Preventive strategies in schizophrenia: a preclinical study

精神分裂症（SZ）是一种慢性神经精神疾病，影响全球约1%的人口。由于10-30%的治疗失败率，正在不断寻求替代治疗方法，包括预防全面SZ症状发生的可能性。由于功能失调的抗氧化防御系统和/或神经炎症被认为是SZ神经进展的潜在机制，因此抗氧化剂和抗炎药物的早期干预已成为预防SZ发展的候选药物，但尚未对此进行研究。本研究使用经充分验证的聚I：C大鼠SZ模型来i）测试抗氧化和抗炎化合物N-乙酰半胱氨酸、ω-3脂肪酸或米诺环素将防止SZ表型的行为和神经生物学缺陷的出现的假设; ii）确定这种异常的出现是否在炎症和/或氧化异常之前; iii）研究这些干预的预防能力是否与预防炎症和/或氧化异常相关。该研究将根据所提供的早期干预的发展阶段，即青春期或怀孕期，包括两个项目。它还将包括在三个层面上对这些早期干预措施的预防效果进行全面评估：行为层面、神经生物学层面（包括大脑代谢活动和生化评估）和氧化应激/炎症层面。将在从青春期早期到成年的不同发育窗口调查水平。这将使我们能够建立氧化/炎症异常的发展轨迹，并确定这些异常是否i）先于并因此可以作为行为异常的生物标志物，或ii）响应于疾病过程而发展。在这两种情况下，主要的问题将是这些进程是否可以通过早期干预加以制止。我们的研究将具有很强的转化前景，为未来在SZ中使用预防性抗氧化和抗炎治疗策略的临床试验的发展以及可能预测结果的相关生物标志物提供概念验证结果。

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.