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首页> 外文期刊>The Internet Journal of Neurology >Reversal Of Acute Human Brain Ischemic Injury By Lysine Induced Therapeutic Angiogenesis: Preliminary Results Of A Pilot Study
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Reversal Of Acute Human Brain Ischemic Injury By Lysine Induced Therapeutic Angiogenesis: Preliminary Results Of A Pilot Study

机译：赖氨酸诱导的治疗性血管生成逆转急性人脑缺血性损伤：一项初步研究的初步结果

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Effects of L-lysine monohydrochloride on ischemia reversibility were studied using diffusion and perfusion MRI in 11 patients and 4 controls with large territory ischemic brain injury. Parametric maps of vascular physiological function were synthesized. Region of interest analysis was done from the infracted and corresponding contralateral normal regions. Statistical analysis demonstrated significant changes in terms of lesion volumes, National Institute of Health Stroke Scale (NIHSS) scores, relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), mean transit time (MTT) ratios in patients treated with lysine compared to controls. A significant increase in rCBV ratio in lysine treated patients suggests that increased angiogenesis is probably responsible for tissue reversibility and functional recovery in these patients. Introduction It is established that by 6 months after a stroke about 20-30% of patients have died, 20-30% are moderately to severely disabled, 20-25% have mild to moderate disability, and the remainder are without deficit [1, 2]. Initial clinical deficits can improve dramatically or worsen during the first 48-72 hrs [2,3,4]. Changes in the clinical status might sometimes be related to pathophysiologic events such as early reperfusion, hemorrhagic transformation or edema of the ischemic lesions [3]. Thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) has significantly improved the neurological outcome when administered up to 3 hours after the onset of symptoms [5,6,7,8]. However, the brief therapeutic window of 3 hours significantly limits the number of treatable patients. There are concerns about the relatively high rate of symptomatic intracranial hemorrhage in patients treated with intra-arterial thrombolysis [7]. Unfortunately, there has been a lack of progress in acute stroke drug development since the efficacy of rt-PA was demonstrated on the basis of National Institute of Neurological Disorders and Stroke trials in 1995 [7]. Other drugs intended to facilitate reperfusion, such as intra-arterial thrombolysis with prourokinase and the defibrinogenating agent ancord, given intravenously, have shown promise [7]. Despite numerous studies of neuroprotective compounds showing reduction of infarct volume in animal stroke models and in some cases, promising phase II results, none has been proven efficacious on the basis of a positive phase III trial. On this basis it is clear that novel approaches will need to be considered and employed in the future clinical trials [7].Potential of diffusion and perfusion MRI in selecting patients for thrombolysis beyond 3 hours and evaluating the tissue effect of reperfusion has been realized [9]. Parsons et al suggested that patient selection by perfusion and diffusion MRI and its evaluation of response to treatment may identify the patients in whom intravenous rt-PA therapy will be of clinical benefit when therapy is initiated between 3 and 6 hours [10]. Hyperacute lesion volume of more than 89 ml imaged with diffusion weighting imaging (DWI) may be predictive of early neurological deterioration [9]. A combination of relative peak height and time to peak perfusion measurements may be a better predictor of infarct growth than quantitative haemodynamic parameters [9,11].Angiogenesis is defined as the formation of new blood vessels by sprouting of endothelial cells from pre-existing vessels. During the process of sprouting, endothelial cells degrade the underlying basement membrane, migrate into the neighboring tissue, proliferate and assemble into tubes. Finally, tube-to-tube connections are made and blood flow is established [12]. Among the factors capable of modulating angiogenesis characterized to date, vascular endothelium growth factor (VEGF) is the best candidate for a specific regulator of endothelial growth and differentiation. VEGF is expressed in the normal adult brain, mainly in the epithelial cells of choroids plexus, but a
机译：使用扩散和灌注MRI对11例大面积缺血性脑损伤的对照和4例对照研究了L-赖氨酸盐酸盐对缺血可逆性的影响。合成了血管生理功能的参数图。感兴趣区域的分析是从侵犯的和相应的对侧正常区域进行的。统计分析表明，赖氨酸治疗的患者在病灶量，国立卫生研究院卒中量表（NIHSS）评分，相对脑血容量（rCBV），相对脑血流量（rCBF），平均通过时间（MTT）比率方面有显着变化与控件相比。赖氨酸治疗的患者中rCBV比率的显着增加表明，血管生成增加可能是这些患者的组织可逆性和功能恢复的原因。引言已经确定，到中风后6个月，约20-30％的患者死亡，20-30％的中度至重度残疾，20-25％的轻度至中度残疾，其余无缺陷[1， 2]。最初的临床缺陷可以在最初的48-72小时内显着改善或恶化[2,3,4]。临床状态的改变有时可能与病理生理事件有关，例如早期再灌注，出血性转化或缺血性病变的水肿[3]。使用重组组织纤溶酶原激活剂（rt-PA）进行溶栓治疗可在症状发作后3小时内显着改善神经功能[5,6,7,8]。但是，短暂的3小时治疗窗口显着限制了可治疗患者的数量。有人担心动脉内溶栓治疗后症状性颅内出血的发生率相对较高[7]。不幸的是，自从1995年美国国家神经疾病研究所和中风试验证明rt-PA的疗效以来，急性中风药物的开发一直缺乏进展[7]。其他旨在促进再灌注的药物，如静脉内给予原尿激酶和去纤蛋白原剂ancord进行动脉内溶栓治疗，也显示出了希望[7]。尽管对神经保护性化合物的大量研究表明，在动物卒中模型中梗塞体积减小，并且在某些情况下，II期结果令人鼓舞，但在III期阳性试验的基础上，没有证据证明有效。在此基础上，很明显，在未来的临床试验中将需要考虑并采用新的方法[7]。扩散和灌注MRI在选择3个小时以上溶栓患者和评估再灌注组织效果方面的潜力已经实现[ 9]。 Parsons等人建议，通过灌注和扩散MRI进行患者选择及其对治疗反应的评估，可以确定在开始治疗3到6小时之间进行静脉rt-PA治疗的患者具有临床益处[10]。弥散加权成像（DWI）成像的超过89 ml的超急性病变体积可预示早期神经功能恶化[9]。相对峰高和到峰灌注时间的测量值可能比定量血流动力学参数更好地预测梗死的发展[9,11]。血管生成被定义为通过从已存在的血管中萌生内皮细胞而形成新血管。在发芽过程中，内皮细胞降解下面的基底膜，迁移到邻近组织中，增殖并组装成管。最后，进行管到管的连接并建立血液流动[12]。在迄今为止能够表征的能够调节血管生成的因素中，血管内皮生长因子（VEGF）是内皮生长和分化的特定调节剂的最佳候选者。 VEGF在正常成人大脑中表达，主要在脉络丛的上皮细胞中表达，但

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