17 results on '"Ren, Wu"'
Search Results
2. A Multifunctional Cytoprotective Agent That Reduces Neurodegeneration after Ischemia
- Author
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Jiang, Zhi-Gang, Lu, X. -C. May, Nelson, Valery, Yang, Xiaofang, Pan, Weiying, Chen, Ren-wu, Lebowitz, Michael S., Almassian, Bijan, Tortella, Frank C., Brady, Roscoe O., and Ghanbari, Hossein A.
- Published
- 2006
- Full Text
- View/download PDF
3. PAN-811 provides neuroprotection against glutamate toxicity by suppressing activation of JNK and p38 MAPK
- Author
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X.-C. May Lu, Ren-Wu Chen, Hossein A. Ghanbari, Jitendra R. Dave, Changping Yao, Zhilin Liao, Hans H Wei, Zhi-Gang Jiang, and Frank C. Tortella
- Subjects
Thiosemicarbazones ,Cell Survival ,Pyridines ,p38 mitogen-activated protein kinases ,Blotting, Western ,Glutamic Acid ,Tetrazolium Salts ,Pharmacology ,Biology ,p38 Mitogen-Activated Protein Kinases ,Neuroprotection ,Rats, Sprague-Dawley ,Downregulation and upregulation ,Pregnancy ,medicine ,Animals ,Staurosporine ,Cells, Cultured ,Anthracenes ,Cerebral Cortex ,Kinase ,General Neuroscience ,JNK Mitogen-Activated Protein Kinases ,Glutamate receptor ,Genes, bcl-2 ,Rats ,Thiazoles ,Neuroprotective Agents ,Mitogen-activated protein kinase ,biology.protein ,Phosphorylation ,Female ,Excitatory Amino Acid Antagonists ,Neuroscience ,medicine.drug - Abstract
In an earlier study, we demonstrated that PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, provides protection against glutamate, staurosporine, veratridine, or hypoxia/hypoglycemia toxicities in primary cortical neuronal cultures by upregulating Bcl-2 expression [R.-W. Chen, C. Yao, X.C. Lu, Z.-G. Jiang, R. Whipple, Z. Liao, H.A. Ghanbari, B. Almassian, F.C. Tortella, J.R. Dave. PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by upregulating Bcl-2 expression. Neuroscience 135 (2005) 191–201]. Both JNK (c-Jun N-terminal kinase) and p38 MAP (mitogen-activated protein) kinase activation have a direct inhibitory action on Bcl-2 by phosphorylation. In the present study, we continued to explore the mechanism of PAN-811 neuroprotection. Our results indicate that treatment of cultured cortical neurons with glutamate (100 μM) induces phosphorylation of both JNK and p38 MAPK. Specifically, pretreatment of neurons with 10 μM PAN-811 (an optimal neuroprotective concentration) for 1 h, 4 h, or 24 h significantly suppresses glutamate-mediated activation of both JNK and p38 MAPK. Furthermore, the p38 MAPK-specific inhibitor SB203580 and the JNK-specific inhibitor SP600125 prevented glutamate-induced neuronal death in these primary cultures. Our results demonstrate that glutamate-induced phosphorylation of JNK and p38 MAPK is suppressed by PAN-811, which might contribute to Bcl-2 upregulation and PAN-811 neuroprotection.
