Brain Oxidative Stress and Neurodegeneration in the Ketamine Model of Schizophrenia during Antipsychotic Treatment: Effects of N-Acetylcysteine Treatment

Abstract

We aimed to investigate the effect of N-acetylcysteine (NAC) on brain oxidative stress and on the response to therapy with clozapine or haloperidol in the ketamine model of schizophrenia. Mice received intraperitoneal (i.p.) injections of either saline, ketamine (30 mg/kg), NAC (50 mg/kg), ketamine + NAC, ketamine + clozapine (1.5 mg/kg), ketamine + clozapine + NAC, ketamine + haloperidol (1.5 mg/kg), or ketamine + haloperidol + NAC daily for one week. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, and paraoxonase-1 (PON-1) activity were determined in cerebral cortex and in the rest of the brain tissue. Results indicated that: (i) treatment with only NAC had no significant effects on MDA, GSH, or PON-1 activity, but resulted in a marked decrease in nitric oxide content in both the cortex and the rest of the brain compared to the saline control group; (ii) ketamine caused a significant increase in MDA, while decreasing nitric oxide, and GSH concentrations as well as PON-1activity in both the cerebral cortex and the rest of the brain. These biochemical alterations were alleviated by NAC; (iii) in ketamine-treated mice, either clozapine or haloperidol had no significant effect on MDA or GSH levels. Nitric oxide, however, showed a significant increase by either agent. Meanwhile, PON-1 activity showed a significant increase by clozapine in the cortex but was decreased by haloperidol in both the cortex and the rest of the brain compared with the ketamine only group; (iv) NAC resulted in a significant decrease in MDA in the cortex in ketamine + haloperidol-treated mice, and markedly alleviated the decline in GSH and PON-1 activity in both the cortex and the rest of the brain tissue in ketamine + clozapine-or ketamine + haloperidol-treated groups. NAC showed variable effects on brain nitric oxide in these groups; and (v) ketamine caused neurodegeneration in the cortex and striatum changes in the form of shrunken neurons, pyknotic and apoptotic nuclei, perineuronal vacuolations, and red neurons. These pathological changes were marked after treatment with either clozapine or haloperidol but ameliorated by NAC treatment. These data indicate increased brain oxidative stress in the schizophrenia model induced by ketamine in mice and that treatment with antipsychotics impairs brain antioxidants. The study suggests a potential therapeutic benefit for NAC in alleviating brain oxidative stress, lipid peroxidation, and neurodegeneration during antipsychotic drug therapy in schizophrenia.

Sex influences in the preventive effects of N-acetylcysteine in a two-hit animal model of schizophrenia

“…As previously mentioned, oxidative disturbances are important mechanisms underlying schizophrenia. These mechanisms involve the production of reactive oxygen and nitrogen species resulting in lipid peroxidation (Abdel-Salam et al, 2018). In a previous study, we identified oxidative imbalance in the PFC and striatum of rats neonatally challenged with poly I:C that were influenced by sex (Monte et al, 2017).…”

Effects of sodium benzoate, a commonly used food preservative, on learning, memory, and oxidative stress in brain of mice

“…Level of GSH play an important role against SB‐induced oxidative stress. Moreover, the brain GSH depletion and oxidative stress have a potential role in cognitive impairment in psychiatric illnesses …”

“…Oxidative stress and free radical generation have been implicated in the pathogenesis of several brain disorders such as AD, Parkinson's disease, multiple sclerosis, schizophrenia, and autism . It has also been suggested that depletion of GSH, the main CNS antioxidant, as a result of increased oxidative stress, play important role in the decline of cognitive functions and disruption of short‐term spatial memory …”

Sodium benzoate induces neurobehavioral deficits and brain oxido‐inflammatory stress in male Wistar rats: Ameliorative role of ascorbic acid

“…[ 19,20 ] The role of reduced glutathione (GSH) in mopping reactive oxygen species (ROS) in the brain is a key mechanism of neuroprotection against cognitive decline. [ 21 ] Thus, targeting oxidative stress with strong antioxidants could be a promising approach to offer protection against oxidative stress and neurobehavioural impairments.…”