title: Over-expression of DSCR1 protects against post-ischemic neuronal injury.
abstract: OBJECTIVE
  The Down syndrome candidate region 1 (DSCR1) gene is located on human chromosome 21 and its protein is over-expressed in brains of Down syndrome individuals. DSCR1 can modulate the activity of calcineurin, a phosphatase abundant in the brain, but its influence on stroke outcome is not clear. We compared stroke outcome in wildtype (WT) and transgenic (DSCR1-TG) mice which over-express isoform 1 of human DSCR1.
  
  
  METHODS
  Transient cerebral ischemia was produced by occlusion of the middle cerebral artery for 0.5 h. After 23.5 h reperfusion, we assessed neurological impairment, brain infarct and edema volume, leukocyte infiltration and markers of inflammation. Intrinsic resistance to apoptosis following glucose deprivation was also assessed in primary cultures of WT and DSCR1-TG neurons.
  
  
  RESULTS
  In contrast to WT, DSCR1-TG mice had an improved neurological deficit score, greater grip strength, attenuated infarct volume and brain swelling, and lacked hippocampal lesions after stroke. Expression of mouse DSCR1-1, but not DSCR1-4, mRNA and protein was increased by ischemia in both WT and DSCR1-TG. Brain calcineurin activity was increased to a similar degree after ischemia in each genotype. DSCR1-TG mice had fewer infiltrating neutrophils and activated microglia compared with WT, in association with an attenuated upregulation of several pro-inflammatory genes. Neurons from DSCR1-TG mice were more resistant than WT neurons to apoptotic cell death following 24 h of glucose deprivation.
  
  
  CONCLUSIONS
  Over-expression of DSCR1 in mice improves outcome following stroke. Mechanisms underlying this protection may involve calcineurin-independent, anti-inflammatory and anti-apoptotic effects mediated by DSCR1 in neurons.
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: Vanessa H
authors.initials: VH
authors.lastname: Brait
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Martin
authors.forename: Alicia
authors.initials: A
authors.lastname: Corlett
authors.forename: Brad R S
authors.initials: BR
authors.lastname: Broughton
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Thundyil
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Pritchard
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004487:Edema / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D005947:Glucose