- Published
- 2007
4. A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia
- Author
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Xiaofang Yang, Ren-Wu Chen, Bijan Almassian, Zhi-Gang Jiang, Frank C. Tortella, Weiying Pan, Valery Nelson, Michael S. Lebowitz, X.-C. May Lu, Hossein A. Ghanbari, and Roscoe O. Brady
- Subjects
Male ,Thiosemicarbazones ,medicine.medical_specialty ,Time Factors ,Neurology ,Pyridines ,Blotting, Western ,Ischemia ,Infarction ,chemistry.chemical_element ,Apoptosis ,DNA Fragmentation ,Pharmacology ,Calcium ,Neuroprotection ,Rats, Sprague-Dawley ,Necrosis ,medicine ,Animals ,Humans ,Hypoxia ,Chelating Agents ,Cerebral Cortex ,Neurons ,Multidisciplinary ,Dose-Response Relationship, Drug ,L-Lactate Dehydrogenase ,business.industry ,Neurodegeneration ,Neurotoxicity ,Infarction, Middle Cerebral Artery ,Neurodegenerative Diseases ,Free Radical Scavengers ,Biological Sciences ,Fluoresceins ,medicine.disease ,Cytoprotective Agent ,Coculture Techniques ,Corpus Striatum ,Rats ,Disease Models, Animal ,Neuroprotective Agents ,chemistry ,Reactive Oxygen Species ,business - Abstract
Cellular and molecular pathways underlying ischemic neurotoxicity are multifaceted and complex. Although many potentially neuroprotective agents have been investigated, the simplicity of their protective mechanisms has often resulted in insufficient clinical utility. We describe a previously uncharacterized class of potent neuroprotective compounds, represented by PAN-811, that effectively block both ischemic and hypoxic neurotoxicity. PAN-811 disrupts neurotoxic pathways by at least two modes of action. It causes a reduction of intracellular-free calcium as well as free radical scavenging resulting in a significant decrease in necrotic and apoptotic cell death. In a rat model of ischemic stroke, administration of PAN-811 i.c.v. 1 h after middle cerebral artery occlusion resulted in a 59% reduction in the volume of infarction. Human trials of PAN-811 for an unrelated indication have established a favorable safety and pharmacodynamic profile within the dose range required for neuroprotection warranting its clinical trial as a neuroprotective drug.
- Published
- 2006
5. PAN-811 (3-Aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by up-regulating Bcl-2 expression
- Author
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Bijan Almassian, Jitendra R. Dave, Frank C. Tortella, Ren-Wu Chen, Changping Yao, Hossein A. Ghanbari, Rebecca Whipple, Xi-Chun May Lu, Zhi-Gang Jiang, and Zhilin Liao
- Subjects
Thiosemicarbazones ,medicine.medical_specialty ,Cell Survival ,Pyridines ,Blotting, Western ,Apoptosis ,DNA Fragmentation ,Pharmacology ,Biology ,Neuroprotection ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Staurosporine ,Hypoxia ,Cells, Cultured ,Neurons ,Veratridine ,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone ,General Neuroscience ,Neurotoxicity ,Glutamate receptor ,Cytochromes c ,medicine.disease ,Hypoglycemia ,Genes, bcl-2 ,Rats ,Up-Regulation ,Neuroprotective Agents ,Endocrinology ,chemistry ,NMDA receptor ,Excitatory Amino Acid Antagonists ,medicine.drug - Abstract
Neurotoxicity in primary neurons was induced using hypoxia/hypoglycemia (H/H), veratridine (10microM), staurosporine (1microM) or glutamate (100microM), which resulted in 72%, 67%, 75% and 66% neuronal injury, respectively. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (PAN-811; 10microM; Panacea Pharmaceuticals, Gaithersburg, MD) pretreatment for 24 h provided maximal neuroprotection of 89%, 42%, 47% and 89% against these toxicities, respectively. Glutamate or H/H treatment of cells increased cytosolic cytochrome c levels, which was blocked by pretreatment of cells with PAN-811. Pretreatment of neurons with PAN-811 produced a time-dependent increase in the protein level of Bcl-2, which was evident even after glutamate or H/H treatments. An up-regulation in the expression of the p53 and Bax genes was also observed following exposure to these neurotoxic insults; however, this increase was not suppressed by PAN-811 pretreatment. Functional inhibition of Bcl-2 by HA14-1 reduced the neuroprotective efficacy of PAN-811. PAN-811 treatment also abolished glutamate or H/H-mediated internucleosomal DNA fragmentation.
