Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.
Proceedings of the National Academy of Sciences. 2012-11-12; 109(51): 21134-21139
DOI: 10.1073/pnas.1202906109
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1. Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21134-9. doi:
10.1073/pnas.1202906109. Epub 2012 Nov 12.
Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1
cannabinoid receptor.
Pamplona FA(1), Ferreira J, Menezes de Lima O Jr, Duarte FS, Bento AF, Forner S,
Villarinho JG, Bellocchio L, Wotjak CT, Lerner R, Monory K, Lutz B, Canetti C,
Matias I, Calixto JB, Marsicano G, Guimarães MZ, Takahashi RN.
Author information:
(1)Laboratory of Psychopharmacology, Department of Pharmacology, Universidade
Federal de Santa Catarina, 88049-900 Florianópolis, Brazil.
Erratum in
Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1561. Bellochio, Luigi [corrected to
Bellocchio, Luigi].
Comment in
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20781-2.
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.
DOI: 10.1073/pnas.1202906109
PMCID: PMC3529012
PMID: 23150578 [Indexed for MEDLINE]