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Preventive strategies in schizophrenia: a preclinical study

Subject Area Biological Psychiatry
Term from 2017 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 359922117
 
Final Report Year 2022

Final Report Abstract

The neuroprogressive nature of schizophrenia (SZ) implies that there is a potential therapeutic window during which pathophysiological processes may be modified to either halt disease progression or reduce its severity. In this line, there has been growing interest in the possibility of preventing the occurrence of full-blown schizophrenia (SZ) symptoms. Obviously, the pathopysiological foundation of neuroprogression in SZ - and consequently potential targets of preventive intervention strategies - is multifactorial and interactive. Among the various suggested pathways, evidence has mounted that an imbalance in the antioxidant defence system and the presence of oxidative stress (OS) and/or neuroinflammation may contribute to its progression. As a consequence, the likely involvement of OS and inflammation in the pathophysiology of SZ has led investigators to advocate the use of anti-oxidant and anti-inflammatory drugs as therapeutic strategies in this disorder. Based on these findings we designed a project to investigate whether early interventions with anti-inflammatory/anti-oxidant compounds, i.e. N-acetyl cysteine (NAC) and omega-3 can prevent the emergence of behavioral and neurobiological deficits phenotypic of SZ in the maternal immune activation (MIA) model of this disorder. In this neurodevelopmental model, the prenatal exposure to the viral mimic poly I:C leads to the development of a wide spectrum of SZ-like behavioral, neural, immunological and metabolic deficits. Behavioral abnormalities recapitulate the maturational delay of SZ, emerging in adult but not in peri-adolescent offspring, whilst some brain structural, brain network and biochemical changes precede (and thus predict) or emerge in parallel to the delayed manifestation of behavioral abnormalities. Pregnant, female wistar rats were injected with either poly I:C or saline at gestational day 15, followed by daily treatment with either NAC or omega-3 applied until delivery. Rats serving as controls did not receive any preventive treatment. Markers of neuroinflammation and anti-oxidant enzyme activity were assessed troughout development and behavioral testing, neurochemical assessment as well as ex-vivo MRI and FDG-PET was assessed at adulthood. In the offspring of poly I:C controls, an increase in microglial activity was seen across brain structures during adolescence, which was prevented by prenatal exposure to both NAC and omega-3. Further, a partial relief in positive and negative symptoms as well as an improvement in dopaminergic deficits was found following supplementary treatment with both, NAC and omega-3. Interestingly, prenatal exposure to omega-3 but not NAC also enhanced cognitive performance and prevented the enlargement of lateral ventricles. In summary, we here show that supplements with anti-inflammatory agents partially prevent some of the later SZ-related outcomes otherwise seen in the offspring of poly I:C treated dams. Therefore, intake of supplements - already considered to be safe and beneficial during pregnancy - may also be able to target especially neuroinflammatory properties and through this prevent some of the later disease development in an otherwise high-risk population.

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