Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and vasodilator properties of cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as intermittent claudication and recurrent stroke. In this review, the novel action mechanism (s) of cilostazol are overviewed with the focus on the action of cilostazol in in vitro and in vivo studies as a maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in cerebral infarct area was evident in rats subjected to ischemia/reperfusion. Increase in cyclic AMP and decrease in TNF-alpha levels were identified in the ipsilateral cortex under treatment with cilostazol accompanied by decreased Bax formation and cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells. Cilostazol suppressed TNF-alpha-induced decrease in viability of SK-N-SH (human neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by iberiotoxin, a maxi-K(+) channel blocker. Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells. Cilostazol increased K(+) current in SK-N-SH cells by opening the maxi-K channels. Thus, it was suggested that the action of cilostazol to promote cell survival was ascribed to the maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.
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PMID:Cilostazol: therapeutic potential against focal cerebral ischemic damage. 1647 48

Repinotan HCl (repinotan, BAYx3702), a highly selective 5-HT1A receptor agonist with a good record of safety was found to have pronounced neuroprotective effects in experimental models that mimic various aspects of brain injury. Repinotan caused strong, dose-dependent infarct reductions in permanent middle cerebral artery occlusion, transient middle cerebral artery occlusion, and traumatic brain injury paradigms. The specific 5-HT1A receptor antagonist WAY 100635 blocked these effects, indicating that the neuroprotective properties of repinotan are mediated through the 5-HT1A receptor. The proposed neuroprotective mechanisms of repinotan are thought to be the result of neuronal hyperpolarization via the activation of G protein-coupled inwardly rectifying K+ channels upon binding to both pre- and post-synaptic 5-HT1A receptors. Hyperpolarization results in inhibition of neuron firing and reduction of glutamate release. These mechanisms, leading to protection of neurons against overexcitation, could explain the neuroprotective efficacy of repinotan per se, but not necessarily the efficacy by delayed administration. The therapeutic time window of repinotan appeared to be at least 5 h in in vivo animal models, but may be even longer at higher doses of the drug. Experimental studies indicate that repinotan affects various mechanisms involved in the pathogenesis of brain injury. In addition to the direct effect of repinotan on neuronal hyperpolarization and suppression of glutamate release this compound affects the death-inhibiting protein Bcl-2, serotonergic glial growth factor S-100beta and Nerve Growth Factor. It also suppresses the activity of caspase-3 through MAPK and PKCalpha; this effect may contribute to its neuroprotective efficacy. The dose- and time-dependent neuroprotective efficacy of repinotan indicates that the drug is a promising candidate for prevention of secondary brain damage in brain-injured patients suffering from acute ischemic stroke. Unfortunately, however, the first, randomized, double blind, placebo-controlled clinical trial did not demonstrate the efficacy of repinotan in acute ischemic stroke.
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PMID:A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke. 1661 37

Stroke is one of the leading causes of unnatural death and disability. No effective therapy is available. Recombinant human granulocyte colony-stimulating factor (rhG-CSF), as a mobilizing agent for bone marrow stem cells, can promote stem cell mobilization, homing to brain after cerebral ischemia. In the present study, the administration of G-CSF significantly increased number of CD34(+) cells in the marginal zone of the infarction. Rats receiving G-CSF had higher survival rate and lower infarction volume. Neurological behavior was improved, and the expression of fibronectin in the ischemic brain was increased, as compared to rats treated with vehicle. To mimic the ischemia-reperfusion injury in experimental animals, we employed hippocampal slice cultures that were first treated with oxygen and glucose deprivation (OGD) and then with oxygen-glucose resupply, finding that fibronectin significantly increased the neurite outgrowth of OGD hippocampal slices, upregulated the expression of Bcl-2 protein, and ameliorated the ultrastructure damage of OGD hippocampal slices.
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PMID:Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. 1681 50

Pharmacological manipulation of gene expression is considered a promising avenue to reduce postischemic brain damage. Histone deacetylases (HDACs) play a central role in epigenetic regulation of transcription, and inhibitors of HDACs are emerging as neuroprotective agents. In this study, we investigated the effect of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on histone acetylation in control and ischemic mouse brain. We report that brain histone H3 acetylation was constitutively present at specific lysine residues in neurons and astrocytes. It is noteworthy that in the ischemic brain tissue subjected to 6 h of middle cerebral artery occlusion, histone H3 acetylation levels drastically decreased, without evidence for a concomitant change of histone acetyl-transferase or deacetylase activities. Treatment with SAHA (50 mg/kg i.p.) increased histone H3 acetylation within the normal brain (of approximately 8-fold after 6 h) and prevented histone deacetylation in the ischemic brain. These effects were accompanied by increased expression of the neuroprotective proteins Hsp70 and Bcl-2 in both control and ischemic brain tissue 24 h after the insult. It is noteworthy that at the same time point, mice injected with SAHA at 25 and 50 mg/kg had smaller infarct volumes compared with vehicle-receiving animals (28.5% and 29.8% reduction, p < 0.05 versus vehicle, Student's t test). At higher doses, SAHA was less efficient in increasing Bcl-2 and Hsp70 expression and did not afford significant ischemic neuroprotection (13.9% infarct reduction). Data demonstrate that pharmacological inhibition of HDACs promotes expression of neuroprotective proteins within the ischemic brain and underscores the therapeutic potential of molecules inhibiting HDACs for stroke therapy.
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PMID:Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. 1694 32

