Studies on N-acetyl cysteine as a therapeutic intervention in methamphetamine-associated bio-behavioural changes in an immune-inflammatory model
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Purpose: Schizophrenia is a severe illness, affecting 0.5-1% of the world population. The clinical manifestation of schizophrenia is characterized by three distinct categories of symptoms, namely positive, negative and cognitive symptoms. Schizophrenia has been linked to monoamine alterations, oxidative stress and inflammation. The aetiological and biological processes of schizophrenia are largely unknown, while current treatment regimens remain sub-optimal in clinical practice. The two-hit hypothesis of schizophrenia states that multiple prominent biological events (or “hits”) distributed over various life periods can result in the development of schizophrenia. Moreover, studies report on an increased risk to develop schizophrenia in individuals exposed to infectious agents during the prenatal period. On the other hand, early life methamphetamine (MA) abuse is associated with an increased risk of developing enduring psychosis later in life. Taking this into account, we developed a (1) prenatal inflammation model and a (2) dual-hit model (prenatal inflammation + MA abuse) of schizophrenia to explore the behavioural and neurochemical changes induced by these models. We then incorporated the antioxidant, N-acetyl cysteine (NAC) as a novel treatment, hypothesizing that it will reverse these alterations in the models. Methods: Pregnant Sprague-Dawley rats received lipopolysaccharide (LPS) at a dose of 100 μg/kg on gestational day (GD) 15-16 subcutaneously (SC) or saline as control group. After weaning, male pups born from pregnant dams were divided into MA or saline receiving groups. MA was administered at a dose of 0.2 mg/kg escalating daily up to a final dose of 6 mg/kg SC from PND 35 to 50. The prenatal inflammation and the dual-hit groups received treatment with NAC at 150 mg/kg/day or saline SC from PND 51-64. All treatment groups were subjected to a battery of behavioural tests viz. (1) social interaction (SI) on PND 62, (2) novel object recognition (nORT) on PND 63, and (3) %prepulse inhibition (%PPI) on PND 64. One day later the animals were decapitated and trunk blood and brain tissue were collected and stored at -80 °C until the day of biochemical analyses. Analyses included monoamines, pro- and anti-inflammatory cytokines, reactive oxygen species (ROS) and lipid peroxidation. Results: Deficits in %PPI were seen in (1) the LPS alone group at prepulses of 74 dB and 84 dB, (2) the MA alone group at 72 dB and 74 dB and (3) the dual-hit model at 72 db, 74 db and 85 db. NAC tended to reverse PPI deficits in the LPS alone and dual-hit models (especially at 84 dB), but only revealed significant results at 72 dB in the dual-hit model. Social interaction was significantly increased in the LPS-alone and the dual-hit models. NAC successfully reversed these alterations. In the nORT, only the double-hit model caused significant deficits in memory function. NAC tended to reverse these changes, but missed statistical significance. Increased markers of lipid peroxidation were observed in the LPS alone group in the frontal cortex, striatum and hippocampus while NAC reversed these changes in the striatum and hippocampus. Lipid peroxidation was increased in the dual-hit model in the frontal cortex and striatum with NAC reversing these changes in the striatum. The LPS alone and the dual-hit groups revealed significant elevations in plasma ROS levels. NAC successfully reversed this elevation in the prenatal LPS group. Administration of MA alone did not alter markers of oxidative stress. Frontal cortical dopamine (DA) levels were significantly increased in the LPS alone group and were reversed by NAC treatment. Both the LPS alone and the dual-hit groups had significantly decreased levels of serotonin in the frontal cortex while NAC normalized these deficits. Frontal cortical and striatal noradrenaline (NA) levels were significantly reduced in the LPS alone and dual-hit model, as well as after MA alone administration. NAC treatment reversed these changes in both animal models and in both brain regions. LPS alone and the dual-hit model significantly reduced levels of the anti-inflammatory cytokine, interleukin-10 (IL-10). LPS alone also significantly increased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α). NAC treatment reversed the decreased levels of IL-10 in the LPS alone and dual-hit models as well as the elevation in TNF-α levels in the LPS alone model. Conclusion: Here we provide evidence that both a prenatal inflammation and a dual-hit model cause behavioural changes akin to schizophrenia symptomology. Maternal inflammation induced immune-redox changes, while the dual-hit model only caused noticeable changes in redox status. Irregularities of important monoamine levels confirm that both these schizophrenia models may influence neuro-function. We suggest that prenatal inflammation may alter brain development and increase the risk of developing schizophrenia. Coupled with a second hit, cognitive changes become more apparent, suggesting that dual-hit aetiology may be involved in the complete manifestation of schizophrenia. NAC showed beneficial effects on behavioural, neurochemical and redox-inflammatory markers, proposing that anti-oxidant treatment may be of value in schizophrenia treatment, and may have value in treating psychosis associated with prior MA abuse.
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