Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia
Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia
复制标题
DOI：
10.1016/j.nbd.2015.08.018
复制
发表时间：
2015-11-01
影响因子：
6.1
通讯作者：
Doeppner, Thorsten R.
中科院分区：
文献类型：
--
作者：
Hermann, Dirk M.;Zechariah, Anil;Doeppner, Thorsten R.
根据法国悖论，即使在高度饱和脂肪酸摄入的情况下，红葡萄酒的消费也会降低血管疾病的发病率。这种现象被广泛归因于植物抗毒素白藜芦醇，一种红葡萄酒成分。实验研究表明，白藜芦醇具有神经保护特性，大多采用与短期观察期相关的预防性给药策略。这些研究并没有得出关于白藜芦醇在中风后的治疗效果的结论。在此，我们系统地分析了预防性、急性和急性后递送白藜芦醇（50 mg/kg）对小鼠大脑中动脉闭塞引起的局灶性脑缺血后神经恢复、组织存活和血管神经发生的影响。在四周的观察期内，只有延长急性后白藜芦醇递送诱导持续的神经恢复，如通过旋转杆、紧绳和转角测试所评估的。尽管预防性和急性白藜芦醇给药在缺血后2天通过升高白藜芦醇的下游信号sirtuin-1，增加细胞存活信号，（磷酸化Akt、血红素加氧酶-1、Bcl-2）和减少细胞死亡信号（Bax，活化的半胱天冬酶-3），在三种实验条件中的任何一种中均未观察到第28天梗死面积的持续减少。相反，在接受急性后白藜芦醇递送的动物中注意到增强的血管生成和神经发生，这与脑中GDNF和VEGF浓度升高有关。因此，白藜芦醇诱导的持续神经恢复取决于成功的脑重塑，而不是结构性神经保护。延迟白藜芦醇释放的促进恢复作用为中风治疗开辟了前景。(C)2015 Elsevier Inc. All rights reserved.
According to the French paradox, red wine consumption reduces the incidence of vascular diseases even in the presence of highly saturated fatty acid intake. This phenomenon is widely attributed to the phytoalexin resveratrol, a red wine ingredient. Experimental studies suggesting that resveratrol has neuroprotective properties mostly used prophylactic delivery strategies associated with short observation periods. These studies did not allow conclusions to be made about resveratrol's therapeutic efficacy post-stroke. Herein, we systematically analyzed effects of prophylactic, acute and post-acute delivery of resveratrol (50 mg/kg) on neurological recovery, tissue survival, and angioneurogenesis after focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion in mice. Over an observation period of four weeks, only prolonged post-acute resveratrol delivery induced sustained neurological recovery as assessed by rota rod, tight rope and corner turn tests. Although prophylactic and acute resveratrol delivery reduced infarct volume and enhanced blood-brain-barrier integrity at 2 days post-ischemia by elevating resveratrol's downstream signal sirtuin-1, increasing cell survival signals (phosphorylated Akt, heme oxygenase-1, Bcl-2) and decreasing cell death signals (Bax, activated caspase-3), a sustained reduction of infarct size on day 28 was not observed in any of the three experimental conditions. Instead, enhanced angiogenesis and neurogenesis were noted in animals receiving post-acute resveratrol delivery, which were associated with elevated concentrations of GDNF and VEGF in the brain. Thus, sustained neurological recovery induced by resveratrol depends on successful brain remodeling rather than structural neuroprotection. The recovery promoting effect of delayed resveratrol delivery opens promising perspectives for stroke therapy. (C) 2015 Elsevier Inc. All rights reserved.