To determine whether Bcl-2 could influence adult neurogenesis and prevent apoptosis of newborn neurons, we injected Bcl-2 expressing plasmid into the lateral ventricle of rat brain immediately following a 30-min occlusion of the middle cerebral artery (MCAO). We found that Bcl-2 increased neural progenitor cells (BrdU+-DCX+) in the ipsilateral striatum, newborn immature neurons (BrdU+-Tuj-1+) and newborn mature neurons (BrdU+-MAP-2+) in the ipsilateral striatum and frontal cortex at 1 to 4 weeks following MCAO. Bcl-2 overexpression promoted development of newborn neurons into GABAergic and cholinergic neurons in the ipsilateral striatum. Moreover, Bcl-2 significantly decreased the apoptosis of newborn neurons, determined by double staining of Tuj-1 and activated caspase-3 (Tuj-1+-Casp+). These results indicate that overexpression of Bcl-2 in adult rat brain enhances neurogenesis and survival of newborn neurons. Increasing neurogenesis and preventing the death of newborn neuron may be a strategy to aid in the repair of adult brain after stroke.
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PMID:Bcl-2 enhances neurogenesis and inhibits apoptosis of newborn neurons in adult rat brain following a transient middle cerebral artery occlusion. 1699 45

Sustained progression of neuronal cell death causes brain tissue loss and subsequent functional deficits following stroke or central nervous system trauma and in neurodegenerative diseases. Despite obvious differences in the pathology of these neurological disorders, the underlying delayed neuronal demise is carried out by a common biochemical cell death programme. Mitochondrial membrane permeabilization and subsequent release of apoptotic factors are key mechanisms during this process. Bcl-2 family proteins, e.g. the pro-apoptotic Bid, Bax or Bad and the antiapoptotic Bcl-2, Bcl-X(L), play a crucial role in the regulation of this mitochondrial checkpoint in neurons. In particular, cleavage of cytosolic Bid and subsequent mitochondrial translocation have been detected in many paradigms of neuronal cell death related to acute or chronic neurodegeneration. The current review focuses on the emerging role of Bid as an integrating key regulator of the intrinsic death pathway that amplifies caspase-dependent and caspase-independent execution of neuronal apoptosis. Therefore pharmacological inhibition of Bid provides a promising therapeutic strategy in neurological diseases where programmed cell death is prominent.
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PMID:Targeting Bid to prevent programmed cell death in neurons. 1707 14

Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of apoptosis proteins (IAPs), heat shock protein 70 (HSP70), receptor interacting protein (RIP), etc., besides targeting directly the genes itself. However, selecting promising targets from various signalling cascades, for drug discovery and development is very challenging, nevertheless such novel approaches may lead to the emergence of new avenues for therapeutic intervention in cerebral ischemia.
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PMID:Molecular targets in cerebral ischemia for developing novel therapeutics. 1722 14

In recent years, the phosphoinositide-3-kinase/Akt cell survival signaling pathway has been increasingly researched in the field of stroke. Akt activity is suggested to be upregulated by phosphorylation through the activation of receptor tyrosine kinases by growth factors. Although the upstream signaling components phosphoinositide-dependent protein kinase (PDK)1 and integrinlinked kinase enhance the activity of Akt, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) decreases it. Upon activation, Akt phosphorylates an array of molecules, including glycogen synthase kinase3beta (GSK3beta), forkhead homolog in rhabdomyosarcoma (FKHR), and Bcl-2-associated death protein, thereby blocking mitochondrial cytochrome c release and caspase activity. Generally, the level of Akt phosphorylation at site Ser 473 (P-Akt) transiently increases after focal ischemia, whereas the levels of phosphorylation of PTEN, PDK1, forkhead transcription factor, and GSK3beta decrease. Numerous compounds (such as growth factors, estrogen, free radical scavengers, and other neuroprotectants) reduce ischemic damage, possibly by upregulating P-Akt. However, preconditioning and hypothermia block ischemic damage by inhibiting an increase of P-Akt. Inhibition of the Akt pathway blocks the protective effect of preconditioning and hypothermia, suggesting the Akt pathway contributes to their protective effects and that the P-Akt level does not represent its true kinase activity. Together, attenuation of the Akt pathway dysfunction contributes to neuronal survival after stroke.
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PMID:Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. 1730 56

When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.
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PMID:Calcium and neurodegeneration. 1732 89

Neonatal hypoxia-ischemia (HI) is an important clinical problem with few effective treatments. Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has been shown to be neuroprotective in focal ischemia in vivo and is currently in phase I/II clinical trials for ischemic stroke in humans. We tested G-CSF in a rat model of neonatal hypoxia-ischemia in postnatal day 7 unsexed rat pups. Three groups of animals were used: hypoxia-ischemia (HI, n=67), hypoxia-ischemia with G-CSF treatment (HI+G, n=65), and healthy control (C, n=53). G-CSF (50 microg/kg, subcutaneous) was administered 1 h after HI and given on four subsequent days (five total injections). Animals were euthanized 24 h, 1, 2, and 3 weeks after HI. Assessment included brain weight, histology, immunohistochemistry, and Western blotting. G-CSF treatment was associated with improved quantitative brain weight and qualitative Nissl histology after hypoxia-ischemia. TUNEL demonstrated reduced apoptosis in group HI+G. Western blot demonstrated decreased expression of Bax and cleaved caspase-3 in group HI+G. G-CSF treatment was also associated with increased expression of STAT3, Bcl-2, and Pim-1, all of which may have participated in the anti-apoptotic effect of the drug. We conclude that G-CSF ameliorates hypoxic-ischemic brain injury and that this may occur in part by an inhibition of apoptotic cell death.
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PMID:Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia-ischemia in rats. 1735 43


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