SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia

Legos, Jeffrey J.; Erhardt, Joseph A.; White, R. F.; Lenhard, Stephen C.; Chandra, Sudeep; Parsons, Andrew A.; Tuma, Ronald F.; Barone, Frank C.

doi:10.1016/s0006-8993(00)03228-5

Cited by 99 publications

(65 citation statements)

References 38 publications

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“…Inhibition of p38 MAPK confers neuroprotection in vitro against excitotoxic exposure (48) and reduces acute ischemic injury in vivo (49). In the present study, SH caused a significant increase in p38 MAPK activity and serious injury to the neurons, whereas a p38 MAPK inhibitor reduced the increase in pp38 levels and reduced SH injury.…”

Section: Figsupporting

confidence: 39%

Oxygen-sensitive δ-Opioid Receptor-regulated Survival and Death Signals

Chieh

Qian

Ghassemi

et al. 2005

Journal of Biological Chemistry

150

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The detrimental effect of severe hypoxia (SH) on neurons can be mitigated by hypoxic preconditioning (HPC), but the molecular mechanisms involved remain unclear, and an understanding of these may provide novel solutions for hypoxic/ischemic disorders (e.g. stroke). Here, we show that the ␦-opioid receptor (DOR), an oxygen-sensitive membrane protein, mediates the HPC protection through specific signaling pathways. Although SH caused a decrease in DOR expression and neuronal injury, HPC induced an increase in DOR mRNA and protein levels and reversed the reduction in levels of the endogenous DOR peptide, leucine enkephalin, normally seen during SH, thus protecting the neurons from SH insult. The HPC-induced protection could be blocked by DOR antagonists. The DOR-mediated HPC protection depended on an increase in ERK and Bcl 2 activity, which counteracted the SH-induced increase in p38 MAPK activities and cytochrome c release. The cross-talk between ERK and p38 MAPKs displays a "yinyang" antagonism under the control of the DOR-G protein-protein kinase C pathway. Our findings demonstrate a novel mechanism of HPC neuroprotection (i.e. the intracellular up-regulation of DOR-regulated survival signals).Neuronal death as a result of neuronal injury following hypoxic/ischemic insults, such as stroke, is an irreversible process that leads to long term neurological deficit. The prevention of neuronal injury is therefore critical in rescuing the brain from neurological disaster. However, clinical strategies that may help mitigate the effects of hypoxic/ischemic injury are still very limited.One strategy that has been shown to provide effective protection from harmful stress is known as preconditioning. This involves transient, but sublethal, exposure to a stress, resulting in enhanced cellular resistance to subsequent severe stress. It was initially demonstrated in the heart (1) and subsequently found to work in other organ beds (2). The effects of preconditioning have been widely studied in the whole brain (3, 4), as well as in vitro in brain slices (5, 6) and neuronal cultures (7-9). Most studies to date have shown the beneficial effects of preconditioning on rescuing neurons from cell injury in response to subsequent severe insults. Hypoxic preconditioning (HPC), 1 for example, caused by lowering the oxygen content or by combined oxygen and glucose deprivation, protects against subsequent hypoxic injury (4,7,8,10). However, a recent study failed to show neuronal protection with HPC treatment (11), suggesting that the neuronal response to preconditioning may vary depending on neuronal situation and involve complex mechanisms. These molecular mechanisms remain unclear, especially with regard to intracellular signal transduction. In this study, we demonstrated that, in neurons in culture, HPCinduced neuroprotection is dependent on specific factors and that the effect is mediated by intracellular up-regulation of ␦-opioid receptor (DOR)-regulated survival signals, which suppress the increased activity of intracellular death s...