- Published
- 2005
6. Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model
- Author
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Vladimir V. Senatorov, De-Maw Chuang, Ming Ren, and Ren-Wu Chen
- Subjects
Male ,Reflex, Startle ,Excitotoxicity ,Ischemia ,Apoptosis ,Blood Pressure ,Brain damage ,Lithium ,Pharmacology ,medicine.disease_cause ,Neuroprotection ,Body Temperature ,Rats, Sprague-Dawley ,Therapeutic index ,medicine ,Animals ,Multidisciplinary ,business.industry ,Cerebral infarction ,Cerebral Infarction ,Biological Sciences ,medicine.disease ,Startle reaction ,Rats ,Cerebral blood flow ,Ischemic Attack, Transient ,Cerebrovascular Circulation ,Reperfusion ,Brain Damage, Chronic ,medicine.symptom ,business - Abstract
Lithium has long been a primary drug used to treat bipolar mood disorder, even though the drug's therapeutic mechanisms remain obscure. Recent studies demonstrate that lithium has neuroprotective effects against glutamate-induced excitotoxicity in cultured neurons and in vivo . The present study was undertaken to examine whether postinsult treatment with lithium reduces brain damage induced by cerebral ischemia. We found that s.c. injection of lithium dose dependently (0.5–3 mEq/kg) reduced infarct volume in the rat model of middle cerebral artery occlusion/reperfusion. Infarct volume was reduced at a therapeutic dose of 1 mEq/kg even when administered up to 3 h after the onset of ischemia. Neurological deficits induced by ischemia were also reduced by daily administration of lithium over 1 week. Moreover, lithium treatment decreased the number of neurons showing DNA damage in the ischemic brain. These neuroprotective effects were associated with an up-regulation of cytoprotective heat shock protein 70 (HSP70) in the ischemic brain hemisphere as determined by immunohistochemistry and Western blotting analysis. Lithium-induced HSP70 up-regulation in the ischemic hemisphere was preceded by an increase in the DNA binding activity of heat shock factor 1, which regulates the transcription of HSP70. Physical variables and cerebral blood flow were unchanged by lithium treatment. Our results suggest that postinsult lithium treatment reduces both ischemia-induced brain damage and associated neurological deficits. Moreover, the heat shock response is likely to be involved in lithium's neuroprotective actions. Additionally, our studies indicate that lithium may have clinical utility for the treatment of patients with acute stroke.
- Published
- 2003
7. Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection
- Author
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Ren-Wu Chen, Zheng-Hong Qin, Hirohiko Kanai, De-Maw Chuang, Ming Ren, Elzbieta Chalecka-Franaszek, and Peter Leeds
- Subjects
medicine.medical_specialty ,biology ,SB 203580 ,Excitotoxicity ,Glutamate receptor ,medicine.disease_cause ,Biochemistry ,Neuroprotection ,Cell biology ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Mitogen-activated protein kinase ,medicine ,biology.protein ,NMDA receptor ,ASK1 ,Protein kinase A - Abstract
In rat cerebellar granule cells, glutamate induced rapid activation of c-Jun N-terminal kinase (JNK) and p38 kinase to phosphorylate c-Jun (at Ser63) and p53 (at Ser15), respectively, and a subsequent marked increase in activator protein-1 (AP-1) binding that preceded apoptotic death. These glutamate-induced effects and apoptosis could largely be prevented by long-term (7 days) pretreatment with 0.5–2 mm lithium, an antibipolar drug. Glutamate's actions could also be prevented by known blockers of this pathway, MK-801 (an NMDA receptor blocker), SB 203580 (a p38 kinase inhibitor) and curcumin (an AP-1 binding inhibitor). The concentration- and time-dependent suppression of glutamate's effects by lithium and curcumin correlated well with their neuroprotective effects. These results suggest a prominent role of JNK and p38, as well as their downstream AP-1 binding activation and p53 phosphorylation in mediating glutamate excitotoxicity. Moreover, the neuroprotective effects of lithium are mediated, at least in part, by suppressing NMDA receptor-mediated activation of the mitogen-activated protein kinase pathway.
