title: Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: amelioration by COX-2 inhibition.
abstract: Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31-33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3mg/kg) in adulthood (PND>90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31-33 (105%, p=0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p=0.027, and 31% p=0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p=0.014). Adolescent treatment with celecoxib (2.5 and 5mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.
authors.affiliation: School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia. Electronic address: k.zavitsanou@neura.edu.au.
authors.forename: Katerina
authors.initials: K
authors.lastname: Zavitsanou
authors.affiliation: MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine (ASAM), Macquarie University, NSW 2109 Australia.
authors.forename: Chai K
authors.initials: CK
authors.lastname: Lim
authors.affiliation: Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Tertia
authors.initials: T
authors.lastname: Purves-Tyson
authors.affiliation: Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Karl
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia; Brain and Mind Research Institute, Sydney, NSW 2050, Australia; Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia; Brain and Mind Research Institute, Sydney, NSW 2050, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.affiliation: MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine (ASAM), Macquarie University, NSW 2109 Australia.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia.
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D006948:Hyperkinesis / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000097:blood / Q000378:metabolism*; D008297:Male; D010848:Picolinic Acids / Q000097:blood; D011070:Poly I-C / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011720:Pyrazoles / Q000627:therapeutic use*; D017378:Quinolinic Acid / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia; D012741:Sexual Maturation; D013449:Sulfonamides / Q000627:therapeutic use*; D014364:Tryptophan / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D010848:Picolinic Acids; D011720:Pyrazoles; D013449:Sulfonamides; D007737:Kynurenine; D016291:Dizocilpine Maleate; D014364:Tryptophan; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D000068579:Celecoxib; D011070:Poly I-C; C030614:picolinic acid
keywords: Adolescence; COX-2 inhibition; Celecoxib; Kynurenine pathway; Maternal immune activation; PolyI:C; Prevention; Wistar rat