Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic administration of kainate induces cell death in vulnerable regions of the rodent brain. Neuronal degeneration is associated with internucleosomal DNA fragmentation and induction of presumptive cell death effector genes (e.g. p53, c-fos) suggesting that kainate activates an apoptotic pathway. In the present study, kainate-induced DNA damage has been demonstrated at the cellular level by in situ nick translation in the mouse hippocampus and neocortex at 24 h and 48 h after intraperitoneal injections. In the same regions, the intensity of Bcl-2 immunoreactivity decreased by about 45% as measured by digital image analysis. Most important, kainate treatment evoked a nearly 3-fold increase in bax mRNA levels within the mouse brain. The down-regulation of bcl-2, which promotes cell survival, and the up-regulation of bax, which promotes programmed cell death, may have functional significance in kainate-mediated excitotoxicity and in the selective vulnerability of specific brain regions.
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PMID:Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. 767 27

Attempts to rescue retinal ganglion cells from retrograde degeneration have had limited success, and the residual function of surviving neurons is not known. Recently, it has been found that axotomized retinal ganglion cells die by apoptotic mechanisms. We have used adult transgenic mice overexpressing the Bcl-2 protein, a powerful inhibitor of apoptosis, as a model for preventing injury-induced cell death in vivo. Several months after axotomy, the majority of retinal ganglion cells survived and exhibited normal visual responses. In control wild-type mice, the vast majority of axotomized retinal ganglion cells degenerated, and the physiological responses were abolished. These results suggest that strategies aimed at increasing Bcl-2 expression, or mimicking its function, might effectively counteract trauma-induced cell death in the central nervous system. Neuronal survival is a necessary condition in the challenge for promoting regeneration and eventually restoring neuronal function.
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PMID:The visual response of retinal ganglion cells is not altered by optic nerve transection in transgenic mice overexpressing Bcl-2. 896 63

The ability of the protein synthesis inhibitor cycloheximide (CHX) to prevent neuronal death in different paradigms has been interpreted to indicate that the cell death process requires synthesis of "killer" proteins. On the other hand, data indicate that neurotrophic factors protect neurons in the same death paradigms by inducing expression of neuroprotective gene products. We now provide evidence that in embryonic rat hippocampal cell cultures, CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including the antiapoptotic gene bcl-2 and antioxidant enzymes. Neuronal survival after exposure to glutamate, FeSO4, and amyloid beta-peptide was increased in cultures pretreated with CHX at concentrations of 50-500 nM; higher and lower concentrations were ineffective. Neuroprotective concentrations of CHX caused only a moderate (20-40%) reduction in overall protein synthesis, and induced an increase in c-fos, c-jun, and bcl-2 mRNAs and protein levels as determined by reverse transcription-PCR analysis and immunocytochemistry, respectively. At neuroprotective CHX concentrations, levels of c-fos heteronuclear RNA increased in parallel with c-fos mRNA, indicating that CHX acts by inducing transcription. Neuroprotective concentrations of CHX suppressed accumulation of H2O2 induced by FeSO4, suggesting activation of antioxidant pathways. Treatment of cultures with an antisense oligodeoxynucleotide directed against bcl-2 mRNA decreased Bcl-2 protein levels and significantly reduced the neuroprotective action of CHX, suggesting that induction of Bcl-2 expression was mechanistically involved in the neuroprotective actions of CHX. In addition, activity levels of the antioxidant enzymes Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and catalase were significantly increased in cultures exposed to neuroprotective levels of CHX. Our data suggest that low concentrations of CHX can promote neuron survival by inducing increased levels of gene products that function in antioxidant pathways, a neuroprotective mechanism similar to that used by neurotrophic factors.
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PMID:Neuroprotective action of cycloheximide involves induction of bcl-2 and antioxidant pathways. 906 Apr 77

