NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia
NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia
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DOI：
10.1016/j.brainres.2012.06.021
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发表时间：
2012-08-21
期刊：
影响因子：
2.9
通讯作者：
Lyeth, Bruce G.
中科院分区：
文献类型：
--
作者：
Feng, Jun-feng;Gurkoff, Gene G.;Lyeth, Bruce G.
创伤性脑损伤（TBI）导致细胞外环境中谷氨酸快速和过度升高，导致神经元变性和星形胶质细胞损伤。创伤后缺氧是一种临床相关的继发性损伤，其增加了TBI后谷氨酸释放的幅度和持续时间。N-乙酰基谷氨酸酯（NAAG）是CNS中普遍存在的神经肽，其通过作用于mGluR 3（II组代谢型谷氨酸受体）来抑制突触前谷氨酸释放。然而，细胞外NAAG被催化酶谷氨酸羧肽酶U（GCPII）快速转化为NAA和谷氨酸，从而减少突触前抑制。我们先前报道了GCPII抑制剂ZJ-43及其前药二酯PGI-02776在损伤后的前30分钟内全身注射时减少过量细胞外谷氨酸的有害作用。我们现在报道，PGI-02776（10 mg/kg）在TB模型中损伤后30分钟给药时具有神经保护作用！低氧30 min（FiO（2）=11%）。脑外伤后24 h缺氧时，同侧海马CA 1、CA 2/3、CA 3c、门区和齿状回神经元死亡率显著增加。此外，同侧CA 1、CA 2/3和CA 3c/门/齿状回中的星形胶质细胞数量显著减少。缺氧停止后立即给予PGI-02776显著减少了海马所有区域的神经元和星形胶质细胞死亡。这些发现表明，NAAG肽酶抑制剂给予损伤后，可以显着减少TBI结合继发hypmdc损伤的有害影响。(C)2012爱思唯尔有限公司版权所有。
Traumatic brain injury (TBI) leads to a rapid and excessive glutamate elevation in the extracellular milieu, resulting in neuronal degeneration and astrocyte damage. Posttraumatic hypoxia is a clinically relevant secondary insult that increases the magnitude and duration of glutamate release following TBI. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, suppresses presynaptic glutamate release by its action at the mGluR3 (a group II metabotropic glutamate receptor). However, extracellular NAAG is rapidly converted into NAA and glutamate by the catalytic enzyme glutamate carboxypeptidase U (GCPII) reducing presynaptic inhibition. We previously reported that the GCPII inhibitor ZJ-43 and its prodrug di-ester PGI-02776 reduce the deleterious effects of excessive extracellular glutamate when injected systemically within the first 30 min following injury. We now report that PGI-02776 (10 mg/kg) is neuroprotective when administered 30 min post-injury in a model of TB! plus 30 min of hypoada (FiO(2)=11%). 24 h following TBI with hypoxia, significant increases in neuronal cell death in the CA1, CA2/3, CA3c, hilus and dentate gyrus were observed in the ipsilateral hippocampus. Additionally, there was a significant reduction in the number of astrocytes in the ipsilateral CA1, CA2/3 and in the CA3c/hilus/dentate gyrus. Administration of PGI-02776 immediately following the cessation of hypoxia significantly reduced neuronal and astrocytic cell death across all regions of the hippocampus. These findings indicate that NAAG peptidase inhibitors administered post-injury can significantly reduce the deleterious effects of TBI combined with a secondary hypmdc insult. (C) 2012 Elsevier B.V. All rights reserved.