Aripiprazol protege camundongos jovens do comportamento autista-símile e déficits de memória induzidos por tratamento materno com ácido valproico

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviors. Aripiprazole (APZ) is an atypical antipsychotic that decreases the autistic-like behavior induced by valproic acidVPA in mice. In the present study, the effects of maternal APZ treatment (10 mg / kg, i.p.) on young mice exposed in the prenatal period to VPA were examined. For this, female Swiss mice (n = 8) were mated with males (n = 8) in separate cages (1 couple per cage = 8 couples) during the reproductive period (6-8 weeks of age) and distributed to Vehicle (V); V + APZ; VPA and VPA + APZ. Vaginal lavages were collected every morning for cytological analysis, and the presence of sperm was considered the first day of pregnancy “gestational day” (GD). On the 11.5th and 12th gestational days, pregnant females of V group received 0.9% saline (ip) and V + APZ group received 0.9% saline + APZ (10 mg/kg), (ip). The pregnant females of the VPA and VPA + APZ groups received VPA (500 mg/kg, ip) on the 12th day for the induction of the animal model of autism and the VPA + APZ group, two preventive doses of Aripiprazole (10 mg/kg, ip); the first dose on the 11.5th day and the second dose on the 12th day. In this same group, VPA (500 mg/kg, i.p.) was administered on the 12,5th day. The offspring from these parturitions were analyzed in behavioral tests related to neurodevelopment, social interaction, communication, stereotypes, memory and anxiety. In the medial prefrontal cortex (mPFC) and hippocampus, neuronal viability, dopamine levels, expressions of Synaptophysin (Syp), 25kDa Synaptosome Associated Protein (SNAP-25) and Microtubule-Associated Protein 2 were evaluated (MAP-2). In addition, a possible interference of APZ in the anticonvulsant effect of VPA was evaluated, using the pentylenetetrazole-induced seizure model (PTZ). Maternal treatment with APZ significantly prevented body weight loss, delayed postural self-straightening and eye opening. APZ also avoided the deficits in interactions and social communications assessed in the juvenile play test, in the three-chamber apparatus and in the test involving odors (olfactory test in discriminative paradigm and maternal smell test). Regarding stereotypy, APZ significantly prevented animals from repetitive, obsessive and anxiogenic behavior induced by VPA. With regard to memory, APZ prevented mice exposed to VPA, from deficits in working memory (Y-labyrinth test) and aversive memory (passive avoidance test). APZ significantly prevented neuronal death and decreased dopamine levels in mCFP, and prevented reduced cell viability and immunoreactivity for synaptophysin, SNAP-25 and MAP-2 in mCFP and the hippocampus. In addition, APZ (10 mg / kg) did not interfere with the anticonvulsant effect of VPA (15 mg / kg) in animals with PTZ-induced seizures. We conclude that treatment with APZ in pregnant mice exposed to VPA protects the offspring from inducing the behavioral phenotype similar to TEA and this effect may be related, at least in part, to increased dopaminergic function, neuronal protection and synaptic plasticity in CPFm and hippocampus. APZ can serve as an effective therapeutic target in preventing autistic behavior induced by treatment with VPA during pregnancy