PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS ALPHA AGONISTS ANTIDEPRESSANT-LIKE EFFECT: BEHAVIORAL CHARACTERIZATION IN RATS

Depression is a chronic and recurrent severe mood disorder that affectsa high percentage of the worldwide population. Unfortunately at least 40% of patients do not respond to the treatment. Therefore, considerable effort is invested in the development of alternative therapeutic approaches for the pharmacotherapy of depression. Peroxisome proliferator-activated receptorsalpha (PPAR-α) are widely expressed in the brain andare activated by endogenous ligands likethe fatty acid amides N-palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are involved in the regulation of different physiological function such as inflammation and neuroprotection.Only few studies have been published onPPAR-α mediated behavioral effects, whichsuggests that PEA exerts anxiolytic and antidepressant-like effect in mice(Crupi et al., 2013, Yu et al., 2011).Thus, the aim of our study was to characterize the pharmacological profile of endogenous and synthetic PPAR-α agonists as PEA, OEA and clofibrate by motor activity test to evaluate possible motor impairments, the forced swim test (FSI) for the antidepressant activity,the elevated plus maze (EPM)and the social interaction test (SI)for anxiolytic like effects. The compounds,tested at different doses and regimen(sub-chronically and chronically) significantly decreased immobility time and increased swimming in the FST test as compared to vehicle treated animals. Theseantidepressant-likeeffectswere reverted the acute administration of the specific PPAR-α antagonist MK886 and of the CB1 antagonist/inverse agonist rimonabant, demonstrating an involvementof thePPAR-α receptor but also an entourage effect of the endocannabinoid system.Moreover,none of thePPAR-αagonists injected subchronically, produced anxiolytic or anxiogenic-like behaviors in the EMP test, while an anxiogenicprofile was observed after acute treatment in the SI test, with a reduction of the total time spent in social interactions but an unaltered numbers of contacts.In conclusion, thesedata show that both endogenous and synthetic PPAR-α ligandsproduce antidepressant-like effects in an experimental animal model, an effect that is specifically mediated via PPAR-α activation but that also involve the endocannabinoid system. PPAR-α agonists, and in particular clofibrate that is still prescribed for the treatment of primary hypercholesterolemia, mixed dyslipidemia, and hypertriglyceridemia, deserve further characterization as a new candidate for the pharmacotherapy of depression. Crupi R. et al. (2013) CNS Neurol Disord Drug Targets;12(7):989-1001. Yu HL. et al (2011) Pharmacol Rep.;63(3):834-9