Extensive programmed cell death (PCD) occurs in the developing nervous system. Neuronal death occurs, at least in part, because neurons are produced in excess during development and compete with each other for the limited amounts of the survival-promoting trophic factors secreted by target tissues. Neuronal death is apoptotic and utilizes components that are conserved in other PCD pathways. In this review, we discuss the mechanism of trophic factor-dependent neuronal cell death by focusing on the pathway of nerve growth factor (NGF) deprivation-induced sympathetic neuronal death. We describe the biochemical and genetic events that occur in NGF-deprived sympathetic neurons undergoing PCD. Participation of the Bcl-2 family of proteins and the interleukin-1beta-converting enzyme family of proteases (caspases) in this and other models of neuronal death is also examined. The order and importance of these components during NGF deprivation-induced sympathetic neuronal death are discussed.
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PMID:Programmed cell death in neurons: focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons. 918 55

Recent research indicates that apoptotic mechanisms may be involved in cell death in Alzheimer's disease (AD). We studied the expression of three members of the Bcl-2 protein family, Bcl-2, Bcl-x, and Bax, in a selection of senile and DS-related AD patients as well as in controls. These proteins are all associated with apoptotic mechanisms. In contrast to previous reports, neuronal Bcl-2 labeling was not detected in our cases, although there was some weak and inconsistent glial cell labeling. Neuronal Bcl-x expression was virtually absent in controls and the presence of the protein in AD patients was neither consistent nor specific. Some reactive glial cells were strongly labeled with the Bcl-x antibody. In contrast Bax, a protein that is believed to promote apoptosis, was widely expressed by neurones but was mainly present in areas other than CA1 in the hippocampus. Neuritic elements of some senile plaques were clearly and strongly labeled with this antibody, whereas neurofibrillary tangles and neuropil threads were not. Double labeling studies indicated that AT8-positive cells and neurites were never Bax-positive and vice versa. The possible implications of the different expression patterns are discussed in relation to neurone death in AD.
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PMID:Apoptosis-related protein expression in the hippocampus in Alzheimer's disease. 946 Oct 54

Neuronal vacuolation, involving the cerebellar roof nuclei, Purkinje cells, selected nuclei of the brain stem, thalamus, Clarke's column, anterior and posterior horns of the spinal cord, visceral autonomic ganglia and myenteric plexus, as well as axonal degeneration of the white matter of the brain stem, cerebellar pedunculi, dorsolateral columns of the spinal cord and ventral roots of the spinal cord, were observed in two young Rottweiler dogs which were clinically afflicted with hind limb weakness progressing to paraparesia, ataxia, intention tremor, and difficulty in swallowing and barking. The absence of modifications in Bcl-2 and Bax immunoreactivity, a lack of strong c-Jun/AP-1 (N) immunoreactivity in vacuolated cells, and the absence of DNA breaks, as seen with the method of in situ end-labeling of nuclear DNA fragmentation, all suggest that there is no involvement of the apoptotic pathway in vacuolated cells in this new neurodegenerative disorder.
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PMID:Neuronal vacuolation in young Rottweiler dogs. 992 31

Neuronal death is an essential feature in the normal development of the nervous system and in neurodegenerative states of the adult or ageing brain. Bcl-2 is the prototype of a growing family of proteins which control cell death. Many of these proteins are expressed in the nervous system during development and in the adult. Numerous observations have suggested that this family of proteins plays a central role in the control of naturally occurring and pathological neuronal death. In this review, I will discuss the possible mechanisms of action of these proteins as well as their potential use in treating neurodegenerative diseases.
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PMID:Bcl-2 family members in the development and degenerative pathologies of the nervous system. 1020 90