- Published
- 2003
8. Neuroprotective effects of lithium in cultured cells and animal models of diseases
- Author
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Ming Ren, Christopher J. Hough, De-Maw Chuang, Elzbieta Chalecka-Franaszek, Toyoko Hiroi, Ren-Wu Chen, Hirohiko Kanai, Ryota Hashimoto, Vladimir V. Senatorov, and Peter Leeds
- Subjects
Lithium (medication) ,business.industry ,Excitotoxicity ,Glutamate receptor ,Brain damage ,Pharmacology ,medicine.disease_cause ,Neuroprotection ,Psychiatry and Mental health ,chemistry.chemical_compound ,chemistry ,medicine ,NMDA receptor ,medicine.symptom ,business ,Protein kinase B ,Neuroscience ,Biological Psychiatry ,medicine.drug ,Quinolinic acid - Abstract
Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.
- Published
- 2002
9. Long Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression
- Author
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De-Maw Chuang and Ren-Wu Chen
- Subjects
Cerebellum ,Cytochrome c ,Neurodegeneration ,Excitotoxicity ,Glutamate receptor ,Cell Biology ,Biology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Neuroprotection ,Cell biology ,Bcl-2-associated X protein ,medicine.anatomical_structure ,Downregulation and upregulation ,biology.protein ,medicine ,Molecular Biology - Abstract
This study was undertaken to investigate the molecular mechanisms underlying the neuroprotective actions of lithium against glutamate excitotoxicity with a focus on the role of proapoptotic and antiapoptotic genes. Long term, but not acute, treatment of cultured cerebellar granule cells with LiCl induces a concentration-dependent decrease in mRNA and protein levels of proapoptotic p53 and Bax; conversely, mRNA and protein levels of cytoprotective Bcl-2 are remarkably increased. The ratios of Bcl-2/Bax protein levels increase by approximately 5-fold after lithium treatment for 5–7 days. Exposure of cerebellar granule cells to glutamate induces a rapid increase in p53 and Bax mRNA and protein levels with no apparent effect on Bcl-2 expression. Pretreatment with LiCl for 7 days prevents glutamate-induced increase in p53 and Bax expression and maintains Bcl-2 in an elevated state. Glutamate exposure also triggers the release of cytochrome c from the mitochondria into the cytosol. Lithium pretreatment blocks glutamate-induced cytochrome c release and cleavage of lamin B1, a nuclear substrate for caspase-3. These results strongly suggest that lithium-induced Bcl-2 up-regulation and p53 and Bax down-regulation play a prominent role in neuroprotection against excitotoxicity. Our results further suggest that lithium, in addition to its use in the treatment of bipolar depressive illness, may have an expanded use in the intervention of neurodegeneration.
- Published
- 1999
10. NNZ-2566, a glypromate analog, improves functional recovery and attenuates apoptosis and inflammation in a rat model of penetrating ballistic-type brain injury
- Author
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Zhilin Liao, Ren-Wu Chen, Jitendra R. Dave, Hans H Wei, Xiaofang Yang, Frank C. Tortella, Changping Yao, and Xi-Chun May Lu
- Subjects
Pathology ,medicine.medical_specialty ,Rat model ,Anti-Inflammatory Agents ,Inflammation ,Apoptosis ,Tripeptide ,Pharmacology ,Neuroprotection ,Rats, Sprague-Dawley ,Medicine ,Animals ,Gliosis ,Movement Disorders ,Dose-Response Relationship, Drug ,business.industry ,Neurodegeneration ,Brain ,Recovery of Function ,medicine.disease ,Bioavailability ,Rats ,Disease Models, Animal ,Neuroprotective Agents ,Treatment Outcome ,Astrocytes ,Brain Injuries ,Injections, Intravenous ,Nerve Degeneration ,Encephalitis ,Histopathology ,Neurology (clinical) ,Microglia ,medicine.symptom ,business ,Apoptosis Regulatory Proteins ,Oligopeptides - Abstract
Glycine-proline-glutamate (GPE) is an N-terminal tripeptide endogenously cleaved from insulin-like growth factor-1 in the brain and is neuroprotective against hypoxic-ischemic brain injury and neurodegeneration. NNZ-2566 is an analog of GPE designed to have improved bioavailability. In this study, we tested NNZ-2566 in a rat model of penetrating ballistic-type brain injury (PBBI) and assessed its effects on injury-induced histopathology, behavioral deficits, and molecular and cellular events associated with inflammation and apoptosis. In the initial dose-response experiments, NNZ-2566 (0.01-3 mg/kg/h x 12 h intravenous infusion) was given at 30 min post-injury and the therapeutic time window was established by delaying treatments 2-4 h post-injury, but with the addition of a 10- or 30-mg/kg bolus dose. All animals survived 72 h. Neuroprotection was evaluated by balance beam testing and histopathology. The effects of NNZ-2566 on injury-induced changes in Bax and Bcl-2 proteins, activated microgliosis, neutrophil infiltration, and astrocyte reactivity were also examined. Behavioral results demonstrated that NNZ-2566 dose-dependently reduced foot faults by 19-66% after acute treatments, and 35-55% after delayed treatments. Although gross lesion volume was not affected, NNZ-2566 treatment significantly attenuated neutrophil infiltration and reduced the number of activated microglial cells in the peri-lesion regions of the PBBI. PBBI induced a significant upregulation in Bax expression (36%) and a concomitant downregulation in Bcl-2 expression (33%), both of which were significantly reversed by NNZ-2566. Collectively, these results demonstrated that NNZ-2566 treatment promoted functional recovery following PBBI, an effect related to the modulation of injury-induced neural inflammatory and apoptotic mechanisms.
- Published
- 2009
11. Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation
- Author
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Changping Yao, Jitendra R. Dave, Ren-Wu Chen, Frank C. Tortella, Anthony J. Williams, and Zhilin Liao
- Subjects
Phosphodiesterase Inhibitors ,Phosphodiesterase 3 ,Neurotoxins ,Apoptosis ,Cell Cycle Proteins ,Biology ,Neuroprotection ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,medicine ,Staurosporine ,Animals ,Cyclin D1 ,Enzyme Inhibitors ,Rolipram ,Cells, Cultured ,Cerebral Cortex ,Neurons ,Dose-Response Relationship, Drug ,Caspase 3 ,Phosphoric Diester Hydrolases ,General Neuroscience ,Trequinsin ,Phosphodiesterase ,Cell cycle ,Cell biology ,Rats ,Neuroprotective Agents ,chemistry ,Nerve Degeneration ,medicine.drug - Abstract
Cellular injury can involve the aberrant stimulation of cell cycle proteins in part through activation of phosphodiesterases (PDEs) and downstream expression of cell-cycle components such as cyclin D1. In mature non-proliferating cells activation of the cell cycle can lead to the induction of programmed cell death. In the present study, we investigated the in vitro neuroprotective efficacy and mechanism of action of vinpocetine (PDE1 inhibitor), trequinsin (PDE3 inhibitor), and rolipram (PDE4 inhibitor) in four mechanistically-distinct models of injury to primary rat cortical neurons as related to cell cycle regulation and apoptosis. Cellular injury was induced by hypoxia/hypoglycemia, veratridine (10 microM), staurosporine (1 microM), or glutamate (100 microM), resulting in average neuronal cell death rates of 43-48% as determined by MTT assay. Treatment with each PDE inhibitor (PDEI) resulted in a similar concentration-dependent neuroprotection profile with maximal effective concentrations of 5-10 microM (55-77% neuroprotection) in all four neurotoxicity models. Direct cytotoxicity due to PDE inhibition alone was not observed at concentrations below 100 microM. Further studies indicated that PDEIs can suppress the excitotoxic upregulation of cyclin D1 similar to the effects of flavopiridol, a cyclin-dependent kinase inhibitor, including suppression of pro-apoptotic caspase-3 activity. Overall, these data indicate that PDEIs are broad-spectrum neuroprotective agents acting through modulation of cell cycle elements and may offer a novel mode of therapy against acute injury to the brain.
