title: Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.
abstract: 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.
authors.affiliation: Laboratory of Psychopharmacology, Department of Pharmacology, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Brazil. fabriciopamplona@gmail.com
authors.forename: Fabricio A
authors.initials: FA
authors.lastname: Pamplona
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.forename: Octávio
authors.initials: O
authors.lastname: Menezes de Lima
authors.forename: Filipe Silveira
authors.initials: FS
authors.lastname: Duarte
authors.forename: Allisson Freire
authors.initials: AF
authors.lastname: Bento
authors.forename: Stefânia
authors.initials: S
authors.lastname: Forner
authors.forename: Jardel G
authors.initials: JG
authors.lastname: Villarinho
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellocchio
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellochio
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Wotjak
authors.forename: Raissa
authors.initials: R
authors.lastname: Lerner
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Claudio
authors.initials: C
authors.lastname: Canetti
authors.forename: Isabelle
authors.initials: I
authors.lastname: Matias
authors.forename: João Batista
authors.initials: JB
authors.lastname: Calixto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Marilia Z P
authors.initials: MZ
authors.lastname: Guimarães
authors.forename: Reinaldo N
authors.initials: RN
authors.lastname: Takahashi
mesh_terms: D000495:Allosteric Site; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D007249:Inflammation; D007700:Kinetics; D044045:Lipoxins / Q000378:metabolism*; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013037:Spatial Behavior
chemical_list: D058227:Amyloidogenic Proteins; D000893:Anti-Inflammatory Agents; D063388:Endocannabinoids; D044045:Lipoxins; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D043562:Receptors, G-Protein-Coupled; C040527:lipoxin A4