A dual role for nitric oxide in NMDA-mediated toxicity in vivo.
A dual role for nitric oxide in NMDA-mediated toxicity in vivo.
复制标题
一氧化氮在 NMDA 介导的体内毒性中的双重作用。
DOI：
10.1038/jcbfm.1995.115
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Ginsberg,MD
中科院分区：
文献类型：
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作者：
Globus,MY;Prado,R;Sanchez-Ramos,J;Zhao,W;Dietrich,WD;Busto,R;Ginsberg,MD
一氧化氮在体外与N-甲基-D-天冬氨酸(NMDA)介导的损伤有关，但其在体内兴奋性毒性损伤中的作用尚不清楚。在本研究中，我们评估了纹状体内注射不同剂量的NMDA对组织病理学和血流动力学的影响，并确定了一氧化氮合酶抑制对这些变化的影响。纹状体内注射N-ω-硝基-L-精氨酸甲酯或不加N-硝基-L-精氨酸甲酯，剂量分别为50、150和300nmoL(L，100μg，本地)。注射3天后，通过对病变区域从病变前缘到后缘的多个切片进行形态计量学分析，进行组织病理学评估。用~(14)C-安替比林放射自显影测定注射150和300nmol N-甲基-D-天冬氨酸(±L)后30分钟局部脑血流量。所有接受NMDA处理的动物都显示出一个界限清晰的病变延伸到注射部位之外。损伤体积与注射NMDA剂量显著相关。L-NAME对病灶大小的影响呈剂量依赖性。L-NAME对50nmolNMDA性损伤无影响。当剂量为150nmolNMDA时，L-NAME使损伤体积增加43%。相反，在300nmolNMDA联合L-NAME治疗的动物中，观察到损伤面积减少了38%。当剂量为150nmol时，NMDA引起LCBF显著升高，且仅限于注射部位附近的区域，包括纹状体前部和中部的中心区。N-甲基-D-天冬氨酸+L-NAME组大鼠在150nmoL N-甲基-D-天冬氨酸作用下的下丘脑血流量增加明显减轻。300nmolNMDA引起的LCBF变化与150nmolNMDA组无明显差异，但受累区域较大。LCBF增加见于所有纹状体区域，包括中央和周围区域。L-NAME对N-甲基-D-天冬氨酸诱导的下丘脑血流量变化无明显影响。这些数据表明，在体内，一氧化氮对NMDA毒性的参与取决于NMDA的剂量和NMDA暴露后继发的血流动力学机制的参与。
Nitric oxide has been implicated inN-methyl-d-aspartate (NMDA)-mediated damage in vitro; however, its role in excitotoxic damage in vivo is not clear. In the present study we evaluated the histopathological and hemodynamic consequences of intrastriatal injections of various doses of NMDA and determined the effects of nitric oxide synthase inhibition on these changes. NMDA was injected into the striatum at doses of 50, 150, and 300 nmol with or withoutNω-nitro-l-arginine methyl ester (L-NAME; 100 μg, locally). Three days following injections histopathological assessment was performed by morphometric analysis of the lesion area in multiple sections taken from the anterior to the posterior borders of the lesion. In animals injected with 150 and 300 nmol of NMDA (±L-NAME), local CBF (lCBF) was determined 30 min following injections using14C-iodoantipyrine autoradiography. All NMDA-treated animals showed a well-demarcated lesion extending beyond the injection site. The volume of the lesion correlated significantly with the NMDA dose injected. The effects of L-NAME on lesion size were dependent on the dose of the NMDA. The lesion induced by 50 nmol of NMDA was not affected by L-NAME. With a dose of 150 nmol of NMDA, L-NAME induced a 43%increasein lesion volume. In contrast, a 38%decreasein lesion size was observed in animals treated with 300 nmol of NMDA combined with L-NAME. At a dose of 150 nmol, NMDA induced a significant elevation in lCBF, which was restricted to regions close to the injection site including the center areas of the anterior and middle striatum. The increase in lCBF observed with 150 nmol of NMDA was significantly attenuated in the NMDA + L-NAME-treated group. The lCBF changes induced by 300 nmol of NMDA were not significantly different from those in the 150-nmol group; however, the extent of the regions involved was larger. The increases in lCBF were observed in all striatal regions including the central and peripheral areas. L-NAME did not have a significant effect on the lCBF changes induced by NMDA at a dose of 300 nmol. These data suggest that in vivo the involvement of nitric oxide in NMDA toxicity depends on the NMDA dose and on the participation of hemodynamic mechanisms secondary to NMDA exposure.