title: Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy.
abstract: Autism spectrum disorders (ASDs) now affect 1-2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg(-1) intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 μM pmol μl(-1) (±0.50) and 5.15 pmol mg(-1) (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.
authors.affiliation: Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Naviaux
authors.affiliation: Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Schuchbauer
authors.affiliation: 1] The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, CA, USA [2] Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: 1] The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, CA, USA [2] Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA [2] Veterans Affairs Center for Excellence in Stress and Mental Health (CESAMH), La Jolla, CA, USA.
authors.forename: V B
authors.initials: VB
authors.lastname: Risbrough
authors.affiliation: Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Powell
authors.affiliation: 1] The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, CA, USA [2] Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA [3] Veterans Affairs Center for Excellence in Stress and Mental Health (CESAMH), La Jolla, CA, USA [4] Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA [5] Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Naviaux
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D058914:Purinergic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000378:metabolism*; D011897:Random Allocation; D012919:Social Behavior; D013498:Suramin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D058914:Purinergic Antagonists; D011687:Purines; D013498:Suramin