- Published
- 2007
12. Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons
- Author
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Sawa A, Peter Leeds, De-Maw Chuang, Ren-Wu Chen, and Kanai H
- Subjects
Excitotoxicity ,Apoptosis ,Biology ,medicine.disease_cause ,Neuroprotection ,Histone Deacetylases ,Rats, Sprague-Dawley ,Glutamates ,Genetics ,medicine ,Animals ,Enzyme Inhibitors ,Cells, Cultured ,Pharmacology ,Cell Nucleus ,Neurons ,Histone deacetylase 5 ,Cell Death ,Dose-Response Relationship, Drug ,Valproic Acid ,Glyceraldehyde-3-Phosphate Dehydrogenases ,Molecular biology ,Rats ,Histone Deacetylase Inhibitors ,Trichostatin A ,Acetylation ,Molecular Medicine ,Histone deacetylase ,Histone deacetylase activity ,Chromatin immunoprecipitation ,Excitatory Amino Acid Antagonists ,medicine.drug - Abstract
Valproic acid (VPA), used to treat bipolar mood disorder and seizures, also inhibits histone deacetylase (HDAC). Here, we found that VPA and other HDAC inhibitors, butyrate and trichostatin A, robustly protected mature cerebellar granule cell cultures from excitotoxicity induced by SYM 2081 ((2S, 4R)-4-methylglutamate), an inhibitor of excitatory amino-acid transporters and an agonist of low-affinity kainate receptors. These neuroprotective effects required protracted treatment and were correlated with enhanced acetylated histone levels, indicating HDAC inhibition. SYM-induced excitotoxicity was blocked by MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate), supporting that the toxicity was largely N-methyl-D-aspartate receptor dependent. SYM excitotoxicity had apoptotic characteristics and was prevented by a caspase inhibitor. SYM-induced apoptosis was associated with a rapid and robust nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a housekeeping gene previously shown to be proapoptotic. VPA pretreatment suppressed SYM 2081-induced GAPDH nuclear accumulation, concurrent with its neuroprotective effects. Chromatin immunoprecipitation (ChIP) revealed that GAPDH is copresent with acetylated histone H3, including Lys9-acetylated histone, and that VPA treatment caused a time-dependent decrease in the levels of nuclear GAPDH with a concomitant increase in acetylated histones in the ChIP complex. Our results strongly suggest that VPA protects neurons from excitotoxicity through inhibition of HDAC activity and that this protective effect may involve suppression of excitotoxicity-induced accumulation of GAPDH protein in the nucleus.
- Published
- 2004
13. PAN-811 provides neuroprotection against glutamate toxicity by suppressing activation of JNK and p38 MAPK
- Author
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Chen, Ren-Wu, Lu, X.-C. May, Yao, Changping, Liao, Zhilin, Jiang, Zhi-Gang, Wei, Hans, Ghanbari, Hossein A., Tortella, Frank C., and Dave, Jitendra R.
