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Query: UNIPROT:A9QXG9 (bcl-2)
7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transient global ischemia results in selective neuronal damage of hippocampal CA1 neurons. Five minutes of bilateral common carotid artery occlusion, in the Mongolian gerbil, effectively restricts forebrain blood flow, resulting in a delayed neuronal death of CA1 pyramidal cells. While there is a delay of approximately 72 h in the appearance of cell death, markers related to the mechanism of ischemic death become apparent well before neurons die. Ischemia-induced increases in the cell-death-promoting protein, bax, may disrupt the bcl-2/bax ratio necessary for normal neuronal functioning and thus promote transient ischemic death. In order to locally maintain this critical bcl-2/bax ratio and thus protect CA1 neurons from delayed neuronal death, a herpes simplex viral (HSV) vector was used to selectively introduce human bcl-2, under the control of the herpes IE 4/5 promoter, into the CA1 region of the gerbil hippocampus. Twenty-four hours prior to ischemia surgery, 1 microl of HSVbcl-2 was infused unilaterally into the CA1 region at a rate of 2 nl/min. Seventy-two hours after ischemia the animals were sacrificed and processed using Nissl, silver degeneration, and immunohistochemical (anti-human bcl-2) staining. Immunohistochemistry demonstrated both glial and neuronal bcl-2 expression around the HSVbcl-2 infusion site. The evaluation following silver degeneration staining indicated a further degeneration of CA1 neurons in the immediate area of the viral vector infusion. This damage seems to be the result of cellular debris associated with the processing of the viral amplicons. Silver degeneration staining is not present in the areas that demonstrate bcl-2 staining. These neurons appear to have been rescued from ischemic damage. This result was confirmed using the Nissl staining. Therefore, by altering the local ratio of bcl-2/bax using the HSVbcl-2 vector one may protect CA1 pyramidal cell from the delayed neuronal death of transient global ischemia.
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PMID:BCL-2 transduction, using a herpes simplex virus amplicon, protects hippocampal neurons from transient global ischemia. 1019 84

This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.
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PMID:[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy]. 1020 84

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.
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PMID:Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. 1041 67

Neuronal death after brain ischemia is mainly due to necrosis but there is also evidence for involvement of apoptosis. To test the importance of apoptosis, we investigated the effect of targeted disruption of the apoptosis-suppressive gene bcl-2 on the severity of ischemic brain injury. Transient focal ischemia for 1 hour was induced by occlusion of the middle cerebral artery in homozygous (n=7) and heterozygous (n=6) bcl-2 knockout mice as well as in their wildtype littermates (n=5). Bcl-2 ablation did not influence cerebral blood flow but it significantly increased infarct size and neurological deficit score at 1 day after reperfusion in a gene-dose dependent manner. The exacerbation of tissue damage in the absence of Bcl-2 underscores the importance of apoptotic pathways for the manifestation of ischemic injury after transient vascular occlusion.
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PMID:Targeted disruption of the bcl-2 gene in mice exacerbates focal ischemic brain injury. 1048 13

Five minutes of transient global ischemia results in the delayed neuronal death of CA1 hippocampal cells. These pyramidal cells follow an apoptotic cell death cascade of events, initiated by the activation of the bcl-2 family of regulatory proteins and ending with caspase activation. The mitochondrial protein cytochrome c has been demonstrated to activate the precursor forms of caspase to their active forms. This is under the control of the bcl-2 protein family. The present study examined the accumulation of cytosolic cytochrome c following transient ischemia. At 72 h post-carotid artery occlusion there was a translocation of cytochrome c from the mitochondria to the cytoplasm just prior to the onset of cell death. By 7 days, when CA1 cell death is complete, there was no longer a significant difference between control and ischemic tissue. Therefore, cytochrome c appears to be a vital component in the apoptotic sequence of events following global ischemia.
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PMID:Translocation of cytochrome c following transient global ischemia in the gerbil. 1055 53

