Influência do ômega 3 sobre sintomas extrapiramidais, deficiência cognitiva e parâmetros de estresse oxidativo em animais tratados com neurolépticos

Abstract

Haloperidol and fluphenazine are typical neuroleptics widely used in the treatment of mental illness, whose chronic use is associated with adverse effects that affect the motor function and memory, among others. The motor disturbances can be moderate, and include parkinsonism, akathisia, dystonia, but also a more severe syndrome, known as tardive dyskinesia (TD). Studies have shown that essential polyunsaturated fatty acids (EPUFAs) may affect physiological functions involved in movement and memory disorders through of the membrane phospholipid composition of neuronal cells. This study investigated the effects of supplementation of EPUFA (omega-3) on orofacial dyskinesia and memory dysfunction induced by haloperidol and fluphenazine, designated as experiment 1 and 2, respectively. In both experiments, male Wistar rats received in place of drinking water, a suspension with capsules of fish oil (FO), whose composition was determined by gas chromatography (EPA-20%, DHA- 6%, linolenic acid- 0, 4%), or vehicle (C). After 8 weeks of treatment, half the animals of each experimental group received a weekly administration of neuroleptic (12mg/kg/mL-im) (H-haloperidol or F-fluphenazine in experiments 1 and 2, respectively) or vehicle for 4 weeks. The intake of omega-3 ad libitum in the drinking water was maintained during this time. The animals were observed weekly for the quantification of orofacial dyskinesia (OD), (vacuous chewing movements frequency- VCM) in 7th, 14th, 21st and 28th days after the first dose of neuroleptic/vehicle. Immediately after each orofacial observation, the rats treated with neuroleptic (H and FO+H, experiment 1, F and FO+F, experiment 2) were submitted to catalepsy-time quantifications. In the last week of treatment, the rats of both experiments were previously trained for 4 consecutive days and submitted to memory test in water-maze task. On the 8th day after the last dose of neuroleptic/vehicle, the rats were sacrificed by exsanguinations (by cardiac puncture), with blood collection and removal of brain tissue (hippocampus and substantia nigra) for determination of lipid peroxidation. Data of OD (VCMs) and catalepsy time were analyzed by three-way and one way ANOVA with repeated measure, respectively, followed by Duncan s test (VCMs only) and paired T test; Data of water-maze task and assessments of lipid peroxidation (TBARs) were evaluated by two way ANOVA followed by Duncan s test. Statistical significances were considered for P <0.05 values for all assessments. The omega-3 decreased the motor disorders (VCMs and catalepsy time), the loss of memory and parameters of lipid peroxidation induced by neuroleptics, suggesting that these effects are related to the anti-apoptotic properties of EPUFAs. Our results emphasize the importance of including fatty acids n-3 from diet or its supplementation, which may prevent or reduce motor and memory disorders, often related to chronic treatment with typical neuroleptics, which until now has no effective treatment.