Anti-inflammatory lipoxin A(4) is an endogenous allosteric enhancer of CB1 cannabinoid receptor

作者：Pamplona Fabricio A^*; Ferreira Juliano; de Lima Octavio Menezes Jr; Duarte Filipe Silveira; Bento Allisson Freire; Forner Stefania; Villarinho Jardel G; Bellocchio Luigi; Wotjak Carsten T; Lerner Raissa; Monory Krisztina; Lutz Beat; Canetti Claudio; Matias Isabelle; Calixto Joao Batista; Marsicano Giovanni; Guimaraes Marilia Z P; Takahashi Reinaldo N

来源：Proceedings of the National Academy of Sciences, 2012, 109(51): 21134-21139.

DOI：10.1073/pnas.1202906109

• allosteric modulation
• psychopharmacology
• GPCR
• inflammation
• neuroprotection

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 CB1 cannabinoid receptor. Lipoxin A(4) was detected in brain tissues, did not compete for the orthosteric binding site of the CB1 receptor (vs. H-3-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 CB1 receptor-dependent protective effect against beta-amyloid (1-40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.

• 出版日期2012-12-18