RESUMO
Schizophrenia is a neurodevelopmental disorder characterized by a loss of dendritic spines in the medial prefrontal cortex (mPFC). Multiple subclinical and clinical studies have evidenced the ability of antipsychotics to improve neuroplasticity. In this study, it was evaluated the effect of the atypical antipsychotic aripiprazole (ARI) on the behavioral and mPFC neuronal disturbances of rats with neonatal ventral hippocampus lesion (nVHL), which is a heuristic developmental model relevant to the study of schizophrenia. ARI attenuated open field hyperlocomotion in the rats with nVHL. Also, ARI ameliorated structural neuroplasticity disturbances of the mPFC layer 3 pyramidal cells, but not in the layer 5 neurons. These effects can be associated with the ARI capability of increasing brain-derived neurotrophic factor (BDNF) levels. Moreover, in the animals with nVHL, ARI attenuated the immunoreactivity for some oxidative stress-related molecules such as the nitric oxide synthase 2 (NOS-2), 3-nitrotyrosine (3-NT), and cyclooxygenase 2 (COX-2), as well as the reactive astrogliosis in the mPFC. These results contribute to current knowledge about the neurotrophic, anti-inflammatory, and antioxidant properties of antipsychotics which may be contributing to their clinical effects and envision promising therapeutic targets for the treatment of schizophrenia.
Assuntos
Antipsicóticos , Animais , Ratos , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Aripiprazol/uso terapêutico , Animais Recém-Nascidos , Hipocampo , Córtex Pré-FrontalRESUMO
Second-generation antipsychotics are the drugs of choice for the treatment of neurodevelopmental-related mental diseases such as schizophrenia. Despite the effectiveness of these drugs to ameliorate some of the symptoms of schizophrenia, specifically the positive ones, the mechanisms beyond their antipsychotic effect are still poorly understood. Second-generation antipsychotics are reported to have anti-inflammatory, antioxidant and neuroplastic properties. Using the neonatal ventral hippocampus lesion (nVHL) in the rat, an accepted schizophrenia-related model, we evaluated the effect of the second-generation antipsychotic olanzapine (OLZ) in the behavioral, neuroplastic, and neuroinflammatory alterations exhibited in the nVHL animals. OLZ corrected the hyperlocomotion and impaired working memory of the nVHL rats but failed to enhance social behavior disturbances of these animals. In the prefrontal cortex (PFC), OLZ restored the pyramidal cell structural plasticity in the nVHL rats, enhancing the dendritic arbor length, the spinogenesis and the proportion of mature spines. Moreover, OLZ attenuated astrogliosis as well as some pro-inflammatory, oxidative stress, and apoptosis-related molecules in the PFC. These findings reinforce the evidence of anti-inflammatory, antioxidant, and neurotrophic mechanisms of second-generation antipsychotics in the nVHL schizophrenia-related model, which allows for the possibility of developing more specific drugs for this disorder and thus avoiding the side effects of current schizophrenia treatments.