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Maternal immune activation impacts on the kynurenine pathway in preadolescent offspring: Preventive effects of anti-inflammatory treatment.

Maternal immune activation impacts on the kynurenine pathway in preadolescent offspring: Preventive effects of anti-inflammatory treatment.

To determine a) whether polyIC-induced maternal immune activation leads to changes in the levels of KP metabolites in preadolescent offspring (postnatal days (PNDs) 31-33); b) whether treatment with a COX-2 inhibitor (celecoxib) at PNDs 35-47 prevents the development of behavioural abnormalities characteristic in adult offspring of polyIC treated mothers. Methods: Pregnant rats were treated with polyIC at gestational day 19. KP metabolites were quantified in serum of offspring at PNDs 31-33 using HPLC and GC/MS. mRNA expression of COX-2, cytokines (IL6, TNF-a) and KP enzymes (KATII, KMO) were measured in the hippocampus using qPCR. Offspring were given celecoxib (2.5 and 5 mg/kg/day) from PNDs 35-47. Hyperlocomotor response to MK801 (0.3mg/kg) was tested in adulthood (PNDs>90).

Offspring of polyIC treated mothers had decreased kynurenine (KYN) (29%, p=0.009), KYNA (27%, p=0.055) and increased quinolinic acid (p=0.055) in serum at PNDs 31-33. In the hippocampus, KATII mRNA was reduced by 16% (p=0.037) and KMO mRNA was reduced by 54% (p=0.02). COX2, IL6 and TNF-a mRNAs were not significantly altered. Correlations were observed between KYN levels in serum and KATII (r=0.681, p=0.003) and KMO (r=-0.484, p=0.049) expression in the brain. Treatment with 2.5-5 mg/kg/day celecoxib prevented the increase in MK-801induced hyperlocomotion found in adults with prenatal polyIC exposure.

Prenatal polyIC has significant effects on the KP metabolomics in both brain and periphery in preadolescent offspring. COX-2 inhibition appears to prevent the adult schizophrenia-like behavioural changes associated with prenatal polyIC.

Conference: ASC 2013, MAPrc
Areas of Interest / Categories: ASC 2013, MAPrc 2015

MAPrc 2015

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