Behavioral and neurochemical effects of alpha lipoic acid associated with omega-3 in tardive dyskinesia induced by chronic haloperidol in rats

Abstract

Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.

Haloperidol‐Induced Preclinical Tardive Dyskinesia Model in Rats

“…8). The groups treated with haloperidol and the combination of lipoic acid and omega-3 fatty acids had increased locomotor activity and reduced incidence of catalepsy, MCV, and tongue protrusion (de Araújo et al, 2017).…”

“…Rodents serve as reliable preclinical models of TD induced by antipsychotic drugs such as haloperidol. In Wistar (in our laboratory) and Sprague-Dawley rats, TD presents through orofacial dyskinesia characterized by repetitive involuntary movements, including tongue protrusion, pouting lips, chewing in the absence of any object, and facial grimacing, symptoms that are also observed in humans (Daya, Tan, Sookram, Skoblenick, & Mishra, 2011;de Araújo et al, 2017). Antipsychotic-induced vacuous chewing movements (VCMs) seem to occur in the same low frequency range (1 to 3 Hz) as tardive dyskinetic symptoms in humans, and the same movements appear in rats in the first weeks of antipsychotic treatment (Turrone, Remington, & Nobrega, 2002).…”

“…The open field test is designed to study the action of the dopaminergic, serotonergic, and noradrenergic systems on emotional and exploratory behavior through assessment of horizontal exploration (locomotion), vertical movement (rearing), and self-cleaning (grooming). This test is used to evaluate the effect of haloperidol on these neurotransmission systems and the development of motor changes (Araújo et al, 2017).…”

“…These models are sometimes used for the investigation of drugs with a neuroprotective effects, mainly drugs with antioxidant activity, because there is evidence that oxidative stress plays an important role in the pathophysiology of TD and catalepsy (de Araújo et al, 2017;de Oliveira et al, 2013). The first-generation neuroleptics promote blockage of dopamine D2 receptors, which results in upregulation of these receptors in dopamine-rich areas, such as the basal ganglia.…”

“…The increase in catecholamine levels results in the overproduction of reactive oxygen species (ROS). The presence of haloperidol reduces gene expression of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GHP), thus reducing the complex cellular antioxidant defenses and increasing lipid peroxidation and nitrite/nitrate levels in the prefrontal cortex, hippocampus, and striatum (de Araújo et al, 2017).…”