Jin Rong, Jiang Xin-Ying, Ma Xing, Gu Shu-Ling, Dai Ti-Jun
Department of Pharmacology, Xuzhou Medical College, Xuzhou 221002, China.
Yao Xue Xue Bao. 2007 Aug;42(8):838-42.
This study is to investigate the effect of gamma-hydroxybutyric acid receptor (GHBR) on focal cerebral ischemia-reperfusion injury in rats and its mechanism. NCS-356 (the agonist of GHBR) and NCS-382 (the antagonist of GHBR) were adopted as the tool medicine. The ripe male Sprague-Dawley rats weighing 240 - 280 g were randomly divided into seven groups: sham operation group (sham), ischemia-reperfusion group (Isc/R), NCS-356 160 microg x kg(-1) group (N1), NCS-356 320 microg x kg(-1) group (N2), NCS-356 640 microg x kg(-1) group (N3), NCS-382 640 microg x kg(-1) + NCS-356 640 microg x kg(-1) group (NCS-382 + N3), and nimodipine (Nim) 600 microg x kg(-1) group. The middle cerebral artery occlusion (MCAO) model referring to Longa's method with modifications was adopted. The effect of GHBR on behavioral consequence of MCAO rats was studied after 2 h of ischemia-reperfusion. After 24 h of ischemia-reperfusion, part of animals were used to measure the cerebral infarction volume by TTC staining; ischemic cortex of another part of animals were used to measure the content of intracellular free calcium by flow cytometry, the tNOS, iNOS activity and the content of NO by spectrophotometric method, the content of cGMP by radioimmunoassay. The neurological function score and infarction volume rate in Isc/R group rats increased significantly than that in sham group; The content of intracellular calcium ([Ca2+]) of cortex neuron and cGMP, the activities of tNOS and iNOS, and the content of NO in Isc/R group were higher than that in sham group obviously (P < 0.01); These consequence we mentioned of N1, N2, N3 and Nim group were lower than that of Isc/R. NCS-382 + N3 group could significantly antagonize the above effect of N3. Thus, NCS-356 has protective effects against ischemia-reperfusion brain injury by activating GHBR. The neuroprotective effect of GHBR is related with decreasing the content of [Ca2+]i, NO, cGMP and tNOS, iNOS activity in MCAO rats.
本研究旨在探讨γ-羟基丁酸受体（GHBR）对大鼠局灶性脑缺血再灌注损伤的影响及其机制。采用NCS-356（GHBR激动剂）和NCS-382（GHBR拮抗剂）作为工具药。将体重240～280g的成年雄性Sprague-Dawley大鼠随机分为7组：假手术组（sham）、缺血再灌注组（Isc/R）、NCS-356 160μg·kg⁻¹组（N1）、NCS-356 320μg·kg⁻¹组（N2）、NCS-356 640μg·kg⁻¹组（N3）、NCS-382 640μg·kg⁻¹+NCS-356 640μg·kg⁻¹组（NCS-382+N3）、尼莫地平（Nim）600μg·kg⁻¹组。采用改良的Longa法制备大脑中动脉闭塞（MCAO）模型。缺血再灌注2h后观察GHBR对MCAO大鼠行为学结果的影响。缺血再灌注24h后，部分动物用TTC染色法测定脑梗死体积；另一部分动物取缺血皮层，用流式细胞术测定细胞内游离钙含量，用分光光度法测定tNOS、iNOS活性及NO含量，用放射免疫法测定cGMP含量。Isc/R组大鼠神经功能评分及梗死体积率较假手术组明显升高；Isc/R组皮层神经元细胞内钙（[Ca²⁺]）、cGMP含量、tNOS及iNOS活性、NO含量均明显高于假手术组（P<0.01）；N1、N2、N3及Nim组上述结果均低于Isc/R组。NCS-382+N3组可明显拮抗N3组的上述作用。因此，NCS-356通过激活GHBR对缺血再灌注脑损伤具有保护作用。GHBR的神经保护作用与降低MCAO大鼠细胞内[Ca²⁺]、NO、cGMP含量及tNOS、iNOS活性有关。
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