Omega-3 fatty acids during adolescence prevent schizophrenia-related behavioural deficits: Neurophysiological evidences from the prenatal viral infection with PolyI:C

Abstract

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35-49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2-ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.

Keywords: FDG-PET/resonance; Inflammation/oxidative stress; Mental health prevention; Omega-3 fatty acids; PolyI:C model of schizophrenia.