Beamer Celine A, Brooks Diane M, Lurie Diana I
Center for Environmental Health Sciences, School of Pharmacy and Allied Health Sciences, University of Montana, Missoula 59812-1552, USA.
J Neurosci Res. 2006 May 15;83(7):1220-30. doi: 10.1002/jnr.20825.
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.
我们之前已经证明，蛋白酪氨酸磷酸酶SHP-1似乎在神经胶质细胞发育中发挥作用，并且在损伤后不分裂的星形胶质细胞中上调。本研究检测了SHP-1缺失对中枢神经系统对永久性局灶性缺血反应的影响。SHP-1缺陷型（me/me）小鼠和野生型同窝小鼠接受永久性大脑中动脉闭塞（MCAO）。在MCAO后1天、3天和7天，对梗死体积、神经元存活和细胞死亡、胶质增生以及炎性细胞因子水平进行定量。与野生型小鼠相比，SHP-1缺陷型me/me小鼠在MCAO后7天显示梗死体积较小，缺血半暗带内神经元存活增加，缺血核心区内裂解的半胱天冬酶3+细胞数量减少。此外，与野生型相比，me/me小鼠GFAP+反应性星形胶质细胞、F4-80+小胶质细胞增加，并且白细胞介素12（IL-12）水平较基线水平伴随性升高。综上所述，这些结果表明，SHP-1缺失导致梗死愈合更好，这是由于缺血核心区内细胞凋亡减少、神经元存活增加，并且提示SHP-1的药理学失活在限制缺血性中风后中枢神经系统变性方面可能具有潜在治疗价值。
