Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor
Autor: | Fabricio A, Pamplona, Juliano, Ferreira, Octávio, Menezes de Lima, Filipe Silveira, Duarte, Allisson Freire, Bento, Stefânia, Forner, Jardel G, Villarinho, Luigi, Bellocchio, Luigi, Bellochio, Carsten T, Wotjak, Raissa, Lerner, Krisztina, Monory, Beat, Lutz, Claudio, Canetti, Isabelle, Matias, João Batista, Calixto, Giovanni, Marsicano, Marilia Z P, Guimarães, Reinaldo N, Takahashi |
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Rok vydání: | 2012 |
Předmět: |
Cannabinoid receptor
Allosteric regulation Anti-Inflammatory Agents Spatial Behavior Endogeny Amyloidogenic Proteins Mice Transgenic Biology Pharmacology Receptors G-Protein-Coupled 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Receptor Cannabinoid CB1 In vivo Memory Commentaries Animals Receptor 030304 developmental biology Inflammation Mice Knockout 0303 health sciences Multidisciplinary musculoskeletal neural and ocular physiology Brain Anandamide URB597 Biological Sciences Endocannabinoid system 3. Good health Lipoxins Mice Inbred C57BL Kinetics Neuroprotective Agents chemistry nervous system lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery psychological phenomena and processes Allosteric Site Endocannabinoids |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 109(51) |
ISSN: | 1091-6490 |
Popis: | 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. |
Databáze: | OpenAIRE |
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