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Section: Figsupporting

confidence: 39%

Oxygen-sensitive δ-Opioid Receptor-regulated Survival and Death Signals

Chieh

Qian

Ghassemi

et al. 2005

Journal of Biological Chemistry

150

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“…150 The MAPK/ ERK signaling pathway may also regulate inflammation through its effects on PARP-1 activation, which (as detailed later in this review) is an important modulator of proinflammatory gene expression. 151 Pharmacological inhibition of both the p38 152,153 and the MAPK/ERK 154 signaling pathways improves outcomes in a mouse model of ischemia-reperfusion, but the extent to which these effects are due to reduced inflammation has not been established.…”

Section: Mitogen-activated Protein Kinase (Mapk) Cascadementioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…p38 is a stressactivated kinase, and its inhibition can attenuate cell death because of neuronal ischemia and glutamate-induced toxicity (14,(17)(18)(19)(20)(21)(22). However, p38 also controls the physiological processes of gene regulation through activating transcription factor 2 (ATF-2) and of synaptic plasticity through initiation of long term depression (LTD) and inhibition of long term potentiation (LTP) of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents (16,(23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

N-Methyl-D-aspartate Receptor Subtype Mediated Bidirectional Control of p38 Mitogen-activated Protein Kinase

Waxman¹,

Lynch

2005

Journal of Biological Chemistry

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N-methyl-D-aspartate receptor (NMDAR) stimulation activates many downstream mechanisms involved in both cell survival and cell death. The manner in which the NMDAR regulates one of these pathways, the p38 mitogen-activated protein kinase (p38) pathway, is currently unknown. In the present study, we have defined a developmental-, concentration-, and time-dependent phosphorylation and subsequent dephosphorylation of p38. In cultured hippocampal neurons 7-8 days in vitro (DIV7-8), NMDAR stimulation leads to a concentrationdependent increase in p38 phosphorylation (phosphop38). However, in more mature neurons (>DIV17) application of NMDA produces concentration-dependent effects, such that low concentrations result in sustained increases in phospho-p38 levels, and high concentrations dephosphorylate p38 within 5 min. Conantokin G, an antagonist of NR1/2A/2B and NR1/2B receptors, inhibits p38 phosphorylation, while NR1/2B-specific antagonists prevent the rapid dephosphorylation of p38 without affecting p38 activation. Furthermore, inhibition of calcineurin prevents the activation of p38, whereas inhibition of phosphoinositide 3-kinase (PI3K) prevents the rapid dephosphorylation of p38. Our results support the presence of subtype-dependent pathways regulating p38 activation and deactivation: one involves NR1/2A/2B receptors activating calcineurin and resulting in p38 phosphorylation, and the other utilizes NR1/2B receptors binding to and activating PI3K and leading to the dephosphorylation of p38 in a manner involving both NR1/2A/2B receptor activation and tyrosine phosphorylation of NR2B. The ability of NMDAR subtype-specific mechanisms to regulate p38 has implications for NMDAR-mediated synaptic plasticity, gene regulation, and excitotoxicity.The N-methyl-D-aspartate receptor (NMDAR), 1 a member of the ionotropic glutamate receptor family, is required for forms of neuronal synaptic plasticity, for cell death mediated by excitotoxicity and for gene regulation (1, 2). Differential responses mediated through NMDAR stimulation can be caused by the level of activation, the localization of the effect, or by the properties of the receptor. NMDARs likely contain two NR1 and two NR2 subunits (3). Most variations in receptor properties reflect differences in receptor subtype composition involving the four NR2 subunits (NR2A-NR2D) (2).In the hippocampus, NMDARs are composed mainly of NR1 subunits in combination with NR2A and NR2B subunits. The expression and localization of these NR2 subunits are developmentally regulated. Prenatally and early in postnatal development, hippocampal NMDARs are mostly NR1/2B receptors, localized at developing synapses with the synaptic-associated protein SAP-102 (4 -6). During maturation, expression of NR2A subunits increases, and NR2A-containing receptors, bound to post-synaptic density (PSD)-95, predominate in the synapse, whereas NR1/2B receptors become mostly extrasynaptic with SAP102 levels decreasing at the synapse (6 -10). NMDAR composition changes similarly in primary culture, in which imm...

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SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia

Cited by 99 publications

References 38 publications

Oxygen-sensitive δ-Opioid Receptor-regulated Survival and Death Signals

Oxygen-sensitive δ-Opioid Receptor-regulated Survival and Death Signals

Microglial Activation in Stroke: Therapeutic Targets

N-Methyl-D-aspartate Receptor Subtype Mediated Bidirectional Control of p38 Mitogen-activated Protein Kinase

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