Preventive strategies in schizophrenia: a preclinical study

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Schizophrenia (SZ) is a chronic neuropsychiatric disorder that affects approximately 1% of the population worldwide. With a 10-30% treatment failure rate alternative therapeutic approaches are continuously being sought including the possibility of preventing the occurrence of full-blown SZ symptoms. Since dysfunctional antioxidant defense system and/or neuroinflammation have been suggested as potential mechanisms underlying the neuroprogression in SZ, early interventions with antioxidants and anti-inflammatory drugs have emerged as candidates for preventing the development of SZ but this has not been investigated. The present study uses the well validated poly I:C rat model of SZ to i) test the hypothesis that the anti-oxidant and anti-inflammatory compounds N-acetylcysteine, Omega-3 fatty acids or Minocycline will prevent the emergence of behavioral and neurobiological deficits phenotypic of SZ; ii) determine whether the emergence of such abnormalities is preceded by inflammatory and/ oxidative abnormalities; iii) investigate whether the preventive capacity of these interventions is associated with the prevention of inflammatory and/or oxidative abnormalities. The study will include two projects according to the developmental stage of the delivered early intervention, i.e. adolescence or pregnancy. It will further include a comprehensive evaluation of the preventive efficacy of these early interventions at three levels: a behavioral level, a neurobiological level (comprising brain metabolic activity and biochemical assessments) and an oxidative stress/inflammatory level. Levels will be investigated at different developmental windows from early adolescence to adulthood. This will allow us to establish the developmental trajectory of oxidative/ inflammatory abnormalities and ascertain whether such abnormalities i) precede and thus can serve as biomarkers of behavioral abnormalities, or ii) develop in response to the disease process. In both cases, the major question will be whether these processes may be halted by early interventions. Our study will have a strong translational perspective, providing proof-of-concept results for the future development of clinical trials using preventive anti-oxidant and anti-inflammatory treatment strategies in SZ and relevant biomarkers that may predict outcome.