Motheaten (me/me) mice deficient in SHP-1 are less susceptible to focal cerebral ischemia.
We have demonstrated previously that the protein tyrosine phosphatase SHP-1 seems to play a role in glial development and is upregulated in non-dividing astrocytes after injury. The present study examines the effect of loss of SHP-1 on the CNS response to permanent focal ischemia. SHP-1 deficient (me/me) mice and wild-type littermates received a permanent middle cerebral artery occlusion (MCAO). At 1, 3, and 7 days after MCAO, infarct volume, neuronal survival and cell death, gliosis, and inflammatory cytokine levels were quantified. SHP-1 deficient me/me mice display smaller infarct volumes at 7 days post-MCAO, increased neuronal survival within the ischemic penumbra, and decreased numbers of cleaved caspase 3+ cells within the ischemic core compared with wild-type mice. In addition, me/me mice exhibit increases in GFAP+ reactive astrocytes, F4-80+ microglia, and a concomitant increase in the level of interleukin 12 (IL-12) over baseline compared with wild-type. Taken together, these results demonstrate that loss of SHP-1 results in greater healing of the infarct due to less apoptosis and more neuronal survival in the ischemic core and suggests that pharmacologic inactivation of SHP-1 may have potential therapeutic value in limiting CNS degeneration after ischemic stroke.
Beamer
Celine A
CA
Center for Environmental Health Sciences, School of Pharmacy and Allied Health Sciences, University of Montana, Missoula 59812-1552, USA.
Brooks
Diane M
DM
Lurie
Diana I
DI
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002470:Cell Survival / Q000235:genetics; D002540:Cerebral Cortex / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005911:Gliosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018664:Interleukin-12 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D018664:Interleukin-12; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse