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Published on: October 27, 2020
Age-dependent relevance of endogenous 5-lipoxygenase derivatives in anxiety-like behavior in mice
Luciana M Leo1, Suellen Almeida-Corrêa2, Claudio A Canetti3
1D'Or Institute for Research and Education, Rio de Janeiro, Brazil ; Lab. Immunopharmacology, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
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.
Insights
Inhibiting 5-lipoxygenase (5-LO) affects anxiety-like behavior, particularly in aged mice. Exogenous lipoxin A4 shows potential as an anxiolytic treatment.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- The endocannabinoid system, including anandamide (AEA), plays a role in central nervous system (CNS) functions.
- 5-lipoxygenase (5-LO) enzyme activity is linked to AEA's CNS effects, suggesting a connection to the endocannabinoid system.
Purpose of the Study:
- To investigate if inhibiting 5-LO influences physiological functions regulated by the endocannabinoid system.
- To explore the role of 5-LO derivatives, like lipoxin A4, in anxiety-like behaviors.
Main Methods:
- Administered 5-LO inhibitor MK-886 in adult and aged mice via intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) routes.
- Utilized the elevated plus maze (EPM) test to assess anxiety-like behavior.
- Examined 5-LO knockout (KO) mice and the effects of exogenous lipoxin A4 administration.
Main Results:
- MK-886 treatment reduced brain lipoxin A4 levels but did not alter anxiety-like behavior in adult mice.
- 5-LO KO mice did not show altered anxiety-like behavior compared to controls.
- Aged mice, with lower lipoxin A4 levels, exhibited an anxiogenic-like state upon MK-886 treatment.
- Exogenous lipoxin A4 administration induced an anxiolytic-like profile in the EPM test.
Conclusions:
- Endogenous 5-LO derivatives play an age-dependent role in modulating anxiety-like behavior.
- Exogenous lipoxin A4 demonstrates potential as an anxiolytic agent.
- These findings highlight a novel link between 5-LO pathway and anxiety, with implications for age-related behavioral changes.
