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

Abstract

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.

Chronic N-acetylcysteine treatment improves anhedonia and cognition in a mouse model of the schizophrenia prodrome

“…Alongside beneficial effects on anhedonia (see above), improvements of social interaction found in rodent models of both schizophrenia and depression after chronic or acute NAC treatment (see Table 1 ) further support its efficacy in the negative symptom domain. Our findings of null effects on novelty-induced hyperlocomotion do, however, contrast with NAC-induced reductions of hyperactivity seen in other models of schizophrenia ( Fukami et al, 2004 ; Monte et al, 2020 ; Lopes-Rocha et al, 2022 ). This might relate to the fact that NAC may also increase exploratory drive in models of depression ( Mahmoodzadeh et al, 2021 ); since the CD2-KO mouse shows features associated with depression, e.g., a lack of neurogenesis ( Jaholkowski et al, 2009 ), the anti-depressant and the hyperactivity-reducing effects of NAC may cancel each other out in this model.…”

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

“…Based on the hypothesis that a redox imbalance may explain the developmental alterations associated with schizophrenia, preclinical studies have investigated the injection of methylazoxymethanol acetate (MAM) in an animal model of altered neurodevelopment related to oxidative stress. Although the offspring of rats exposed to MAM treatment presented behavioral and neurochemical oxidative impairments in early adulthood consistent with those observed in schizophrenia, treatment with N-acetylcysteine (NAC) reversed the behavioral deficits through a recovery mechanism involving NO, suggesting a potential antipsychotic effect of NAC [ 112 ]. Combined evidence has shown that stress-induced changes in the glutamatergic system in the PFC appear to be biphasic.…”