Previous studies have shown that overexpression of bcl-2 in transgenic mice or by viral vectors protects the brain against cerebral ischemia. However, it is not known whether bcl-2, which is endogenously expressed in response to ischemia, exerts a protective effect. To address this question, the authors blocked the endogenous expression of bcl-2 after ischemia using antisense oligodeoxynucleotides (ODN). Antisense, sense, scrambled ODN, or vehicles were infused in the lateral ventricle of the rat for 24 hours after 30 minutes of temporary middle cerebral artery occlusion. Twenty-four hours later the brains were removed and bcl-2 protein expression was assayed by Western blot. Antisense ODN, but not sense or scrambled ODN treatment, significantly inhibited bcl-2 protein expression after ischemia. Bcl-2 protein expression was also studied 24 hours after 60 minutes of temporary middle cerebral artery occlusion in vehicle and antisense ODN-treated rats. After 60 minutes of ischemia and vehicle treatment, bcl-2 was expressed in many neurons in the ventral cortical mantle and the medial striatum. After antisense ODN treatment there were few neurons in this region expressing bcl-2, instead most neurons TUNEL labeled. Treatment with the antisense ODN, but not sense ODN, increased infarction volume as determined by cresyl violet staining 72 hours after ischemia compared with vehicle controls. These results suggested that endogenously expressed bcl-2 promoted survival in ischemic neurons and was not simply an epiphenomenon in neurons already destined to live or die.
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PMID:Suppression of endogenous bcl-2 expression by antisense treatment exacerbates ischemic neuronal death. 1090 36

The proto-oncogene bcl-2 is known as an anti-apoptotic gene that confers the ability to block neuronal cell death after transient ischemia. In order to examine whether the bcl-2 gene can be used for protection of ischemic brain injury, we generated adeno-associated virus (AAV) vectors capable of expressing human bcl-2. Replication-defective AAV vectors were found effectively to transfer and express bcl-2 gene in the gerbil hippocampal neurons. Transduction with AAV bcl-2 5 days before forebrain ischemia prevented the DNA fragmentation in the CA1 neurons that is commonly associated with ischemia-induced cell death. Furthermore, the application of AAV bcl-2 as late as 1 h following an ischemic insult also prevented DNA fragmentation in CA1 neurons. These results suggest that the bcl-2 protein has neuroprotective functions that inhibit ischemic cell death and demonstrate the potential of AAV bcl-2 for use in post-ischemic gene therapy in the brain. Gene Therapy (2000) 7, 1244-1249.
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PMID:Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death. 1091 94

Phosphorylation of the DNA-binding transcription factor, cyclic AMP response element binding protein, has recently been suggested to provide neuroprotective signals in times of cellular stress. Medium-sized striatal neurons are among the cells that are most vulnerable to ischemic stress in the brain. In the present study, phosphorylation of cyclic AMP response element binding protein was immunohistochemically evaluated in rat striatum in order to examine the ischemic vulnerability of each striatal region from the standpoint of cyclic AMP response element binding protein. Rats were subjected to 90-min focal cerebral ischemia followed by various periods of recirculation. Focal ischemia was induced by occlusion of the middle cerebral artery by the intraluminal suture method. Local cerebral blood flow measured by the 14C-iodoantipyrine method in the lateral and the medial striatal regions during occlusion was 5.0+/-7. 1 and 42.5+/-8.1ml/100g/min, respectively. Cerebral blood flow in each region was restored to the control level during the recirculation period. The lateral and the medial regions of the striatum in the sham animals showed hardly any immunoreactivity with the specific antibody against phosphorylated cyclic AMP response element binding protein. By contrast, at 3.5h of recirculation, a number of phosphorylated cyclic AMP response element binding protein-positive neurons were detected in the medial striatal region on the occluded side, and the increase in the number of immunopositive cells continued until two weeks of recirculation with gradual decline. The lateral striatal region on the ischemic side showed only a mild increase in phosphorylated cyclic AMP response element binding protein-positive cells at 3.5h of recirculation, and the immunoreactivity rapidly disappeared during the subsequent recirculation period. Appreciable increase in immunoreactive cells was also noted in the contralateral striatum during the early phase of recirculation, and this increase seemed to be associated with spontaneous circling movements of the animals. Cresyl Violet staining revealed that striatal neurons in the medial region remained intact until two weeks of recirculation, whereas neurons in the lateral striatal region soon showed ischemic damage, followed by complete neuronal loss, and evolution of a frank infarct. Immunoreactivity for bcl-2, apoptosis-suppressive protein, was clearly detected in many neurons in the medial striatal region, but no such immunoreactivity was detected in the lateral striatal region. These findings suggest that persistently activated phosphorylation of cyclic AMP response element binding protein in the striatum during post-ischemic recirculation may be closely associated with protection of striatal neurons on the ischemic side, while it may be associated with spontaneous circling movements on the contralateral side.
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PMID:Activated phosphorylation of cyclic AMP response element binding protein is associated with preservation of striatal neurons after focal cerebral ischemia in the rat. 1100 72

