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A New Generation Fatty Acid Amide Hydrolase Inhibitor Protects Against Kainate-Induced Excitotoxicity
- Source :
- Journal of Molecular Neuroscience. 43:493-502
- Publication Year :
- 2010
- Publisher :
- Springer Science and Business Media LLC, 2010.
-
Abstract
- 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.
- Subjects :
- Kainic acid
Polyunsaturated Alkamides
Excitotoxicity
Kainate receptor
Arachidonic Acids
Pharmacology
Biology
medicine.disease_cause
Hippocampus
Neuroprotection
Article
Amidohydrolases
Rats, Sprague-Dawley
Tissue Culture Techniques
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Seizures
Fatty acid amide hydrolase
Postsynaptic potential
Cannabinoid Receptor Modulators
medicine
Animals
Kainic Acid
Phenyl Ethers
General Medicine
Anandamide
Endocannabinoid system
Rats
nervous system
chemistry
lipids (amino acids, peptides, and proteins)
Endocannabinoids
Subjects
Details
- ISSN :
- 15591166 and 08958696
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular Neuroscience
- Accession number :
- edsair.doi.dedup.....4f032aa11fd7650e79f04cf6c6e010ec