Wiessner C, Allegrini P R, Ekatodramis D, Jewell U R, Stallmach T, Gassmann M
Novartis Pharma AG, TA NS/ND & CTA/IVM, Basel, Switzerland.
J Cereb Blood Flow Metab. 2001 Jul;21(7):857-64. doi: 10.1097/00004647-200107000-00011.
There is increasing evidence that erythropoietin (Epo) has a protective function in cerebral ischemia. When used for treatment, high Epo plasma levels associated with increases in blood viscosity, however, may counteract beneficial effects of Epo in brain ischemia. The authors generated two transgenic mouse lines that overexpress human Epo preferentially, but not exclusively, in neuronal cells. In mouse line tg21, a fourfold increase of Epo protein level was found in brain only, whereas line tg6 showed a dramatic increase of cerebral and systemic transgene expression resulting in hematocrit levels of 80%. Cerebral blood flow (CBF), as determined by bolus tracking magnetic resonance imaging, was not altered in the tg6 line. The time-to-peak interval for the tracer, however, increased approximately threefold in polyglobulic tg6 mice. Immunohistochemical analysis revealed an increase in dilated vessels in tg6 mice, providing an explanation for unaltered CBF in polyglobulic animals. Permanent occlusion of the middle cerebral artery (pMCAO) led to similar perfusion deficits in wild-type, tg6, and tg21 mice. Compared with wild-type controls, infarct volumes were not significantly smaller (22%) in tg21 animals 24 hours after pMCAO, but were 49% enlarged (P < 0.05) in polyglobulic tg6 mice. In the latter animals, elevated numbers of Mac-1 immunoreactive cells in infarcted tissue suggested that leukocyte infiltration contributed to enlarged infarct volume. The current results indicate that moderately increased brain levels of Epo in tg21 transgenic mice were not sufficient to provide significant tissue protection after pMCAO. The results with tg6 mice indicate that systemic chronic treatment with Epo associated with elevated hematocrit might deteriorate outcome after stroke either because of the elevated hematocrit or other chronic effects.
越来越多的证据表明，促红细胞生成素（Epo）在脑缺血中具有保护作用。然而，在用于治疗时，与血液粘度增加相关的高血浆Epo水平可能会抵消Epo在脑缺血中的有益作用。作者培育了两种转基因小鼠品系，它们优先但并非仅在神经元细胞中过表达人Epo。在tg21小鼠品系中，仅在脑中发现Epo蛋白水平增加了四倍，而tg6品系则显示脑和全身转基因表达显著增加，导致血细胞比容水平达到80%。通过团注追踪磁共振成像测定的脑血流量（CBF）在tg6品系中未发生改变。然而，在红细胞增多的tg6小鼠中，示踪剂的达峰时间间隔增加了约三倍。免疫组织化学分析显示tg6小鼠中扩张血管增多，这为红细胞增多动物中CBF未改变提供了解释。大脑中动脉永久性闭塞（pMCAO）在野生型、tg6和tg21小鼠中导致类似的灌注缺陷。与野生型对照相比，pMCAO后24小时，tg21动物的梗死体积并未显著减小（22%），但在红细胞增多的tg6小鼠中梗死体积增大了49%（P<0.05）。在后者动物中，梗死组织中Mac-1免疫反应性细胞数量增加表明白细胞浸润导致梗死体积增大。目前的结果表明，tg21转基因小鼠脑中Epo水平适度升高不足以在pMCAO后提供显著的组织保护。tg6小鼠的结果表明，与血细胞比容升高相关的Epo全身慢性治疗可能会使中风后的预后恶化，这可能是由于血细胞比容升高或其他慢性影响。
