Evidence from cultured rat cortical neurons of differences in the mechanism of ischemic preconditioning of brain and heart

Tauskela, Joseph S.; Chakravarthy, Balu; Murray, Christine L.; Wang, Yizheng; Comas, Tanya; Hogan, Matthew J.; Hakim, Antoine M.; Morley, Paul

doi:10.1016/s0006-8993(99)01322-0

Cited by 52 publications

(47 citation statements)

References 60 publications

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“…Tauskela et al (1999) found that neuroprotection by IPC was maintained despite pharmacological inhibition of PKC, suggesting that PKC does not play a role during IPC. In contrast, Reshef et al (2000) showed that the preconditioning-induced neuroprotection initiated by adenosine receptors was mediated through activation of PKC in primary rat neuronal cultures.…”

Section: Discussionmentioning

confidence: 98%

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εPKC Is Required for the Induction of Tolerance by Ischemic and NMDA-Mediated Preconditioning in the Organotypic Hippocampal Slice

et al. 2003

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Glutamate receptors and calcium have been implicated as triggering factors in the induction of tolerance by ischemic preconditioning (IPC) in the brain. However, little is known about the signal transduction pathway that ensues after the IPC induction pathway. The main goals of the present study were to determine whether NMDA induces preconditioning via a calcium pathway and promotes translocation of the protein kinase C ⑀ (⑀PKC) isozyme and whether this PKC isozyme is key in the IPC signal transduction pathway. We corroborate here that IPC and a sublethal dose of NMDA were neuroprotective, whereas blockade of NMDA receptors during IPC diminished IPC-induced neuroprotection. Calcium chelation blocked the protection afforded by both NMDA and ischemic preconditioning significantly, suggesting a significant role of calcium. Pharmacological preconditioning with the nonselective PKC isozyme activator phorbol myristate acetate could not emulate IPC, but blockade of PKC activation with chelerythrine during IPC blocked its neuroprotection. These results suggested that there might be a dual involvement of PKC isozymes during IPC. This was corroborated when neuroprotection was blocked when we inhibited ⑀PKC during IPC and NMDA preconditioning, and IPC neuroprotection was emulated with the activator of ⑀PKC. The possible correlation between NMDA, Ca 2ϩ , and ⑀PKC was found when we emulated IPC with the diacylglycerol analog oleoylacetyl glycerol, suggesting an indirect pathway by which Ca 2ϩ could activate the calcium-insensitive ⑀PKC isozyme. These results demonstrated that the ⑀PKC isozyme played a key role in both IPC-and NMDA-induced tolerance.

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Section: Discussionmentioning

confidence: 98%

“…Strong evidence exists of the involvement of PKC in the induction of IPC tolerance in the heart (Downey et al, 1994). In brain, however, different preconditioning models have shown contradictory results Tauskela et al, 1999;Reshef et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

εPKC Is Required for the Induction of Tolerance by Ischemic and NMDA-Mediated Preconditioning in the Organotypic Hippocampal Slice

et al. 2003

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“…For HPC treatment, the culture was placed in a 5% O 2 and 5% CO 2 environment in an incubator for 3, 6, or 9 h. For SH treatment, the cultures were exposed to 1% oxygen for 5 days, unless stated otherwise. For HPC plus SH treatment, cells were treated with HPC for the indicated time, followed by SH treatment 24 h later (10).…”

Section: Methodsmentioning

confidence: 99%

“…To examine the signaling molecules involved between the DOR signal and MAPKs, we also used pertussis toxin (100 ng ml Ϫ1 ; Sigma) to block pertussis toxin-sensitive G protein function. Calphostin C (0.1 M, LC Laboratories, MA) or H89 (N-[2-((pbromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide hydrochloride) (0.5 M; Calbiochem) was used to specifically inhibit intracellular PKC or PKA activity, as previously reported (10).…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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NMDA receptor‐driven calcium influx promotes ischemic human cardiomyocyte apoptosis through a p38 MAPK‐mediated mechanism

Liu

Zhong

Tian

et al. 2019

J of Cellular Biochemistry

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N‐methyl‐D‐aspartate receptor (NMDAR) activity plays a key role in cerebral ischemia. Although NMDAR is also expressed in cardiomyocytes, little research has been performed on NMDAR activity in myocardial ischemia. Here, using an in vitro oxygen‐glucose deprivation (OGD) cardiomyocyte model, we evaluated the effects of NMDAR activity upon calcium influx, viability, apoptosis, and investigated the roles of several key mitogen‐activated protein kinases (MAPKs). Primary human neonatal cardiomyocytes were cultured under OGD conditions to mimic in vivo ischemic conditions. Enhancing NMDAR activity via NMDA significantly promoted calcium influx, decreased cell viability, increased apoptosis, and enhanced p38 MAPK phosphorylation in OGD cardiomyocytes (all P < 0.05). These effects were rescued by several calcium‐channel blockers (ie, MK‐801, La3+, Gap26 peptide, 18β‐glycyrrhetinic acid) but most potently rescued via the NMDAR‐specific antagonist MK‐801 or removal of extracellular free calcium (all P < 0.05). Knocking‐down p38 MAPK activity by small‐molecule inhibition or genetic methods significantly increased cell viability and reduced apoptosis (all P < 0.05). Enhancing p38 MAPK activity abolished MK‐801′s apoptosis‐reducing effects in a p38 MAPK‐dependent manner. In conclusion, NMDAR‐driven calcium influx promotes apoptosis in ischemic human cardiomyocytes, an effect which can be attributed to enhanced p38 MAPK activity.

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Evidence from cultured rat cortical neurons of differences in the mechanism of ischemic preconditioning of brain and heart

Cited by 52 publications

References 60 publications

εPKC Is Required for the Induction of Tolerance by Ischemic and NMDA-Mediated Preconditioning in the Organotypic Hippocampal Slice

εPKC Is Required for the Induction of Tolerance by Ischemic and NMDA-Mediated Preconditioning in the Organotypic Hippocampal Slice

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

NMDA receptor‐driven calcium influx promotes ischemic human cardiomyocyte apoptosis through a p38 MAPK‐mediated mechanism

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