Clofibrate, a synthetic fibric acid derivative, is clinically used for the treatment of primary hypercholesterolemia, mixed dyslipidemia and hypertriglyceridemia, and acts as agonist of the alpha subtype of peroxisome proliferator-activated receptor (PPAR alpha). PPARα are nuclear receptors that are strongly expressed in many tissues including specific areas of the brain, possess anti-inflammatory and neuroprotective effects, and regulate lipid metabolism (Pistis M. and Melis M., 2010). Recent data from literature (Crupi R. et al., 2013) and our laboratories have reported that the endogenous ligands, like N-palmitoylethanolamide (PEA), exhibits an antidepressant-like profile in rodent behavioural models of depression. Thus, the present study was designed to investigate the antidepressant and anxiolytic potential of clofibrate using the Forced Swim test (FST) and the Social Interaction test (SI) in rats. We found that the sub-chronic treatment with clofibrate (25 mg/Kg), administered 24, 4 and 1 hour before starting the test, significantly decreased immobility time and increased swimming time in the FST with respect to vehicle-treated control group, without influencing the baseline locomotion in the motility test. Social behavior was evaluated by means of the SI test that could provide a measure of anxiety, with time spent in social interactions being usually elevated by anxiolytic drugs. Animals acutely treated with 12,5 and 25 mg/kg (i.p.) of clofibrate significantly decrease the total time spent in social interactions but do not modify the total numbers of contacts with respect to vehicle-treated controls, thus revealing an anxiogenic-like response. Taken together, our results demonstrate an anxiogenic-like effect of clofibrate after acute administration in the SI, in agreement with the notion that several antidepressants show an anxiogenic profile after a single injection, and an antidepressant profile in subchronic regime of treatment in the FST. If clofibrate and fibrate medications will prove to possess an antidepressant-like effect also in chronic treatment, they might constitute an attractive and safe strategy for the management of depressive disorders since they are already in clinical use. Pistis M. and Melis M., Curr Med Chem. 2010 17:1450-67. Crupi R. et al., CNS Neurol Disord Drug Targets. 2013 12:989-1001.
Antidepressant-like effect of clofibrate: a synthetic PPAR-a agonist
COLLU, ROBERTO;MAMELI, ALESSANDRA;FRATTA, WALTER;FADDA, PAOLA
2014-01-01
Abstract
Clofibrate, a synthetic fibric acid derivative, is clinically used for the treatment of primary hypercholesterolemia, mixed dyslipidemia and hypertriglyceridemia, and acts as agonist of the alpha subtype of peroxisome proliferator-activated receptor (PPAR alpha). PPARα are nuclear receptors that are strongly expressed in many tissues including specific areas of the brain, possess anti-inflammatory and neuroprotective effects, and regulate lipid metabolism (Pistis M. and Melis M., 2010). Recent data from literature (Crupi R. et al., 2013) and our laboratories have reported that the endogenous ligands, like N-palmitoylethanolamide (PEA), exhibits an antidepressant-like profile in rodent behavioural models of depression. Thus, the present study was designed to investigate the antidepressant and anxiolytic potential of clofibrate using the Forced Swim test (FST) and the Social Interaction test (SI) in rats. We found that the sub-chronic treatment with clofibrate (25 mg/Kg), administered 24, 4 and 1 hour before starting the test, significantly decreased immobility time and increased swimming time in the FST with respect to vehicle-treated control group, without influencing the baseline locomotion in the motility test. Social behavior was evaluated by means of the SI test that could provide a measure of anxiety, with time spent in social interactions being usually elevated by anxiolytic drugs. Animals acutely treated with 12,5 and 25 mg/kg (i.p.) of clofibrate significantly decrease the total time spent in social interactions but do not modify the total numbers of contacts with respect to vehicle-treated controls, thus revealing an anxiogenic-like response. Taken together, our results demonstrate an anxiogenic-like effect of clofibrate after acute administration in the SI, in agreement with the notion that several antidepressants show an anxiogenic profile after a single injection, and an antidepressant profile in subchronic regime of treatment in the FST. If clofibrate and fibrate medications will prove to possess an antidepressant-like effect also in chronic treatment, they might constitute an attractive and safe strategy for the management of depressive disorders since they are already in clinical use. Pistis M. and Melis M., Curr Med Chem. 2010 17:1450-67. Crupi R. et al., CNS Neurol Disord Drug Targets. 2013 12:989-1001.
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