6533b7d9fe1ef96bd126d75f
RESEARCH PRODUCT
Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.
Pamplona Fabricio AFerreira JulianoMenezes De Lima OctávioDuarte Filipe SilveiraBento Allisson FreireForner StefâniaVillarinho Jardel GBellocchio LuigiBellochio LuigiWotjak Carsten TLerner RaissaMonory KrisztinaLutz BeatCanetti ClaudioMatias IsabelleCalixto João BatistaGiovanni MarsicanoGuimarães Marilia Z PTakahashi Reinaldo Nsubject
Cannabinoid receptorAllosteric regulationAnti-Inflammatory AgentsSpatial BehaviorEndogenyAmyloidogenic ProteinsMice TransgenicBiologyPharmacologyReceptors G-Protein-Coupled03 medical and health scienceschemistry.chemical_compoundMice0302 clinical medicineReceptor Cannabinoid CB1In vivoMemoryCommentariesAnimalsReceptor030304 developmental biologyInflammationMice Knockout0303 health sciencesMultidisciplinarymusculoskeletal neural and ocular physiologyBrainAnandamideURB597Biological SciencesEndocannabinoid system3. Good healthLipoxinsMice Inbred C57BLKineticsNeuroprotective Agentschemistrynervous systemlipids (amino acids peptides and proteins)030217 neurology & neurosurgerypsychological phenomena and processesAllosteric SiteEndocannabinoidsdescription
Allosteric modulation of G-protein–coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A 4 is an endogenous allosteric enhancer of the CB 1 cannabinoid receptor. Lipoxin A 4 was detected in brain tissues, did not compete for the orthosteric binding site of the CB 1 receptor (vs. 3 H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A 4 displayed a CB 1 receptor-dependent protective effect against β-amyloid (1–40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB 1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-11-12 | Proceedings of the National Academy of Sciences of the United States of America |