- Subjects
- *
GLUTAMIC acid , *NERVOUS system , *PROTEIN kinases , *HYPOGLYCEMIC agents - Abstract
Abstract: In an earlier study, we demonstrated that PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, provides protection against glutamate, staurosporine, veratridine, or hypoxia/hypoglycemia toxicities in primary cortical neuronal cultures by upregulating Bcl-2 expression [R.-W. Chen, C. Yao, X.C. Lu, Z.-G. Jiang, R. Whipple, Z. Liao, H.A. Ghanbari, B. Almassian, F.C. Tortella, J.R. Dave. PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by upregulating Bcl-2 expression. Neuroscience 135 (2005) 191–201]. Both JNK (c-Jun N-terminal kinase) and p38 MAP (mitogen-activated protein) kinase activation have a direct inhibitory action on Bcl-2 by phosphorylation. In the present study, we continued to explore the mechanism of PAN-811 neuroprotection. Our results indicate that treatment of cultured cortical neurons with glutamate (100μM) induces phosphorylation of both JNK and p38 MAPK. Specifically, pretreatment of neurons with 10μM PAN-811 (an optimal neuroprotective concentration) for 1h, 4h, or 24h significantly suppresses glutamate-mediated activation of both JNK and p38 MAPK. Furthermore, the p38 MAPK-specific inhibitor SB203580 and the JNK-specific inhibitor SP600125 prevented glutamate-induced neuronal death in these primary cultures. Our results demonstrate that glutamate-induced phosphorylation of JNK and p38 MAPK is suppressed by PAN-811, which might contribute to Bcl-2 upregulation and PAN-811 neuroprotection. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
14. Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation
- Author
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Chen, Ren-Wu, Williams, Anthony J., Liao, Zhilin, Yao, Changping, Tortella, Frank C., and Dave, Jitendra R.
- Subjects
- *
BRAIN injuries , *PHOSPHODIESTERASES , *NOOTROPIC agents , *HYPOGLYCEMIC agents - Abstract
Abstract: Cellular injury can involve the aberrant stimulation of cell cycle proteins in part through activation of phosphodiesterases (PDEs) and downstream expression of cell-cycle components such as cyclin D1. In mature non-proliferating cells activation of the cell cycle can lead to the induction of programmed cell death. In the present study, we investigated the in vitro neuroprotective efficacy and mechanism of action of vinpocetine (PDE1 inhibitor), trequinsin (PDE3 inhibitor), and rolipram (PDE4 inhibitor) in four mechanistically-distinct models of injury to primary rat cortical neurons as related to cell cycle regulation and apoptosis. Cellular injury was induced by hypoxia/hypoglycemia, veratridine (10μM), staurosporine (1μM), or glutamate (100μM), resulting in average neuronal cell death rates of 43–48% as determined by MTT assay. Treatment with each PDE inhibitor (PDEI) resulted in a similar concentration-dependent neuroprotection profile with maximal effective concentrations of 5–10μM (55–77% neuroprotection) in all four neurotoxicity models. Direct cytotoxicity due to PDE inhibition alone was not observed at concentrations below 100μM. Further studies indicated that PDEIs can suppress the excitotoxic upregulation of cyclin D1 similar to the effects of flavopiridol, a cyclin-dependent kinase inhibitor, including suppression of pro-apoptotic capase-3 activity. Overall, these data indicate that PDEIs are broad-spectrum neuroprotective agents acting through modulation of cell cycle elements and may offer a novel mode of therapy against acute injury to the brain. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
15. A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia.
- Author
-
Zhi-Gang Jiang, Lu, X.-C. May, Nelson, Valery, Xiaofang Yang, Weiying Pan, Ren-Wu Chen, Lebowitz, Michael S., Almassian, Bijan, Tortella, Frank C., Brady, Roscoe O., and Ghanbari, Hossein A.
