Selective blockade of the mGluR1 receptor reduces traumatic neuronal injury in vitro and improves outcome after brain trauma
Selective blockade of the mGluR1 receptor reduces traumatic neuronal injury in vitro and improves outcome after brain trauma
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DOI：
10.1006/exnr.2000.7577
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发表时间：
2001-02-01
影响因子：
5.3
通讯作者：
Movsesyan, VA
中科院分区：
文献类型：
--
作者：
Faden, AI;O'Leary, DM;Movsesyan, VA
选择性阻断I组代谢型谷氨酸受体亚型1（mGluR 1）对神经元细胞存活和创伤后恢复的影响进行了研究，使用大鼠在体外和体内创伤模型。选择性mGluR 1拮抗剂（RS）-1-氨基茚满-1，5-二羧酸（AIDA）、7-（羟基亚氨基）环丙烯并[B]色烯-1a-羧酸乙酯（CPCCOEt）和（S）-（+）-α-氨基-4-羧基-2-甲基苯乙酸（LY 367385）在治疗前或治疗后的范例中均对受到机械损伤的大鼠皮质神经元培养物提供了显著的神经保护作用。拮抗剂的管理也衰减谷氨酸诱导的神经元细胞死亡的文化。这些拮抗剂与N-甲基-D-天冬氨酸（NMDA）受体拮抗剂（5 R，10 S）-（+）-5-甲基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺（MK-801）共同应用，在谷氨酸损伤的培养物中具有相加的神经保护作用。侧脑室注射AIDA可明显改善大鼠创伤性脑损伤（TBI）后运动功能障碍的恢复。通过MRI评估，mGluR 1拮抗剂治疗还可显著减少TBI后大鼠的病变体积。似乎这些化合物通过mGluR 1拮抗剂作用介导其神经保护作用，如通过在我们的体外系统中抑制激动剂诱导的磷酸肌醇水解所证明的。此外，AIDA，CPCCOEt，和LY 367385，在浓度被证明是神经保护，稳态NMDA诱发的全细胞电流没有显着的影响。总之，这些数据表明，mGluR 1活性的调制可能具有实质性的治疗脑损伤的潜力。(C)北京：科学出版社.
The effects of selective blockade of group I metabotropic glutamate receptor subtype 1 (mGluR1) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. The selective mGluR1 antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), and (S)-(+)-alpha -amino-4-carboxy-2-methylbezeneacetic acid (LY367385) provided significant neuroprotection in rat cortical neuronal cultures subjected to mechanical injury, in both pretreatment or posttreatment paradigms. Administration of the antagonists also attenuated glutamate-induced neuronal cell death in the cultures. Coapplication of these antagonists with the N-methyl-D-aspartate (NMDA) receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine (MK-801) had additive neuroprotective effects in glutamate injured cultures. Intracerebroventricular administration of AIDA to rats markedly improved recovery from motor dysfunction after lateral fluid percussion induced traumatic brain injury (TBI), Treatment with mGluR1 antagonists also significantly reduced lesion volumes in rats after TBI, as evaluated by MRI. It appears that these compounds mediate their neuroprotective effect through an mGluR1 antagonist action, as demonstrated by inhibition of agonist induced phosphoinositide hydrolysis in our in vitro system. Moreover, AIDA, CPCCOEt, and LY367385, at concentrations shown to be neuroprotective, had no significant effects on the steady state NMDA evoked whole cell current. Taken together, these data suggest that modulation of mGluR1 activity may have substantial therapeutic potential in brain injury. (C) 2001 Academic Press.