Molecular Aspects of Neurodegeneration and Neuroprotection

Novel Mechanism for Oxidative Stress in Neurodevelopmental Pathophysiology and Course of Schizophrenia

Author(s): Anvita Kale, Sadhana R. Joshi and Sahebarao P. Mahadik

Pp: 102-120 (19)

Doi: 10.2174/978160805092511101010102

* (Excluding Mailing and Handling)


Role of oxidative stress and oxidative cellular deficits have been considered for a long time in the etiopathogenesis as well as in course and treatment outcome of schizophrenia. A large number of reviews and monograms have been published primarily on altered levels of indices of oxidative stress and oxidative cell injury in mostly chronic medicated patients and few in drug naïve early psychotic patients. However, since schizophrenia is now generally considered to have neurodevelopmental deficits that most likely start in utero it is important to have a specific mechanism that can trigger the oxidative stress at the critical developmental time. This lack of information has limited the success in developing effective treatment strategies in amelioration of oxidative stress-mediated cellular damage and improved neurodevelopment and consequent clinical outcome. Furthermore, chronic use of the major antipsychotics worsens the oxidative cellular damage and contributes to the poor clinical outcome by increased negative symptoms and the cognitive and motor deficits. We have here presented a hypothesis that states as, the altered metabolism of key maternal nutrients such as folic acid and B12 and omega-3 fatty acids synergistically will trigger the oxidative stress which will alter the early foetal neurodevelopment and alter later in life the cognitive deficits and psychosis key behavioural symptomatology of schizophrenia. The altered metabolism of these maternal nutrients will contribute to the altered one carbon metabolism leading to increased homocysteine and reduced expression of antioxidant enzyme genes and neurotrophic factors by altered chromatin methylation (epigenesis) that contribute to increased oxidative stress. This novel mechanism will also explain the role of a large number of genetic (e.g., altered expression of antioxidant enzymes and neurotrophins) and environmental (e.g., maternal use of alcohol and drug abuse, smoking, under- and mal-nutrition, and socioeconomic stressors) risk factors reported for etiopathogenesis and course of schizophrenia since all of these risk factors trigger the oxidative stress and cellular oxidative damage such as reported in schizophrenia with and without treatment with antipsychotics. Finally, the mechanism based on altered micronutrients may provide effective specific nutritional supplementation strategies for prevention of oxidative stress-mediated pathologies associated with onset of schizophrenia as well as its improved clinical outcome by conventional treatments.

Keywords: Oxidative stress; Schizophrenia; oxidative cellular deficits; folic acid; B12; omega-3fatty acid

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