MK-801 does not prevent development of ischemic tolerance in rat brain

Wrang, Maria L.; Diemer, Nils Henrik

doi:10.1097/00001756-200405190-00014

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…3 The noncompetitive NMDA receptor antagonist MK801 attenuates ischemic cell death and blocks the development of ischemic tolerance in gerbils and in cultured cortical neurons 4,5 ; however, evidence from the rat models of ischemia have not supported this. 6 Drugs that modulate NMDA receptor functions have enormous therapeutic potential because of the involvement of these receptors in a wide array of neurological functions. 7 However, the development of effective NMDA receptor-targeting drugs has been hindered by psychomimetic or cardiovascular side effects.…”

mentioning

confidence: 99%

Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance

Chen

et al. 2008

Stroke

214

154

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Background and Purpose-Activation of NMDA subtypes of glutamate receptors is implicated in cell damage induced by ischemia as well as for the establishment of ischemic tolerance after ischemic preconditioning in animal models. We investigated the contributions of NR2A-and NR2B-containing NMDA receptors to ischemic cell death and ischemic tolerance in a rat model of transient global ischemia. Methods-Transient global ischemia was produced in rats by 4-vessel occlusion. Neuronal injury was analyzed by Fluoro-Jade B and Nissl staining. Phosphorylation of CREB was detected by Western blotting and immunohistochemistry. In situ hybridization and reverse transcriptase-polymerase chain reaction were used to evaluate the mRNA level of cpg15 and bdnf. Results-NR2A subtype-specific antagonist NVP-AAM077 enhanced neuronal death after transient global ischemia and abolished the induction of ischemic tolerance. In contrast, NR2B subtype-specific antagonist ifenprodil attenuated ischemic cell death and enhanced preconditioning-induced neuroprotection. Furthermore, selectively blocking NR2A-, but not NR2B-, containing NMDA receptors inhibited ischemia-induced phosphorylation of CREB and the subsequent upregulation of CREB target genes such as cpg15 and bdnf. Conclusions-We found that NR2A-and NR2B-containing NMDA receptor subtypes play differential roles in ischemic neuronal death and ischemic tolerance, suggesting attractive new strategies for the development of drugs for patients with stroke. (Stroke. 2008;39:3042-3048.)

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confidence: 99%

Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance

Chen

et al. 2008

Stroke

214

154

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“…Neurons can also be preconditioned by exposure to numerous environmental or chemical stimuli that generate "cross-tolerance" to ischemia (2). A key role for activation of the NMDA type of glutamate receptor during preconditioning by ischemia or OGD is well established (3)(4)(5)(6)(7)(8)(9)(10), although agreement is not complete (11,12). Moreover, transient non-lethal exposure to high dose glutamate or NMDA is sufficient on its own to also induce potent cross-tolerance to ischemia (13) or to OGD (1,6,14).…”

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confidence: 99%

Elevated Synaptic Activity Preconditions Neurons against an in Vitro Model of Ischemia

Tauskela

Fang

Hewitt

et al. 2008

Journal of Biological Chemistry

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Tolerance to otherwise lethal cerebral ischemia in vivo or to oxygen-glucose deprivation (OGD) in vitro can be induced by prior transient exposure to N-methyl-D-aspartic acid (NMDA): preconditioning in this manner activates extrasynaptic and synaptic NMDA receptors and can require bringing neurons to the "brink of death." We considered if this stressful requirement could be minimized by the stimulation of primarily synaptic NMDA receptors. Subjecting cultured cortical neurons to prolonged elevations in electrical activity induced tolerance to OGD. Specifically, exposing cultures to a K ؉ -channel blocker,

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“…The role of activation of NMDA receptors in the mechanisms of inducing neuronal tolerance to hypoxia, ischemia and glutamatergic over-excitation has been repeatedly suggested [22,31,59,72]. These data seem to be consistent with the in vivo findings that (+)MK-801 inhibits ischemic preconditioning [6,33], although other data do not support these claims [15,71].…”

Section: Introductionmentioning

confidence: 55%

“…Both direct inhibition of NMDA receptors, which are involved in brain injury caused by ischemia [62], and prolonged hypothermia in (+)MK-801-treated animals [11] may be responsible for neuroprotection. In addition, our present results obtained in the gerbil model of global brain ischemia demonstrate that (+)MK-801, which persists for a long time in the brain and induces by itself a delayed tolerance to ischemia, is not a good tool to study the participation of NMDA receptors in the mechanisms of brain ischemic preconditioning (compare [6,15,33,71]). …”

Section: Discussionmentioning

confidence: 80%

Original article Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

Makarewicz¹,

Sulejczak²,

Duszczyk³

et al. 2014

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A b s t r a c t Introduction: In vitro experiments have demonstrated that preconditioning primary neuronal cultures by temporary application of NMDA receptor antagonists induces long-term tolerance against lethal insults.In the present study we tested whether similar effects also occur in brain submitted to ischemia in vivo and whether the potential benefit outweighs the danger of enhancing the constitutive apoptosis in the developing brain. Material and methods: Memantine in pharmacologically relevant doses of 5 mg/kg or (+)MK-801 (3 mg/kg) was administered i.p. 24, 48, 72 and 96 h before 3-min global forebrain ischemia in adult Mongolian gerbils or prior to hypoxia/ ischemia in 7-day-old rats. Neuronal loss in the hippocampal CA1 in gerbils or weight deficit of the ischemic hemispheres in the rat pups was evaluated after 14 days. Also, the number of apoptotic neurons in the immature rat brain was evaluated. Results: In gerbils only the application of (+)MK-801 24 h before ischemia resulted in significant prevention of the loss of pyramidal neurons. In rat pups administration of (+)MK-801 at all studied times before hypoxia-ischemia

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MK-801 does not prevent development of ischemic tolerance in rat brain

Cited by 7 publications

References 22 publications

Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance

Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance

Elevated Synaptic Activity Preconditions Neurons against an in Vitro Model of Ischemia

Original article Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

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