Chen Tsung-Ying, Goyagi Toru, Toung Thomas J K, Kirsch Jeffrey R, Hurn Patricia D, Koehler Raymond C, Bhardwaj Anish
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
Stroke. 2004 May;35(5):1180-5. doi: 10.1161/01.STR.0000125011.93188.c6. Epub 2004 Mar 18.
We have previously demonstrated that pretreatment with selective kappa-opioid agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic neuroprotection following transient focal ischemia in rats. The present study was undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux of dopamine and its metabolites in the striatum in vivo following transient focal ischemia.
Using the intraluminal filament technique, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2, 4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in vivo microdialysis, extracellular levels of dopamine and its metabolites were determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion.
Infarct volume (% of contralateral structure; mean +/-SEM) in cortex was significantly attenuated when BRL 52537 was administered at reperfusion (22+/-6%), 2 hours (21+/-6%), and 4 hours (18+/-5%) compared with controls (39+/-5%). In striatum, infarct volume was significantly attenuated when BRL 52537 was administered at reperfusion (38+/-9%), 2 hours (40+/-8%), 4 hours (50+/-8%), and 6 hours (46+/-9%) as compared with controls (70+/-4%). A 6- to 8-fold increase in dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in the striatum during MCAO and early reperfusion, as compared with saline controls.
These data demonstrate that BRL 52537 provides robust ischemic neurprotection with a long therapeutic opportunity (at least 6 hours) without altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum during ischemia and early reperfusion.
我们之前已经证明，用选择性κ-阿片受体激动剂盐酸BRL 52537[（±）-1-（3,4-二氯苯基）乙酰基-2-（1-吡咯烷基）甲基哌啶]进行预处理，可在大鼠短暂性局灶性缺血后提供缺血性神经保护作用。本研究旨在：a）确定BRL 52537进行缺血性神经保护的“治疗时机”；b）确定BRL 52537是否能减轻短暂性局灶性缺血后体内纹状体中缺血诱发的多巴胺及其代谢产物的外流。
采用管腔内丝线技术，对用氟烷麻醉的雄性Wistar大鼠进行2小时的大脑中动脉闭塞（MCAO）。大鼠以盲法、随机方式接受生理盐水（溶剂）或1mg/kg/小时的BRL 52537输注22小时，在再灌注开始时、2小时、4小时或6小时开始给药。在另一组利用体内微透析的实验中，在MCAO 2小时和再灌注3小时期间测定纹状体中多巴胺及其代谢产物的细胞外水平。
与对照组（39±5%）相比，在再灌注时（22±6%）、2小时（21±6%）和4小时（18±5%）给予BRL 52537时，皮质梗死体积（对侧结构的百分比；平均值±标准误）显著减小。在纹状体中，与对照组（70±4%）相比，在再灌注时（38±9%）、2小时（40±8%）、4小时（50±8%）和6小时（46±9%）给予BRL 52537时，梗死体积显著减小。MCAO后40分钟内，微透析液中多巴胺增加了6至8倍。与生理盐水对照组相比，用BRL 52537预处理在MCAO和早期再灌注期间并未改变纹状体中多巴胺或其代谢产物的微透析液水平。
这些数据表明，BRL 52537可提供强大的缺血性神经保护作用，且治疗时机长（至少6小时），同时在缺血和早期再灌注期间不会改变纹状体中缺血诱发的多巴胺（DA）及其代谢产物的外流。
