tPA-S481A Prevents Neurotoxicity of Endogenous tPA in Traumatic Brain Injury

被引:13
作者
Armstead, William M. [1 ,2 ]
Riley, John [1 ]
Yarovoi, Serge [3 ]
Cines, Douglas B. [3 ]
Smith, Douglas H. [4 ]
Higazi, Abd Al-Roof [3 ,5 ]
机构
[1] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[4] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA
[5] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Dept Clin Biochem, Sch Med, Jerusalem, Israel
基金
美国国家卫生研究院;
关键词
brain injury; cerebral autoregulation; cerebral circulation; signal transduction; tissue plasminogen activator; TISSUE-PLASMINOGEN ACTIVATOR; NMDA CEREBROVASODILATION; CEREBRAL HEMODYNAMICS; AGE; AUTOREGULATION; IMPAIRMENT; POTASSIUM; INCREASES; CHILDREN; NOC/OFQ;
D O I
10.1089/neu.2012.2328
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Traumatic brain injury (TBI) is associated with loss of autoregulation due to impaired responsiveness to cerebrovascular dilator stimuli, which leads to cerebral hypoperfusion and neuronal impairment or death. Upregulation of tissue plasminogen activator (tPA) post-TBI exacerbates loss of cerebral autoregulation and NMDA-receptor-mediated impairment of cerebral hemodynamics, and enhances excitotoxic neuronal death. However, the relationship between NMDA-receptor activation, loss of autoregulation, and neurological dysfunction is unclear. Here, we evaluated the potential therapeutic efficacy of a catalytically inactive tPA variant, tPA S481A, that acts by competing with wild-type tPA for binding, cleavage, and activation of NMDA receptors. Lateral fluid percussion brain injury was produced in anesthetized piglets. Pial artery reactivity was measured via a closed cranial window, and cerebrospinal fluid (CSF) extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) was quantified by enzyme-linked immunosorbent assay (ELISA). tPA-S481A prevented impairment of cerebral autoregulation and reduced histopathologic changes after TBI by inhibiting upregulation of the ERK isoform of MAPK. Treatment with this tPA variant provides a novel approach for limiting neuronal toxicity caused by untoward NMDA-receptor activation mediated by increased tPA and glutamate following TBI.
引用
收藏
页码:1794 / 1802
页数:9
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