The Antioxidant N-Acetyl-L-Cysteine Restores the Behavioral Deficits in a Neurodevelopmental Model of Schizophrenia Through a Mechanism That Involves Nitric Oxide

Autor(es)

Lopes-Rocha, Ana ; Bezerra, Thiago Ohno ; Zanotto, Roberta ; Lages Nascimento, Inda ; Rodrigues, Angela ; Salum, Cristiane

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHARMACOLOGY; v. 13, p. 15-pg., 2022-07-12.

Resumo

The disruption of neurodevelopment is a hypothesis for the emergence of schizophrenia. Some evidence supports the hypothesis that a redox imbalance could account for the developmental impairments associated with schizophrenia. Additionally, there is a deficit in glutathione (GSH), a main antioxidant, in this disorder. The injection of metilazoximetanol acetate (MAM) on the 17th day of gestation in Wistar rats recapitulates the neurodevelopmental and oxidative stress hypothesis of schizophrenia. The offspring of rats exposed to MAM treatment present in early adulthood behavioral and neurochemical deficits consistent with those seen in schizophrenia. The present study investigated if the acute and chronic (250 mg/kg) treatment during adulthood with N-acetyl-L-cysteine (NAC), a GSH precursor, can revert the behavioral deficits [hyperlocomotion, prepulse inhibition (PPI), and social interaction (SI)] in MAM rats and if the NAC-chronic-effects could be canceled by L-arginine (250 mg/kg, i.p, for 5 days), nitric oxide precursor. Analyses of markers involved in the inflammatory response, such as astrocytes (glial fibrillary acid protein, GFAP) and microglia (binding adapter molecule 1, Iba1), and parvalbumin (PV) positive GABAergic, were conducted in the prefrontal cortex [PFC, medial orbital cortex (MO) and prelimbic cortex (PrL)] and dorsal and ventral hippocampus [CA1, CA2, CA3, and dentate gyrus (DG)] in rats under chronic treatment with NAC. MAM rats showed decreased time of SI and increased locomotion, and both acute and chronic NAC treatments were able to recover these behavioral deficits. L-arginine blocked NAC behavioral effects. MAM rats presented increases in GFAP density at PFC and Iba1 at PFC and CA1. NAC increased the density of Iba1 cells at PFC and of PV cells at MO and CA1 of the ventral hippocampus. The results indicate that NAC recovered the behavioral deficits observed in MAM rats through a mechanism involving nitric oxide. Our data suggest an ongoing inflammatory process in MAM rats and support a potential antipsychotic effect of NAC. (AU)

• Processo FAPESP: 11/09548-3 - Avaliação dos efeitos de inibidores da sintase de óxido nítrico em modelos animais para o estudo da esquizofrenia baseados nas hipóteses farmacológicas e do neurodesenvolvimento
• Beneficiário: Cristiane Otero Reis Salum
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/22142-5 - Investigação da expressão dos marcadores GFAP, iba-1 e parvalbumina no córtex pré-frontal de ratos do modelo MAM
• Beneficiário: Ana Caroline Lopes Rocha
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 18/22079-1 - Investigação de marcadores da neuroinflamação em ratos MAM tratados com N-Acetil-L-Cisteína
• Beneficiário: Thiago Takechi Ohno Bezerra
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica