ABSTRACT
AIMS: Epidemiological findings demonstrated that increased plasma cholesterol levels are frequently observed in depressive patients. In this regard, there is enhancing evidence that hypercholesterolemia is associated with impairment of brain function. Recently, we demonstrated that low-density lipoprotein receptor knockout (LDLr(-/-)) mice- a widely used rodent model of familial hypercholesterolemia - exhibited memory deficits and cortico-cerebral mitochondrial dysfunction. In this study, we aimed to assess the hypercholesterolemic mice in predictive tasks for depressive-like behavior. METHODS: Adult wild type C57BL/6 and LDLr (-/-) mice were evaluated in two tests for depressive like behavior, the splash test and forced swimming test. In addition, the activity of monoamine oxidase isoforms and the mRNA levels of hemeoxygenase-1 were assessed in the hippocampus and cerebral cortex of C57BL/6 and LDLr (-/-) mice. Finally, the blood-brain-barrier (BBB) permeability was investigated using the AQP-4 immunofluorescence staining in the mice hippocampus. RESULTS: The LDLr (-/-) mice showed a significant reduction in the grooming time in the splash test and increased immobility time in the forced swimming test, and both parameters were reversed by fluoxetine antidepressant treatment (10mg/kg, 7 days, o.g.). Interestingly, the depressive like behavior of LDLr (-/-) mice was associated with increased activity of monoamine oxidase A, decreased hemeoxygenase-1 mRNA levels and increase of BBB permeability in the hippocampus. CONCLUSIONS: Overall, these data provide new evidence that hypercholesterolemia could trigger brain alterations involved in depressive disorders.
ABSTRACT
Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1mg/kg, p.o.) and in the FST (10mg/kg, p.o.), similar to fluoxetine (10mg/kg, p.o.), imipramine (1mg/kg, p.o.) and bupropion (10mg/kg, p.o.). The effect of ursolic acid (0.1mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1mg/kg, s.c., a dopamine D(1) receptor agonist), apomorphine (0.5µg/kg, i.p., a preferential dopamine D(2) receptor agonist) or bupropion (1mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D(1) and D(2) receptors.