- Subjects
NEURODEGENERATION ,ISCHEMIA ,BLOOD circulation disorders ,CLINICAL trials ,MEDICAL experimentation on humans ,PHARMACODYNAMICS - Abstract
Cellular and molecular pathways underlying ischemic neurotoxicity are multifaceted and complex. Although many potentially neuroprotective agents have been investigated, the simplicity of their protective mechanisms has often resulted in insufficient clinical utility. We describe a previously uncharacterized class of potent neuroprotective compounds, represented by PAN-811. that effectively block both ischemic and hypoxic neurotoxicity. PAN-811 disrupts neurotoxic pathways by at least two modes of action. It causes a reduction of intracellular-free calcium as well as free radical scavenging resulting in a significant decrease in necrotic and apoptotic cell death. In a rat model of ischemic stroke, administration of PAN-811 i.c.v. 1 h after middle cerebral artery occlusion resulted in a 59% reduction in the volume of infarction. Human trials of PAN-811 for an unrelated indication have established a favorable safety and pharmacodynamic profile within the dose range required for neuroprotection warranting its clinical trial as a neuroprotective drug. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
16. Neuroprotective effects of lithium in cultured cells and animal models of diseases.
- Author
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Chuang, De-Maw, Chen, Ren-Wu, Chalecka-Franaszek, Elzbieta, Ren, Ming, Hashimoto, Ryota, Senatorov, Vladimir, Kanai, Hirohiko, Hough, Christopher, Hiroi, Toyoko, and Leeds, Peter
- Subjects
- *
LITHIUM , *NEURODEGENERATION - Abstract
Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mechanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun – N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
17. Neuronal Apoptosis Induced by Pharmacological Concentrations of 3-Hydroxykynurenine.
- Author
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Wei, Huafeng, Leeds, Peter, Chen, Ren-Wu, Wei, Wenlin, Leng, Yan, Bredesen, Dale E., and Chuang, De-Maw
- Subjects
APOPTOSIS ,NEUROTOXIC agents ,NEUROTOXICOLOGY - Abstract
Abstract: We have studied neurotoxicity induced by pharmacological concentrations of 3-hydroxykynurenine (3-HK), an endogenous toxin implicated in certain neurodegenerative diseases, in cerebellar granule cells, PC12 pheochromocytoma cells, and GT1-7 hypothalamic neurosecretory cells. In all three cell types, the toxicity was induced in a dose-dependent manner by 3-HK at high micromolar concentrations and had features characteristic of apoptosis, including chromatin condensation and internucleosomal DNA cleavage. In cerebellar granule cells, the 3-HK neurotoxicity was unaffected by xanthine oxidase inhibitors but markedly potentiated by superoxide dismutase and its hemelike mimetic, MnTBAP [manganese(III) tetrakis(benzoic acid)porphyrin chloride]. Catalase blocked 3-HK neurotoxicity in the absence and presence of superoxide dismutase or MnTBAP. The formation of H
2 O2 was demonstrated in PC12 and GT1-7 cells treated with 3-HK, by measuring the increase in the fluorescent product, 2′,7′-dichlorofluorescein. In both PC12 and cerebellar granule cells, inhibitors of the neutral amino acid transporter that mediates the uptake of 3-HK failed to block 3-HK toxicity. However, their toxicity was slightly potentiated by the iron chelator, deferoxamine. Taken together, our results suggest that neurotoxicity induced by pharmacological concentrations of 3-HK in these cell types is mediated primarily by H2 O2 , which is formed most likely by auto-oxidation of 3-HK in extracellular compartments. 3-HK-induced death of PC12 and GT1-7 cells was protected by dantrolene, an inhibitor of calcium release from the endoplasmic reticulum. The protection by dantrolene was associated with a marked increase in the protein level of Bcl-2, a prominent antiapoptotic gene product. Moreover, overexpression of Bcl-2 in GT1-7 cells elicited by gene transfection suppressed 3-HK toxicity. Thus, dantrolene may elicit its neuroprotective effects by mechanisms involving up-regulation of the level and function of Bcl-2 protein. [ABSTRACT FROM AUTHOR]- Published
- 2000
- Full Text
- View/download PDF
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