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  Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors

von Engelhardt, J., Coserea, I., Pawlak, V., Fuchs, E., Fuchs, E. C., Köhr, G., et al. (2007). Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors. Neuropharmacology, 53(1), 10-17. doi:10.1016/j.neuropharm.2007.04.015.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-AE51-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-AE52-2
Genre: Journal Article
Alternative Title : Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors

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Neuropharmacol_53_2007_10.pdf (Any fulltext), 412KB
 
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 Creators:
von Engelhardt, Jakob1, Author              
Coserea, Irinel, Author
Pawlak, Verena1, Author              
Fuchs, Elke1, Author              
Fuchs, Elke C.1, Author              
Köhr, Georg1, Author              
Seeburg, Peter H.1, Author              
Monyer, Hannah1, Author              
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              

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Free keywords: NR2A subtype; NR2B subtype; Ifenprodil; CP-101,606; NVP-AAM077; Gene-targeted mice
 Abstract: Excitotoxicity, exacerbating acute brain damage from brain trauma or stroke, is mediated in part by excessive Ca(2+)-influx from prolonged NMDA receptor activation. However, the contribution to excitotoxicity by each of the main NMDAR subtypes in glutamatergic forebrain neurons, the NR2A- and NR2B-types, has remained enigmatic. Here, we investigated this issue by use of pharmacological and genetic tools in cultured cortical neurons. In wild-type neurons the contribution of the NMDA receptor subtypes to excitotoxicity changed with the age of the cultures. The blockade of NR2B-containing NMDA receptors prevented NMDA-mediated toxicity in young cultures after 14days in vitro (DIV14), but both subtypes triggered excitotoxicity in older (DIV21) cultures. Notably, blocking either of the two subtypes failed to prevent NMDA-elicited cell death, indicating that the remaining subtype triggers cell demise. Intriguingly, a neuroprotective aspect of the NR2A subtype became apparent at submaximal NMDA concentration only at DIV21. The NR2A subtype mediated NMDA toxicity as well as partial protection only if it carried a functional C-terminal domain. Upon deletion of this domain in the NR2A subtype, excitotoxicity was mediated entirely via the NR2B subtype, both at DIV14 and DIV21. Our findings predict that successful therapeutic intervention in stroke based on currently available NMDA receptor subtype-selective blockers is unlikely.

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Language(s): eng - English
 Dates: 2007-03-242006-12-012007-04-042007-05-082007-07-01
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
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Title: Neuropharmacology
  Other : Neuropharmacol.
Source Genre: Journal
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Publ. Info: Amsterdam [etc.] : Pergamon
Pages: - Volume / Issue: 53 (1) Sequence Number: - Start / End Page: 10 - 17 Identifier: ISSN: 0028-3908
CoNE: https://pure.mpg.de/cone/journals/resource/954925428257