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.

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In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)-2. The acetylated COX-2 remains active, and upon cell activation, initiates the generation of 15R-HETE, a lipid substrate for 5-lipoxygenase (LOX) leading to the formation of 15-epi-LXA4 (also termed "aspirin-triggered lipoxin," or ATL). Because ATL potently inhibits polymorphonuclear cell (PMN) function, we assessed the relative contribution of this lipid mediator in conjunction with another 5-LOX product, the leukotriene (LT)B4, to the pathogenesis of acute damage and gastric adaptation to aspirin. Data presented herein indicate that acute injury and gastric adaptation to aspirin is associated with ATL generation. Administration of COX inhibitors (celecoxib, indomethacin, ketoprofen) to aspirin-treated rats exacerbated acute injury and abolished adaptation to aspirin. Moreover, it inhibited ATL formation and caused a four- to fivefold increase in LTB4 synthesis. In contrast, licofelone, a COX/5-LOX inhibitor, did not exacerbate acute gastric injury nor did it interfere with gastric adaptation to aspirin. Although licofelone blocked ATL and LTB4 formation in aspirin-treated rats, it attenuated aspirin-induced gastric PMN margination. These findings indicate that the balance between the production of LTB4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.

Products of cyclooxygenase (COX)-2 contribute to mucosal defense. Acetylation of COX-2 by aspirin has been shown to result in the generation of 15(R)-epi-lipoxin A4, which exerts protective effects in the stomach. In gastritis, it is possible that lipoxin A4 makes a greater contribution to mucosal defense. We tested this hypothesis in the rat, by using the iodoacetamide-induced gastritis model. Iodoacetamide was added to the drinking water for 5 days. Rats were then given aspirin, and the extent of gastric damage was blindly assessed 3 h later. Gastric 15(R)-epi-lipoxin A4 and PGE2 levels were determined. The effects of pretreatment with a selective COX-2 inhibitor, rofecoxib, and of a lipoxin receptor antagonist were assessed. Effects of aspirin and the other test drugs on leukocyte adherence within mesenteric venules were assessed by intravital microscopy. Aspirin elicited greater lipoxin synthesis in the inflamed than in the normal stomach, and there was reduced gastric damage. Rofecoxib inhibited lipoxin synthesis and exacerbated aspirin-induced damage. The lipoxin antagonist also exacerbated aspirin-induced damage. In rats with gastritis, aspirin reduced leukocyte adherence (in contrast to an increase in normal rats), and this effect was reversed by rofecoxib or by the lipoxin antagonist. These results support the notion that aspirin-triggered lipoxin synthesis via COX-2 makes an important contribution to mucosal defense in both the normal and inflamed stomach.

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RESUMOA resolução da infl amação é um processo endógeno ativo, e as lipoxinas são importantes mediadores desse processo. Os derivados do ácido araquidônico são biossintetizados principalmente nas mucosas e vasos sanguíneos e atuam principalmente em um receptor acoplado à proteína G (FPR2/ALX) expresso em uma variedade de tipos celulares. As lipoxinas exibem um grande repertório de ações pró-resolução, como a redução da infi ltração de neutrófi los no local infl amado, diminuição da produção de superóxido e citocinas por granulócitos, ativação da fagocitose de microorganismos e de células apoptóticas por macrófagos, além de possuírem ações antinociceptivas diretas. Palavras-chave: Lipoxinas. Resolução. Infl amação. FPR2/ALX. Lipoxigenase. ABSTRACTThe resolution of infl ammation is an active endogenous process, in which lipoxins are important mediators. Lipoxins are mainly biosynthesized in the mucosa and blood vessels, and they and they activate a G-protein coupled receptor (FPR2/ALX) which is widely expressed in several cell types. Lipoxins have several pro-resolution actions, such as the reduction of the infi ltration of neutrophil in the infl ammatory site, the decrease in the production of superoxide and cytokines by granulocytes, the activation of phagocytosis of microorganisms and apoptotic cells by macrophages. In addition, lipoxins display direct antinociceptive effects. Keywords: Lipoxins. Resolution. Infl amation. FPR2/ALX. Lipoxygenase. IntroduçãoA resolução da infl amação, antes considerada um processo passivo, é hoje defi nida como um processo endógeno ativo que protege o hospedeiro de uma resposta infl amatória exa cerbada (BANNENBERG et al., 2005;SERHAN et al., 2007). A infl amação é um dos principais componentes de muitas doenças da civilização moderna, como artrite, doenças cardiovasculares, câncer, obesidade, doença de Alzheimer e sepse, sendo que a infl amação crônica pode ser entendida, pelo menos em parte, como decorrente de um processo de resolução inadequado (HELGADOTTIR et al., 2004;KARP et al., 2004).A resolução da infl amação é considerada um processo distinto de um processo anti-infl amatório.

Annona sylvatica (Annonaceae) is a common medicinal plant used in folk medicine for fever and cough; it is found in several Brazilian states, including Mato Grosso do Sul. The local population uses A. sylvatica leaves for treating fever and cough; however, how this medicinal plant affects the patients is little understood. We evaluated the anti-inflammatory and anti-allergic properties of a methanolic extract of A. sylvatica (MEAS) leaves in mouse models of inflammation and allergy. The study employed male C57bL/6 mice for allergy models and male Swiss mice for the inflammation study. Oral treatments with MEAS (30 to 150 mg/kg) significantly inhibited the carrageenan-induced leukocyte migration and protein extravasation to the cavity in an air pouch model. In the allergic animal models, oral treatment with MEAS (150 mg/kg) significantly reduced histamine-and ovalbumin (OVA)-©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 19 (3): gmr18661 M. Andrade-Silva et al. 2 induced paw edema. Moreover, in the OVA-induced allergic lung inflammation model, oral treatment with MEAS (150 mg/kg) significantly inhibited neutrophil, eosinophil, and mononuclear cells migration to the lung. Pretreatment of neutrophils with MEAS (3, 150, 300 µg/mL) significantly reduced neutrophil chemotaxis induced by N-Formyl-Met-Leu-Ph (fMLP) and complement 5a (C5a, in a concentration-dependent manner. We conclude that A. sylvatica has antiinflammatory and anti-allergic properties. Flavonoids and acetogenins, compounds found in the MEAS, could be responsible for these antiinflammatory and anti-allergic effects.