaling pathway for the activation of death-executing caspases in apoptosis. This signaling pathway has been implicated in the pathophysiology of various neurological disorders, including ischemic brain injury. In this study, we have cloned a novel rat gene product, designated as Apaf-1-interacting protein (AIP), which functions as a dominant-negative inhibitor of the Apaf-1-caspase-9 pathway. AIP is constitutively expressed in the brain, but at substantially lower levels than Apaf-1 and caspase-9. AIP can directly bind to Apaf-1 in vitro through its N-terminal caspase-recruiting domain, and this protein interaction was increased in cells undergoing apoptosis. Cytosolic extracts from cells overexpressing AIP were highly resistant to cytochrome c- dATP-induced activation of caspase-9 and caspase-3. Gene transfection of AIP into cell lines, including the neuronal-differentiated PC12 cells, potently suppressed apoptosis induced by various pro-apoptotic stimuli. To further investigate the functional role of AIP in primary neurons and in the brain, an adeno-associated virus (AAV) vector carrying the AIP cDNA was constructed. AAV-mediated overexpression of AIP in primary cortical- hippocampal neurons markedly reduced cell death and caspase-3 activation triggered by protein kinase C inhibition, DNA damage, or oxygen- glucose deprivation. Moreover, intracerebral infusion of the AAV vector resulted in robust AIP expression in the hippocampus and significantly promoted CA1 neuronal survival after transient global cerebral ischemia. These results suggest that molecular targeting of the Apaf-1-caspase-9 signaling pathway may be a feasible neuroprotective strategy to enhance the endogenous threshold for caspase activation and prevent neuronal loss in stroke and related disorders.
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PMID:Cloning of a novel Apaf-1-interacting protein: a potent suppressor of apoptosis and ischemic neuronal cell death. 1524 Aug 11


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