Preconditioning stress induced by a transient ischemia may increase brain tolerance to oxidative stress, and the underlying neuroprotective mechanisms are not well understood. In a series of experiments, we found that endogenous nitric oxide (NO), S-nitrosoglutathione (GSNO), and antioxidants blocked serum deprivation-induced oxidative stress and apoptosis in human neuroblastoma cells. Similar to nuclear redox factor-1 (Ref-1), mRNA of human neuronal nitric oxide synthase (hNOS1) was maximally up-regulated within 2 h after oxidative stress and down-regulated by NO/GSNO and hydroxyl radical (OH) scavenger. A brief preconditioning stress induced by serum deprivation for 2 h caused a delayed increase in the expression of hNOS1 protein and the associated formation of NO and cGMP, which in turn decreased OH generation and stress-related cell death. In addition to inhibiting caspase-3 through a dithiothreitol-sensitive S-nitrosylation process, preconditioning stress concomitantly up-regulated the expression of the anti-apoptotic bcl-2 protein and down-regulated the p66shc adaptor protein. This beneficial cytoprotective process of preconditioning stress is mediated by newly synthesized NO because it can be suppressed by the inhibition of hNOS1 and guanylyl cyclase. Therefore, the constitutive isoform of hNOS1 is dynamically redox-regulated to meet both functional and compensatory demands of NO for gene regulation, antioxidant defense, and tolerance to oxidative stress.
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PMID:Preconditioning regulation of bcl-2 and p66shc by human NOS1 enhances tolerance to oxidative stress. 1102 98

Many studies have reported ischemia protection using various preconditioning techniques, including single dose 3-nitropropionic acid (3-NPA), a mitochondrial toxin. However, the cellular signal transduction cascades resulting in ischemic tolerance and the mechanisms involved in neuronal survival in the tolerant state still remain unclear. The current study investigated the mRNA and protein expression of the antiapoptotic bcl-2 and the proapoptotic bax. two antagonistic members of the bcl-2 gene family, in response to a single dose of 3-NPA, to global cerebral ischemia-reperfusion. and to the combination of both 3-NPA-pretreatment and subsequent global cerebral ischemia-reperfusion. Brain homogenates of adult Wistar rats (n = 25) were analyzed for bcl-2 and bax mRNA expression using a new highly sensitive and quantitative polymerase chain reaction (PCR) technique that allows real-time fluorescence measurements of the PCR product (LightCycler; Roche Diagnostics, Mannheim, Germany). Animals for mRNA analysis received 3-NPA (20 mg/kg, intraperitoneal; "chemical preconditioning") or vehicle (normal saline), and were either observed for 24 plus 3 hours or were subjected to 15 minutes of global cerebral ischemia 24 hours after the pretreatment and observed for 3 hours of reperfusion. Immunohistochemistry was applied to serial brain sections of additional rats (n = 68) to determine amount and localization of the respective Bcl-2 and Bax protein expression in various brain areas. One set of animals was injected with 3-NPA and observed for 3, 12, 24, and 96 hours; a second set was exposed to 15 minutes global cerebral ischemia, 3, 12, and 24 hours reperfusion; and a third set was pretreated with 3-NPA or saline 24 hours before the ischemic brain insult and observed for 96 hours of reperfusion. The authors found single dose 3-NPA treatment to be associated with an elevated bcl-2:bax ratio (increased bcl-2 expression, decreased bax expression), both on the transcriptional (mRNA) and the translational (protein) level. The differential influence of 3-NPA was maintained during early recovery from global cerebral ischemia (3 hours), when 3-NPA pretreated animals showed higher bcl-2 and lower bax mRNA levels compared with rats with saline treatment. Respective changes in protein expression were localized predominately in neurons vulnerable to ischemic damage. Compared with baseline, Bcl-2 protein was significantly higher in surviving neurons at 96 hours after the insult, whereas Bax protein remained unchanged. However, at this late time of postischemic recovery (96 hours), the protein expression pattern of surviving neurons was not different between animals with and without 3-NPA pretreatment. To the authors' knowledge, the current study is the first report on the differential expression of pro- and antiapoptotic genes after a single, nonlethal dose of 3-NPA. The current results suggest alterations in the balance between pro- and antiapoptotic proteins as a potential explanation for the reported protection provided by chemical preconditioning using 3-NPA in rats.
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PMID:Tolerance-Inducing dose of 3-nitropropionic acid modulates bcl-2 and bax balance in the rat brain: a potential mechanism of chemical preconditioning. 1104 5

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