Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model

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• 作者：Jane C Naviaux (5)
  Lin Wang (1) (2)
  Kefeng Li (1) (2)
  A Taylor Bright (1) (2)
  William A Alaynick (1) (2)
  Kenneth R Williams (1) (2) (8)
  Susan B Powell (5) (6)
  Robert K Naviaux (1) (2) (3) (4) (7)
  
  5. Department of Psychiatry ; University of California ; San Diego School of Medicine ; 214 Dickinson St. ; Bldg CTF ; Rm C102 ; San Diego ; CA ; 92103-8467 ; USA
  1. The Mitochondrial and Metabolic Disease Center ; University of California ; San Diego School of Medicine ; 214 Dickinson St. ; Bldg CTF ; Rm C102 ; San Diego ; CA ; 92103-8467 ; USA
  2. Department of Medicine ; University of California ; San Diego School of Medicine ; 214 Dickinson St. ; Bldg CTF ; Rm C102 ; San Diego ; CA ; 92103-8467 ; USA
  8. General Atomics ; Inc ; San Diego ; CA ; USA
  6. Research Service ; VA San Diego Healthcare System ; La Jolla ; CA ; USA
  3. Department of Pediatrics ; University of California ; San Diego School of Medicine ; 214 Dickinson St. ; Bldg CTF ; Rm C102 ; San Diego ; CA ; 92103-8467 ; USA
  4. Department of Pathology ; University of California ; San Diego School of Medicine ; 214 Dickinson St. ; Bldg CTF ; Rm C102 ; San Diego ; CA ; 92103-8467 ; USA
  7. Veterans Affairs Center for Excellence in Stress and Mental Health (CESAMH) ; La Jolla ; CA ; USA
  
• 关键词：Autism spectrum disorders ; Purinergic signaling ; Antipurinergic therapy (APT) ; Mitochondria ; Metabolism ; Metabolomics ; Fragile X syndrome ; Genetics ; Environment ; Maternal immune activation (MIA) ; Cell danger response (CDR)
• 刊名：Molecular Autism
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：6
• 期：1
• 全文大小：99 KB
• 参考文献：1. Developmental Disabilities Monitoring Network Surveillance Year Principal I, Centers for Disease C, Prevention: Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. / MMWR Surveill Summ 2014, 63:1-1.
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  7. Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S, Hansen RL, / et al.: Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. / Pediatrics. 2012, 129:e1121-128. 10.1542/peds.2011-2583
  8. Naviaux RK, Zolkipli-Cunningham Z, Nakayama T, Naviaux JC, Le T, Wang L, / et al.: Antipurinergic therapy corrects the autism-like features in the Poly(IC) mouse model. / PloS One. 2013, 8:e57380. 10.1371/journal.pone.0057380
  9. Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB, / et al.: Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. / Transl Psychiatry. 2014, 4:e400. 10.1038/tp.2014.33
  10. Chen E, Sharma MR, Shi X, Agrawal RK, Joseph S: Fragile x mental retardation protein regulates translation by binding directly to the ribosome. / Mol Cell. 2014, 54:407-17. 10.1016/j.molcel.2014.03.023
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  13. Bakker CE, Verheij C, Willemsen R, van der Helm R, Oerlemans F, Vermey M, / et al.: Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. / Cell. 1994, 78:23-3.
  14. Micheli V, Camici M, Tozzi MG, Ipata PL, Sestini S, Bertelli M, / et al.: Neurological disorders of purine and pyrimidine metabolism. / Curr Top Med Chem. 2011, 11:923-47. 10.2174/156802611795347645
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• 刊物主题：Neurology; Neurosciences; Neuropsychology; Molecular Medicine; Psychiatry; Pediatrics;
• 出版者：BioMed Central
• ISSN：2040-2392

文摘

Background This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model. Methods We used behavioral analysis, mass spectrometry, metabolomics, electron microscopy, and western analysis to test the hypothesis that the disturbances in social behavior, novelty preference, metabolism, and synapse structure are treatable with antipurinergic therapy (APT). Results Weekly treatment with the purinergic antagonist suramin (20 mg/kg intraperitoneally), started at 9 weeks of age, restored normal social behavior, and improved metabolism, and brain synaptosomal structure. Abnormalities in synaptosomal glutamate, endocannabinoid, purinergic, and IP3 receptor expression, complement C1q, TDP43, and amyloid β precursor protein (APP) were corrected. Comprehensive metabolomic analysis identified 20 biochemical pathways associated with symptom improvements. Seventeen pathways were shared with human ASD, and 11 were shared with the maternal immune activation (MIA) model of ASD. These metabolic pathways were previously identified as functionally related mediators of the evolutionarily conserved cell danger response (CDR). Conclusions The data show that antipurinergic therapy improves the multisystem, ASD-like features of both the environmental MIA, and the genetic Fragile X models. These abnormalities appeared to be traceable to mitochondria and regulated by purinergic signaling.