Caratterizzazione del clofibrato agonista sintetico dei recettori dei proliferatori dei perossisomi (PPARα)in modelli animali di depressione ed ansia

Depression is a severe mood disorder that affects a 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 receptors alpha (PPARα) are widely expressed in the brain and are activated by endogenous ligands like the fatty acid amides N-palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Recent studies have been published on PPARα mediated behavioral effects, which suggests that PEA exerts anxiolytic and antidepressant-like effect in mice (Crupi et al., 2013, Yu et al., 2011). However no studies have been evaluated antidepressant-like effect of synthetic PPARα agonists. Thus, the aim of our study was to characterize the pharmacological profile of synthetic PPARα agonists as clofibrate by motor activity test to evaluate possible motor impairments, the forced swim test (FST) for the antidepressant activity, the elevated plus maze (EPM) and the social interaction test (SI) for anxiolytic like effects. The standard antidepressant drugs used in FST (fluoxetine 5mg/kg and amitriptyline 15 mg/kg, i.p) induced a significant increase of the duration of swimming respect to the vehicle-treated control group. Also the sub-chronic treatment with clofibrate (25 mg/kg, i.p) significantly increased swimming time and decreased immobility time in the FST with respect to vehicle-treated control group. We also investigated the possible contribution of PPARα and the endocannabinoid system on antidepressant-like effect induced by clofibrate, fluoxetine and amitriptyline. Acute administration of the specific PPARα antagonist MK886 (1 mg/kg, i.p) or the CB1 antagonist/inverse agonist SR141716A (1 mg/kg, i.p) did no antagonize the antidepressant-like effect induced by classical antidepressant drugs. In contrast the antidepressant-like affects of clofibrate were reverted by the acute administration of specific PPARα antagonist MK886 demonstrating an involvement of PPARα, while, the CB1r antagonist/inverse agonist SR141716A, conversely MK886, did no antagonize the antidepressant-like effect of clofibrate, excluding a possible involvement of the endocannabinoid system. Interestingly, the co-administration of sub-effective dose of clofibrate (12.5 mg/kg, i.p) and fluoxetine (2 mg/kg, i.p) revealed an increase of swimming and decrease of immobility suggesting a possible interaction between the PPARα receptors and the serotoninergic system. No effect was observed when clofibrate was combined with amitriptyline. Clofibrate and PEA maintain an antidepressant effect also after 14 days of chronic treatment (25 mg/kg, 1 mg/kg, i.p respectively) in the FST. Moreover, none of the PPARα agonists injected acutely, produced anxiolytic or anxiogenic-like behaviors in the EMP test, while an anxiogenic profile 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. No anxiogenic or anxiolytic effect was observable after chronic treatment with both clofibrate and PEA. In conclusion, these data show that clofibrate, synthetic PPARα ligand, produces antidepressant-like effect in animals, effect that is specifically mediated via PPARα-activation but that also hypothesizes an interaction with the serotoninergic system since it potentiates the fluoxetine behavioral action. PPARα agonists, that are still prescribed for the treatment of primary hypercholesterolemia, mixed dyslipidemia, and hypertriglyceridemia, it deserve further characterization as a new candidate for the pharmacotherapy of depression.