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)

Pigment epithelium-derived factor (PEDF) protects immature cerebellar granule cells (1-3 days in vitro) against induced apoptosis and mature cells (5+ days in vitro) against glutamate toxicity, but its precise mechanism is still unknown. Because the transcription factor NFkappaB blocks cell death, including neuronal apoptosis, we have investigated the ability of PEDF to exert its effects via NFkappaB activation. PEDF induced an increased phosphorylation of IkappaBalpha, decreased levels of IkappaB proteins, and translocation of p65 (RelA) to the nucleus followed by a time-dependent increase of NFkappaB-DNA binding activity in both immature and mature neurons. The protective effects of PEDF against both induced apoptosis and glutamate toxicity were blocked by the addition of either the IkappaB kinase inhibitor BAY 11-7082, which inhibits the phosphorylation of IkappaB, or N-acetyl-Leu-Leu-norleucinal, which blocks proteosome degradation of IkappaB, demonstrating that NFkappaB is required for the neuroprotective effects of PEDF. Reverse transcription-polymerase chain reaction analysis revealed that up-regulation of the anti-apoptotic genes for Bcl-2, Bcl-x, and manganese superoxide dismutase was observed in PEDF-treated immature but not mature neurons. Up-regulation of nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor mRNA was long-lasting in mature neurons. These results suggest that PEDF promotes neuronal survival through activation of NFkappaB, which in turn induces expression of anti-apoptotic and/or neurotrophic factor genes.
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PMID:NFkappaB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons. 1155 40

The sensitivity of the developing central nervous system (CNS) to the deleterious effects of ethanol has been well documented, with exposure leading to a wide array of CNS abnormalities. Certain CNS regions are susceptible to ethanol during well-defined critical periods. In the neonatal rodent cerebellum, a profound loss of Purkinje cells is found when ethanol is administered early in the postnatal period [on postnatal days 4 or 5 (P4-5)], while this neuronal population is much less vulnerable to similar ethanol insult slightly later in the postnatal period (P7-9). Prior studies have shown that neurotrophic factors (NTFs) can be altered by ethanol exposure, and both in vitro and in vivo studies have provided evidence that such substances have the potential to protect against ethanol neurotoxicity. In the present study, it was hypothesized that depletion of an NTF shown to be important to cerebellar development would exacerbate ethanol-related effects within this region, when administration was confined to a normally ethanol-resistant ontogenetic period. For this study, brain-derived neurotrophic factor (BDNF) gene-deleted ("knockout") and wild-type mice were exposed to ethanol via vapor inhalation or to control conditions during the normally ethanol-resistant period (P7 and P8). Two hours after termination of exposure on P8, analyses were made of body weight, crown-rump length, and brain weight. In subsequent investigations, the number and density of Purkinje cells and the volume of cerebellar lobule I were determined, and the expression of anti- and pro-apoptotic proteins and the activities of endogenous antioxidants were assessed. It was found that the BDNF knockouts were significantly smaller than the wild-type animals, with smaller brain weights. Purkinje cell number and density was reduced in ethanol-treated knockout, but not wild-type animals, and the volume of lobule I was significantly decreased in the gene-deleted animals compared to wild-types, but was not further affected by ethanol treatment. The loss of Purkinje cells in the BDNF knockouts was accompanied by decreases in anti-apoptotic Bcl-xl and in phosphorylated (and hence inactivated) pro-apoptotic Bad, and reduced activity of the antioxidant glutathione reductase, while the antioxidant catalase was increased by ethanol treatment in this genotype. In the wild-type animals, anti-apoptotic Bcl-2 was decreased by ethanol treatment, but the pro-apoptotic c-Jun N-terminal kinase (JNK) was markedly diminished by ethanol exposure, while the activity of the protective antioxidant superoxide dismutase (SOD) was significantly enhanced. These results suggest that neurotrophic factors have the capacity to protect against ethanol neurotoxicity, perhaps by regulation of expression of molecules critical to neuronal survival such as elements of the apoptosis cascade and protective antioxidants.
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PMID:Influence of ethanol on neonatal cerebellum of BDNF gene-deleted animals: analyses of effects on Purkinje cells, apoptosis-related proteins, and endogenous antioxidants. 1193 57

