| A new generation fatty acid amide hydrolase inhibitor protects against kainate-induced excitotoxicity. | |
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MedLine Citation:
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PMID: 21069475 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endocannabinoids, including anandamide (AEA), have been implicated in neuroprotective on-demand responses. Related to such a response to injury, an excitotoxic kainic acid (KA) injection (i.p.) was found to increase AEA levels in the brain. To modulate the endocannabinoid response during events of excitotoxicity in vitro and in vivo, we utilized a new generation compound (AM5206) that selectively inhibits the AEA deactivating enzyme fatty acid amide hydrolase (FAAH). KA caused calpain-mediated spectrin breakdown, declines in synaptic markers, and disruption of neuronal integrity in cultured hippocampal slices. FAAH inhibition with AM5206 protected against the neurodegenerative cascade assessed in the slice model 24 h postinsult. In vivo, KA administration induced seizures and the same neurodegenerative events exhibited in vitro. When AM5206 was injected immediately after KA in rats, the seizure scores were markedly reduced as were levels of cytoskeletal damage and synaptic protein decline. The pre- and postsynaptic proteins were protected by the FAAH inhibitor to levels comparable to those found in healthy control brains. These data support the idea that endocannabinoids are released and converge on pro-survival pathways that prevent excitotoxic progression. |
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Authors:
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Vinogran Naidoo; Spyros P Nikas; David A Karanian; Jeannie Hwang; Jianhong Zhao; JodiAnne T Wood; Shakiru O Alapafuja; Subramanian K Vadivel; David Butler; Alexandros Makriyannis; Ben A Bahr |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-11 |
Journal Detail:
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Title: Journal of molecular neuroscience : MN Volume: 43 ISSN: 1559-1166 ISO Abbreviation: J. Mol. Neurosci. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-21 Completed Date: 2011-07-21 Revised Date: 2011-09-22 |
Medline Journal Info:
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Nlm Unique ID: 9002991 Medline TA: J Mol Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 493-502 Citation Subset: IM |
Affiliation:
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Biotechnology Research and Training Center, University of North Carolina Pembroke, 115 Livermore Drive, Pembroke, NC 28372-1510, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amidohydrolases
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antagonists & inhibitors* Animals Arachidonic Acids / metabolism Endocannabinoids / pharmacology* Hippocampus / drug effects*, metabolism Kainic Acid / toxicity* Phenyl Ethers / pharmacology* Polyunsaturated Alkamides / metabolism Rats Rats, Sprague-Dawley Seizures / chemically induced Tissue Culture Techniques |
| Grant Support | |
ID/Acronym/Agency:
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DA07215/DA/NIDA NIH HHS; R25 GM077634/GM/NIGMS NIH HHS; R44 DA023737/DA/NIDA NIH HHS; R44 DA023737-03/DA/NIDA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/AM 5206; 0/Arachidonic Acids; 0/Endocannabinoids; 0/Phenyl Ethers; 0/Polyunsaturated Alkamides; 487-79-6/Kainic Acid; 94421-68-8/anandamide; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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