Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotransmitter glutamate can have both excitotoxic and protective effects on neurons. The excitotoxic effects have been intensively studied, whereas the protective effects, including the involvement of metabotropic glutamate receptors (mGluRs), remain unclear. In the present study, we tested the protective effects of the group-I-mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) on organotypic hippocampal slice cultures exposed to excitotoxic concentrations of N-methyl-D-aspartate (NMDA). Effects of DHPG on electrophysiological responses induced by NMDA receptor activation were also recorded. Experiments were performed on organotypic hippocampal slice cultures derived from 7-day-old rats, with cellular uptake of propidium iodide as a marker for neuronal cell death. Slice cultures pretreated with DHPG (10 or 100 microM) for 2 h prior to exposure to 50 microM NMDA for 30 min displayed reduced propidium iodide uptake, compared to cultures exposed to NMDA only. The neuroprotective effect was confirmed by Hoechst 33342 staining, where the appearance of pycnotic nuclei after NMDA treatment was prevented by the DHPG pretreatment. Using caspase-3 activity to monitor the presence of apoptosis, failed to demonstrate this type of cell death in CA1 after NMDA application. The protective effect of DHPG was abolished by the mGluR1 selective antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385; 5 or 10 microM), whereas the mGluR5-selective antagonist 2-methyl-6-phenylethynylpyridine (MPEP; 1 microM) had no effect. Voltage-clamping of CA1 pyramidal cells in cultures treated with 10 microM DHPG for 2 h showed a significant depression of NMDA-induced inward currents compared to untreated controls. We conclude that neuroprotection induced by activation of group-I-mGluRs involve mGluR1 and is associated with decreased NMDA-stimulated currents.
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PMID:Neuroprotection against NMDA excitotoxicity by group I metabotropic glutamate receptors is associated with reduction of NMDA stimulated currents. 1455 68

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.
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PMID:The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. 1455 44

Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1 mmol kg(-1), i.p.) and exposed to 1.5 mg l(-1) (the 96-h LC85) of dichlorvos for 96 h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and gamma-glutamyl transferase (gammaGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96 h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.
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PMID:Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine. 1456 51

Hyperthermia can contribute to brain damage both during development and post-natally. We used rat embryonic striatal neurons in culture to study mechanisms underlying hyperthermia-induced neuronal death. Heat stress at 43 degrees C for 2 h produced no obvious signs of damage during the first 12 h after the stress, but more than 50% of the neurons died during the next 3 days. More than 40% of the neurons had activated caspases 24 h following the heat stress. Caspase-3 activity increased with a delay of more than 10 h following cessation of the heat stress, reaching a peak at approximately 18 h. Neuronal death measured 1-3 days after the stress was reduced by the general caspase inhibitors qVD-OPH (10-20 microm) and zVAD-fmk (50-100 microm). These inhibitors were protective even when added 9 h after cessation of the heat stress, consistent with the delayed activation of caspases. In contrast, blockers of Na+ channels and ionotropic glutamate receptors did not reduce the heat-induced death, indicating that glutamate excitotoxicity was not required for this neuronal death. These results show that the neuronal death produced by heat stress has characteristics of apoptosis, and that caspase inhibitors can delay this death.
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PMID:Caspase activation contributes to delayed death of heat-stressed striatal neurons. 1462 26

Using a bisubstituted caspase-3 target sequence: aspartate-glutamate-valine-aspartate, (z-DEVD)2 peptide derivative of the fluorophore, cresyl violet, we have obtained a cell permeant, fluorogenic, caspase substrate capable of detecting the site-specific presence of functionally active, caspase-3 and caspase-7 up-regulation within intact apoptotic cells. Addition of this substrate to induced and noninduced cell culture populations allows for the rapid site-specific detection of caspase up-regulation without the requirement for a wash step. We demonstrate here the use of (z-DEVD)2-cresyl violet substrate for the detection of apoptosis induction in Jurkat, THP-1, and MCF-7 cells using fluorescence microscopy and 96-well fluorescence plate reader analysis. Intracellular up-regulated DEVDase activity, which was clearly visible by fluorescence microscopy and 96-well fluorescence plate reader measurements, showed greater than 6-fold increases in fluorescence output in induced versus noninduced Jurkat cell samples. A simple fluorogenic substrate conversion method is demonstrated here for detecting apoptosis induction within intact living cells.
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PMID:DEVDase detection in intact apoptotic cells using the cell permeant fluorogenic substrate, (z-DEVD)2-cresyl violet. 1462 83

Dynorphin A (1-17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1-17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl-D-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (-)-naloxone, a general opioid antagonist. The results show that dynorphin A (1-17) (>or=10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors.
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PMID:Dynorphin A (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation. 1464 68

Glutamate induces gene transcription in numerous physiological and pathological conditions. Among the glutamate-responsive transcription factors, NF-kappaB has been mainly implicated in neuronal survival and death. Recent data also suggest a role of NF-kappaB in neural development and memory formation. In non-neuronal cells, degradation of the inhibitor IkappaBalpha represents a key step in NF-kappaB activation. However, little is known of how glutamate activates NF-kappaB in neurons. To investigate the signalling cascade involved we used primary murine cerebellar granule cells. Glutamate induced a rapid reduction of IkappaBalpha levels and nuclear translocation of the NF-kappaB subunit p65. The glutamate-induced reduction of IkappaBalpha levels was blocked by the N-methyl-d-aspartate inhibitor MK801. Specific inhibitors of the proteasome, caspase 3, and the phosphoinositide 3-kinase had no effect on glutamate-induced IkappaBalpha degradation. However, inhibition of the glutamate-activated Ca2+-dependent protease calpain by calpeptin completely blocked IkappaBalpha degradation and reduced the nuclear translocation of p65. Calpeptin also partially blocked glutamate-induced cell death. Our data indicate that the Ca2+-dependent protease calpain is involved in the NF-kappaB activation in neurons in response to N-methyl-d-aspartate receptor occupancy by glutamate. NF-kappaB activation by calpain may mediate the long-term effects of glutamate on neuron survival or memory formation.
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PMID:Glutamate activates NF-kappaB through calpain in neurons. 1468 3

