Age-Dependent Relevance of Endogenous 5-Lipoxygenase Derivatives in Anxiety-Like Behavior in Mice

Luciana M Leo,Olavo B Amaral,Claudio A Canetti,Fabricio A Pamplona,Fernando A Bozza,Suellen Almeida-Corrêa,Ulrike Schmidt

doi:10.1371/journal.pone.0085009

Abstract

When 5-lipoxygenase (5-LO) is inhibited, roughly half of the CNS effect of the prototypic endocannabinoid anandamide (AEA) is lost. Therefore, we decided to investigate whether inhibiting this enzyme would influence physiological functions classically described as being under control of the endocannabinoid system. Although 5-LO inhibition by MK-886 reduced lipoxin A4 levels in the brain, no effect was found in the elevated plus maze (EPM), even at the highest possible doses, via i.p. (10 mg/kg,) or i.c.v. (500 pmol/2 µl) routes. Accordingly, no alterations in anxiety-like behavior in the EPM test were observed in 5-LO KO mice. Interestingly, aged mice, which show reduced circulating lipoxin A4 levels, were sensitive to MK-886, displaying an anxiogenic-like state in response to treatment. Moreover, exogenous lipoxin A4 induced an anxiolytic-like profile in the EPM test. Our findings are in line with other reports showing no difference between FLAP KO or 5-LO KO and their control strains in adult mice, but increased anxiety-like behavior in aged mice. We also show for the first time that lipoxin A4 affects mouse behavior. In conclusion, we propose an age-dependent relevancy of endogenous 5-LO derivatives in the modulation of anxiety-like behavior, in addition to a potential for exogenous lipoxin A4 in producing an anxiolytic-like state.

Highlights

Our laboratory recently described that the 5-lipoxygenase (5LO) derivative lipoxin A4 is a positive allosteric modulator of CB1 cannabinoid receptors [1]
The current set of experiments presents evidence that endogenous 5-LO derivatives’ influence on anxiety-like behavior in mice is age-dependent, exogenous lipoxin A4 induces anxiolytic-like effects
This is important under the light of a recent report showing that lipoxin A4 is an endogenous positive allosteric modulator of CB1 cannabinoid receptors, which enhances the potency of the endocannabinoid AEA [1]

Summary

Introduction

Our laboratory recently described that the 5-lipoxygenase (5LO) derivative lipoxin A4 is a positive allosteric modulator of CB1 cannabinoid receptors [1]. Such mechanism had not been previously described for this or other endogenous lipids, and occurs in addition to the well-described interaction of lipoxin A4 with ALX receptors [2]. We hypothesized that if 5-LO inhibition reduces AEA effects in the brain, mice treated with 5-LO inhibitors would show increased anxiety-like behavior, to what occurs with mice treated with CB1 receptor antagonists [4] and contrary to what occurs after enhancement of AEA levels by URB597 [5]. Exogenous lipoxin A4 induced an anxiolytic-like profile in the elevated plus maze (EPM) test

Methods

Results

Conclusion