Neuronal death was produced in the CA1 and CA3 areas of the hippocampus, amygdala, and piriform and entorhinal cortices after intraperitioneal administration of kainic acid at convulsant doses to adult rats. To assess the involvement of members of the Bcl-2 family in cell death or survival, immunohistochemistry, western and northern blotting to Bcl-2, Bcl-x and Bax, and in situ hybridization to Bax were examined at different time-points after kainic acid treatment. Members of the Bcl-2 family were expressed in the cytoplasm of pyramidal neurons in the hippocampus, and in a subset of neurons of the piriform and the entorhinal cortices, amygdala and neocortex in the normal adult brain. Dying neurons in the pyramidal cell layer of CA1 and CA3 areas, entorhinal and piriform cortices, and amygdala also expressed Bcl-2, Bax and Bcl-x following excitotoxicity, although many dying cells did not. In addition, a number of cells in the affected areas showed Bax immunoreactivity in their nuclei at 24-48 h following kainic acid administration, thus indicating Bax nuclear translocation in a subset of dying cells. Western blots disclosed no modifications in the intensity of the bands corresponding to Bcl-2, Bcl-x and Bax, between control and kainic acid-treated rats. No modifications in the intensity of the bcl-2 messenger RNA band on northern blots was observed in kainic acid-treated rats. However, a progressive increase in the intensity of the bax messenger RNA band was found in kainic acid-treated rats at 6 h, 12 h and 24 h following kainic acid administration. Interestingly, a slight increase in Bax immunoreactivity was observed in the cytoplasm of neurons of the dentate gyrus at 24-48 h, a feature which matches the increase of bax messenger RNA in the same area, as shown by in situ hybridization at 12-24 h following kainic acid injection. The present results suggest that cell death or survival does not correlate with modifications of Bcl-2, Bax and Bcl-x protein, and messenger RNA expression, but rather that kainic acid excitotoxicity is associated with Bax translocation to the nucleus in a subset of dying cells.
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PMID:Bcl-2, Bax and Bcl-x expression following kainic acid administration at convulsant doses in the rat. 1039 51

Semliki Forest virus (SFV) infection of mice is used as a model to study pathogenic processes occurring in viral encephalitis. It has previously been shown that avirulent strains of SFV differ from virulent strains in showing restricted multiplication in neurones and in producing localized rather than widespread lesions in the central nervous system (CNS). Restricted neuronal damage is age-dependent and does not occur in neonatal animals. In this study, cell death mechanisms occurring in the CNS of adult rats infected intranasally (i.n.) with a virulent (SFV4) and an avirulent (A7) strain of SFV have been investigated. Although i.n. infection of rats was less efficient than that of mice, SFV4 reached a higher titre in the CNS of infected animals than A7. Neuronal destruction and leucocytic infiltration occurred throughout the forebrain of SFV4-infected rats. A7-infected rats remained clinically normal although degenerate neurons and inflammatory changes were present primarily in the olfactory system. Following infection with either A7-SFV or SFV4, TUNEL-positive nuclei were seen in areas of leucocytic infiltration and among the poorly differentiated cells of the rostral migratory stream. Migrating cells had condensed nuclear chromatin, compacted cytoplasm and intact cellular membranes, characteristic of apoptosis, and were sparsely immunolabelled for viral antigen. In SFV4-infected rats, large numbers of contiguous neurones in forebrain areas exhibited cytoplasmic eosinophilia and karyolysis and were surrounded by phagocytic cells. Such neurones contained dense intracytoplasmic deposits of viral antigen and showed weak cytoplasmic TUNEL staining; electron microscopy showed membrane disruption, organelle disintegration, irregular chromatin condensation and cytoplasmic aggregation of virus particles. Bcl-2 staining was similar in infected and control rats and was most intense in randomly distributed Purkinje cells in the cerebellum; neurons in the olfactory bulbs were unstained. These findings indicate that during SFV encephalitis, infiltrating leucocytes and neural precursor cells undergo apoptosis whilst productively infected neurons undergo necrosis.
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PMID:Cell death mechanisms in the olfactory bulb of rats infected intranasally with Semliki forest virus. 1041 65

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


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