Armstead William M, Kiessling J Willis, Riley John, Cines Douglas B, Higazi Abd Al-Roof
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA.
Neurol Res. 2011 Sep;33(7):726-33. doi: 10.1179/016164110X12807570509853.
N-methyl-D-aspartate (NMDA)-induced pial artery dilation (PAD) is reversed to vasoconstriction after fluid percussion brain injury (FPI). Tissue type plasminogen activator (tPA) is up-regulated and the tPA antagonist, EEIIMD, prevents impaired NMDA PAD after FPI. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is also up-regulated after traumatic brain injury (TBI). We hypothesize that tPA impairs NMDA-induced cerebrovasodilation after FPI in a MAPK isoform-dependent mechanism.
Lateral FPI was induced in newborn pigs. The closed cranial window technique was used to measure pial artery diameter and to collect cerebrospinal fluid (CSF). ERK, p38, and JNK MAPK concentrations in CSF were quantified by ELISA.
CSF JNK MAPK was increased by FPI, increased further by tPA, but blocked by JNK antagonists SP600125 and D-JNKI1. FPI modestly increased p38 and ERK isoforms of MAPK. NMDA-induced PAD was reversed to vasoconstriction after FPI, whereas dilator responses to papaverine were unchanged. tPA, in post-FPI CSF concentration, potentiated NMDA-induced vasoconstriction while papaverine dilation was unchanged. SP 600125 and D-JNKI1, blocked NMDA-induced vasoconstriction and fully restored PAD. The ERK antagonist U 0126 partially restored NMDA-induced PAD, while the p38 inhibitor SB203580 aggravated NMDA-induced vasoconstriction observed in the presence of tPA after FPI.
These data indicate that tPA contributes to impairment of NMDA-mediated cerebrovasodilation after FPI through JNK, while p38 may be protective. These data suggest that inhibition of the endogenous plasminogen activator system and JNK may improve cerebral hemodynamic outcome post-TBI.
N-甲基-D-天冬氨酸（NMDA）诱导的软脑膜动脉扩张（PAD）在流体冲击脑损伤（FPI）后转变为血管收缩。组织型纤溶酶原激活剂（tPA）上调，且tPA拮抗剂EEIIMD可预防FPI后NMDA诱导的PAD受损。丝裂原活化蛋白激酶（MAPK）是一个至少由三种激酶（ERK、p38和JNK）组成的家族，在创伤性脑损伤（TBI）后也会上调。我们假设tPA通过MAPK亚型依赖性机制损害FPI后NMDA诱导的脑血管舒张。
在新生猪中诱导侧方FPI。采用封闭颅窗技术测量软脑膜动脉直径并收集脑脊液（CSF）。通过酶联免疫吸附测定法（ELISA）对CSF中ERK、p38和JNK MAPK的浓度进行定量。
FPI使CSF中JNK MAPK增加，tPA使其进一步增加，但JNK拮抗剂SP600125和D-JNKI1可阻断这种增加。FPI使MAPK的p38和ERK亚型适度增加。FPI后，NMDA诱导的PAD转变为血管收缩，而对罂粟碱的舒张反应未改变。FPI后CSF中的tPA浓度增强了NMDA诱导的血管收缩，而罂粟碱舒张未改变。SP 600125和D-JNKI1阻断了NMDA诱导的血管收缩并完全恢复了PAD。ERK拮抗剂U 0126部分恢复了NMDA诱导的PAD，而p38抑制剂SB203580加重了FPI后在tPA存在时观察到的NMDA诱导的血管收缩。
这些数据表明，tPA通过JNK导致FPI后NMDA介导的脑血管舒张受损，而p38可能具有保护作用。这些数据表明，抑制内源性纤溶酶原激活系统和JNK可能改善TBI后的脑血流动力学结果。