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.
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PMID:Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. 1239 85

The developing central nervous system is extremely sensitive to ethanol, with well-defined temporal periods of vulnerability. Many brain regions are particularly susceptible to ethanol during the early neonatal period, corresponding to the human third trimester, which represents a dynamic period of growth and differentiation. For this study, neonatal rats were acutely exposed to ethanol or control conditions at a neonatal age when the developing striatum has been shown to be vulnerable to ethanol (postnatal day 3 [P3]), and at a later age (P14), when this developing region is relatively ethanol-resistant. We then analyzed basal levels of neurotrophic factors (NTFs), and ethanol-mediated changes in NTFs, apoptosis-related proteins, antioxidants, and reactive oxygen species (ROS) generation, which may underlie this differential temporal vulnerability. Sequential analyses were made following ethanol exposure on these two postnatal days, with assessments of NTFs nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4); apoptosis-related proteins Bcl-2, Bcl-xl, Bax, Akt and c-jun N-terminal kinase (JNK); antioxidants superoxide dismutase, glutathione reductase and catalase; and ROS. The results indicated that basal levels of BDNF, and to some degree NGF, were greater at the older age, and that ethanol exposure at the earlier age elicited considerably more pro-apoptotic and fewer pro-survival changes than those produced at the later age. Thus, differential temporal vulnerability to ethanol in this CNS region appears to be related to differences in both differential levels of protective substances (e.g. NTFs), and differential cellular responsiveness which favors apoptosis at the most sensitive age and survival at the resistant age.
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PMID:Effects of ethanol on neurotrophic factors, apoptosis-related proteins, endogenous antioxidants, and reactive oxygen species in neonatal striatum: relationship to periods of vulnerability. 1258 29

The percentage of grafted embryonic DA neurons that survive transplantation is low, estimated at 5-20%. Significant agreement has emerged from the work of research groups worldwide that specific conditions associated with the transplant procedure and post-transplantation interval render grafted mesencephalic cells susceptible to apoptotic death. Detrimental triggers including hypoxia/ischemia, trophic factor withdrawal, and oxidative stress appear to exert the most impact on grafted DA neuron survival. Treatment strategies that aim to reduce or eliminate the triggers of grafted cell death appear to be more successful than approaches that target the intracellular apoptotic cascade. In particular, treatment of mesencephalic cell suspensions with isolated neurotrophic factors (GDNF, BDNF, NT 4/5) as well as glial-derived factors, antioxidant therapies and augmentation of graft vasculature have demonstrated consistent survival promoting effects. Caspase inhibition, although initially quite promising, has not been demonstrated to reliably increase grafted cell survival. Bcl-2 overexpression similarly has yet to prove beneficial, although this may be due to biologically irrelevant levels of bcl-2 present during the critical immediate post-grafting interval. Future strategies will target a "cocktail" approach in which effective treatment agents are combined to maximize grafted DA neuron survival. Refinements in ex vivo transduction parameters will allow for efficient sustained delivery of survival promoting agents to grafted cells. Once identified, the optimal survival-enhancing treatment of grafted primary embryonic DA neurons should also benefit future transplant therapies utilizing alternatively derived DA neurons.
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PMID:Strategies for the augmentation of grafted dopamine neuron survival. 1270 87

Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.
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PMID:[Neuroprotective actions of lithium]. 1270 Dec 14

Epidemiologic studies revealed that the prevalence of Parkinson disease is higher in males than in females and that the progression of the disease might be rapid in males compared with females. The reason for the gender difference is unknown; however, estrogens may be involved. Many studies have revealed that estrogens provide neuroprotective effects and that the protective mechanisms include antioxidant property and upregulation of Bcl-2, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor (GDNF). Upregulation of Bcl-2 or GDNF is mediated by nonnuclear estrogen receptor (ER) in addition to transcription regulation by ER. To avoid undesirable effect of estrogens, several selective ER modulators, raloxifene and genistein are considered.
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PMID:Estrogens and Parkinson disease: novel approach for neuroprotection. 1277 6

