Protective Effects of mGluR5 Positive Modulators Against Traumatic Neuronal Injury Through PKC-Dependent Activation of MEK/ERK Pathway
Protective Effects of mGluR5 Positive Modulators Against Traumatic Neuronal Injury Through PKC-Dependent Activation of MEK/ERK Pathway
复制标题
mGluR5 正调节剂通过 PKC 依赖性激活 MEK/ERK 通路对创伤性神经元损伤的保护作用
DOI：
10.1007/s11064-011-0691-z
复制
发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Fei, Zhou
中科院分区：
文献类型：
--
作者：
Chen, Tao;Cao, Lei;Fei, Zhou
利用选择性药理学拮抗剂的几个先前的研究已经证明，5型代谢型谷氨酸受体（mGluR 5）是用于治疗中枢神经系统的许多病症的潜在治疗靶标，但是mGluR 5活化在创伤性脑损伤（TBI）中的作用尚未完全理解。在体外TBI模型中，使用mGluR 5激动剂（RS）-2-氯-5-羟基苯甘氨酸（CHPG）和正变构调节剂3-氰基-N-（1，3-二苯基-1H-吡唑-5-基）苯甲酰胺（CDPPB）来研究mGluR 5激活的神经保护效力。结果表明，CHPG和CDPPB均能剂量依赖性地抑制创伤性神经元损伤引起的LDH释放和caspase-3激活，且在损伤后1 h加入这些化合物也能起到保护作用。Western blot检测细胞外信号调节激酶（ERK）、c-Jun N末端激酶（JNK）和p38激酶（p38）的活性。CHPG和CDPPB可增强创伤性神经元损伤后ERK的激活，而选择性MEK/ERK抑制剂PD 98059和U 0126可部分逆转这种保护作用。此外，我们还研究了蛋白激酶C（PKC）在CHPG和CDPPB诱导的神经保护中的作用。PKC抑制剂chelerythrine chloride预处理可阻断CHPG和CDPPB对创伤后LDH释放和caspase-3激活的抑制作用。所有这些发现扩展了mGluR 5激活在TBI体外模型中的保护作用，并表明这些保护作用可能是通过PKC依赖的MEK/ERK通路的激活介导的。这些结果可能对开发mGluR 5调节剂治疗TBI具有重要意义。
Several previous studies utilizing selective pharmacological antagonists have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are potential therapeutic targets for the treatment of numerous disorders of the central nervous system, but the role of mGluR5 activation in traumatic brain injury (TBI) is not fully understood. Here in an in vitro TBI model, the mGluR5 agonist (RS)-2-chloro-5- hydroxyphenylglycine (CHPG) and the positive allosteric modulators 3-cyano-N-(1,3- diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) were used to investigate the neuroprotective potency of mGluR5 activation. Data showed that CHPG and CDPPB suppressed the increase of LDH release and caspase-3 activation induced by traumatic neuronal injury in a dose-dependent manner, and the salutary effects were also present when these compounds were added 1 h after injury. Western blot was used to examine the activation of three members of mitogen-activated protein kinases: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase (p38). CHPG and CDPPB enhanced the activation of ERK after traumatic neuronal injury, and PD98059 and U0126, two selective MEK/ERK inhibitors, partly revised the protective effects. Furthermore, we also investigated the role of protein kinase C (PKC) in CHPG and CDPPB-induced neuroprotection. With the pretreatment of chelerythrine chloride, a PKC inhibitor, the surpressing effects of CHPG and CDPPB on traumatic injury-evoked LDH release and caspase-3 activation were blocked. All of these findings extended the protective role of mGluR5 activation in an in vitro model of TBI and suggested that these protective effects might be mediated by the PKC-dependent activation of MEK/ERK pathway. These results may have important implications for the development of mGluR5 modulators to treat TBI.