In cultured rat cerebellar granule cells, glutamate or N-methyl-d-aspartate (NMDA) activation of the NMDA receptor caused a sustained increase in cytosolic Ca(2+) levels ([Ca(2+)](i)), reactive oxygen species (ROS) generation, and cell death (respective EC(50) values for glutamate were 12, 30, and 38 microM) but no increase in caspase-3 activity. Removal of extracellular Ca(2+) blocked all three glutamate-induced effects, whereas pretreatment with an ROS scavenger inhibited glutamate-induced cell death but had no effect on the [Ca(2+)](i) increase. This indicates that glutamate-induced cell death is attributable to [Ca(2+)](i) increase and ROS generation, and the [Ca(2+)](i) increase precedes ROS generation. Apoptotic cell death was not seen until 24 h after exposure of cells to glutamate. S-nitrosoglutathione abolished glutamate-induced ROS generation and cell death, and only a transient [Ca(2+)](i) increase was seen; similar results were observed with another nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine, but not with glutathione, which suggests that the effects were caused by NO. The transient [Ca(2+)](i) increase and the abolishment of ROS generation induced by glutamate and S-nitrosoglutathione were still seen in the presence of an ROS scavenger. Glial cells, which were present in the cultures used, showed no [Ca(2+)](i) increase in the presence of glutamate, and glutamate-induced granule cell death was independent of the percentage of glial cells. In conclusion, NO donors protect cultured cerebellar granule cells from glutamate-induced cell death, which is mediated by ROS generated by a sustained [Ca(2+)](i) increase, and glial cells provide negligible protection against glutamate-induced excitotoxicity.
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PMID:Rat cerebellar granule cells are protected from glutamate-induced excitotoxicity by S-nitrosoglutathione but not glutathione. 1500 26

Complete glucose deprivation has been shown to induce neuronal apoptosis, but the effect of moderate glucose deprivation under normal and pathological conditions is not fully understood. We investigated the effect of a restricted supply of glucose on neuronal vulnerability to glutamate by assaying cellular ATP levels (cellular energy production), 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction (mitochondrial function), lactate dehydrogenase (LDH) release (cellular viability) and activation of caspase-3 (apoptosis) in rat hippocampal neurons cultured in media (1.7, 5 and 25 mM glucose) with or without 100 microM glutamate. Cellular ATP levels were significantly reduced in neurons cultured in 1.7 mM glucose, while addition of glutamate markedly lowered cellular ATP levels even at the normal glucose concentration. MTT reduction was also significantly inhibited by 1.7 mM glucose; however, unlike cellular ATP levels, glutamate inhibition of MTT reduction was glucose concentration dependent. The LDH assay suggested that neuronal survival declines with decreasing glucose concentration in media, and glutamate potentiates this effect. Since low glucose media caused a decrease in cellular ATP and cell viability, we investigated apoptosis-related changes in cultured neurons by examining activity of caspase-3. Low glucose media (1.7 and 5 mM glucose) increased caspase-3 activity, and glutamate potentiated this effect. Our results suggest that a low glucose supply in culture media activates an apoptosis mediator and markedly increases susceptibility to glutamate toxicity. Thus, even moderate glucose deprivation could be a serious risk factor that potentiates the pathophysiological consequences of certain neurodegenerative diseases.
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PMID:Glucose insufficiency alters neuronal viability and increases susceptibility to glutamate toxicity. 1503 34

Oligodendroglial death due to overactivation of the AMPA/kainate glutamate receptors is implicated in white matter damage in multiple CNS disorders. We previously demonstrated that glutamate induces caspase-3 activation and death of the late oligodendrocyte progenitor known as the pro-oligodendroblast (pro-OL) via activation of the AMPA/kainate glutamate receptors. We also demonstrated that IGF-I had the unique ability to sustain activation of Akt in the pro-OL and provide long-term protection of these cells from glutamate-mediated apoptosis. The goal of these studies was to investigate the mechanisms of glutamate toxicity and IGF-I-mediated survival in the pro-OL. IGF-I prevented glutamate-induced loss of mitochondrial membrane potential, cytochrome c release, and caspase-9 activation. In contrast to IGF-I mediated survival mechanisms in neurons, IGF-I had no effect on the influx or recovery of intracellular calcium levels or on levels of major pro- and anti-apoptotic molecules including Bax or Bcl-xL. Rather, IGF-I prevented the glutamate-induced translocation of Bax to the mitochondria. Moreover, IGF-I prevented caspase-3 activation in pro-OLs as long as 8 h after exposure of the cells to glutamate, suggesting that delayed activation of IGF-I-mediated survival pathways can block glutamate-mediated apoptosis in pro-OLs. The results of these experiments define the mechanisms by which glutamate kills oligodendrocyte progenitor cells and by which IGF-I blocks glutamate-induced apoptosis in these cells. The data also demonstrate that IGF-I disrupts the glutamate-mediated apoptotic pathway in the pro-OL through mechanisms that are distinct from its survival-promoting actions in neurons.
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PMID:IGF-I prevents glutamate-mediated bax translocation and cytochrome C release in O4+ oligodendrocyte progenitors. 1504 85


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