Ubiquitin is thought to be a stress protein that plays an important role in protecting cells under stress conditions; however, its precise role is unclear. Ubiquitin expression level is controlled by the balance of ubiquitinating and deubiquitinating enzymes. To investigate the function of deubiquitinating enzymes on ischemia-induced neural cell apoptosis in vivo, we analyzed gracile axonal dystrophy (gad) mice with an exon deletion for ubiquitin carboxy terminal hydrolase-L1 (UCH-L1), a neuron-specific deubiquitinating enzyme. In wild-type mouse retina, light stimuli and ischemic retinal injury induced strong ubiquitin expression in the inner retina, and its expression pattern was similar to that of UCH-L1. On the other hand, gad mice showed reduced ubiquitin induction after light stimuli and ischemia, whereas expression levels of antiapoptotic (Bcl-2 and XIAP) and prosurvival (brain-derived neurotrophic factor) proteins that are normally degraded by an ubiquitin-proteasome pathway were significantly higher. Consistently, ischemia-induced caspase activity and neural cell apoptosis were suppressed approximately 70% in gad mice. These results demonstrate that UCH-L1 is involved in ubiquitin expression after stress stimuli, but excessive ubiquitin induction following ischemic injury may rather lead to neural cell apoptosis in vivo.
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PMID:Role of ubiquitin carboxy terminal hydrolase-L1 in neural cell apoptosis induced by ischemic retinal injury in vivo. 1469 19

FOXO3a is a ubiquitously expressed mammalian forkhead transcription factor with a high expression level in adult brain. The activity of FOXO3a is inhibited by growth factors through activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which phosphorylates FOXO3a and decreases the level of FOXO3a in the nucleus. In the present study, we examined the regulation of FOXO3a by brain-derived neurotrophic factor (BDNF) in retinoic acid (RA)-differentiated human SH-SY5Y neuroblastoma cells. BDNF caused a rapid and time-dependent decrease of nuclear FOXO3a with a corresponding increase of cytosolic FOXO3a. The rate of the BDNF-induced nuclear/cytosolic redistribution was consistent with the time course of BDNF-induced threonine32-phosphorylation of FOXO3a, and was mediated by the PI3K/Akt signaling pathway. Active FOXO3a rapidly increased the level of Bcl-2-interacting mediator (bim) in differentiated SH-SY5Y cells, and BDNF decreased the FOXO3a-induced increase of bim through activation of both PI3K/Akt and Erk signaling pathways. Thapsigargin, an endoplasmic reticulum (ER) stress-inducing agent, significantly decreased threonine32-phosphorylation of FOXO3a, and increased nuclear and decreased cytosolic FOXO3a, suggesting that thapsigargin activates FOXO3a. Treatment with BDNF completely reversed and blocked the thapsigargin-induced dephosphorylation and nuclear accumulation of FOXO3a. In addition, protein phosphatase 1/2A inhibitors increased threonine32-phosphorylation of FOXO3a, decreased nuclear FOXO3a, and blocked thapsigargin-induced activity of FOXO3a. The regulatory effect of BDNF on FOXO3a and its target genes may play a significant role in the BDNF-mediated neuronal survival, differentiation, and plasticity.
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PMID:Regulation of FOXO3a by brain-derived neurotrophic factor in differentiated human SH-SY5Y neuroblastoma cells. 1520 15

This study provides new insights into neuroprotection involving interaction of protein kinase C (PKC) pathway with Bcl-2 family proteins. Using a model of serum deprivation, we investigated the mechanism by which the anti-Parkinson/monoamine oxidase (MAO)-B inhibitor drug, rasagiline, exerts its neuroprotective effect in rat pheochromocytoma PC12 cells. Here, we report that rasagiline (0.1-10 microM) decreased apoptosis via multiple protection mechanisms, including the stimulation of PKC phosphorylation; up-regulation of PKCalpha and PKC mRNAs, induction of Bcl-xL, Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and down-regulation of Bad and Bax mRNAs. Moreover, rasagiline inhibited the cleavage and activation of procaspase-3 and poly (ADP-ribose) polymerase (PARP), whereas the PKC inhibitor, GF109203X, reversed these actions. Similarly, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC in rasagiline-induced cell survival. Furthermore, these studies have established that PKC- and Bcl-2-dependent neuroprotective activity of rasagiline is dependent on its propargyl moiety, because propargylamine had similar effects with the same potency.
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PMID:Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. 1524 50


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