title: Neuroprotection by NMDA preconditioning against glutamate cytotoxicity is mediated through activation of ERK 1/2, inactivation of JNK, and by prevention of glutamate-induced CREB inactivation.
abstract: N-methyl-D-aspartate (NMDA) preconditioning is a major endogenous brain protective mechanism, activated by sub-lethal stimulation of the NMDA glutamate receptors. Selective drug activation of this mechanism is considered to be a promising neuroprotective treatment against stroke and other traumatic brain insults. We have established an experimental in vitro model of NMDA preconditioning in primary rat neuronal cultures composed of three consecutive periods: preconditioning (NMDA 50 9M for 18 h), insult (glutamic acid 200 9M for 1 h), and reperfusion (regular medium for 24 h). The insulted neuronal cultures exhibited a 2.8-fold increase in LDH release into the media during the post-insult reperfusion period, which was completely abolished in the preconditioned cultures. The alterations in the activity level of the pro-survival kinase extracellular signal-regulated kinase (ERK) 1/2, the death machine activator c-Jun N-terminal kinase (JNK), and the pro-survival transcription factor cAMP responsive element binding (CREB) were monitored in preconditioned neuronal cultures in comparison to non-preconditioned cells during the three periods of the experimental model. The preconditioned neurons exhibited increased activity levels of ERK 1/2 and decreased activity levels of JNK during all periods of the model. In addition, the non-preconditioned neurons exhibited a marked reduction in the activity level of CREB during the insult period, which was totally prevented in the preconditioned cultures. These results suggest that the neuroprotection conferred by NMDA preconditioning against glutamate cytotoxicity is mediated (at least in part) through activation of ERK 1/2, inactivation of JNK and by prevention of glutamate-induced CREB inactivation.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Navon
authors.forename: Yael
authors.initials: Y
authors.lastname: Bromberg
authors.forename: Oded
authors.initials: O
authors.lastname: Sperling
authors.forename: Esther
authors.initials: E
authors.lastname: Shani
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D019194:Ischemic Preconditioning / Q000379:methods; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D061251:Primary Cell Culture; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018698:Glutamic Acid; D016202:N-Methylaspartate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3