Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage.
Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage.
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DOI：
10.1161/strokeaha.114.005183
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发表时间：
2014-08
期刊：
影响因子：
8.3
通讯作者：
Bae ON
中科院分区：
文献类型：
--
作者：
Baek SH;Noh AR;Kim KA;Akram M;Shin YJ;Kim ES;Yu SW;Majid A;Bae ON
尽管缺血性脑卒中的全球负担迅速增加，但目前尚无针对脑卒中的神经保护治疗方案。最近的研究表明，自噬在缺血性神经元死亡中起着关键作用，针对自噬的治疗可能是神经保护的一种新策略。我们研究了自噬是否受肌肽的调节，肌肽是一种内源性的多效二肽，对缺血性脑损伤具有强大的神经保护活性。我们研究了肌肽对大鼠局灶性缺血和神经元培养中线粒体功能障碍和自噬过程的影响。自噬途径如磷酸化mTOR/p70S6K的减少和LC3-I向LC3-II的转化在缺血脑中增强。然而，肌肽治疗显著减弱缺血脑的自噬信号，改善脑线粒体功能和自噬信号。肌肽对初代皮层神经元自噬的保护作用也得到证实。综上所述，我们的数据表明肌肽的神经保护作用至少部分是由线粒体保护和有害自噬过程的衰减介导的。我们的发现揭示了这种令人兴奋的神经保护剂影响的机制途径。
Despite the rapidly increasing global burden of ischemic stroke, no therapeutic options for neuroprotection against stroke currently exist. Recent studies have shown that autophagy plays a key role in ischemic neuronal death and treatments that target autophagy may represent a novel strategy in neuroprotection. We investigated whether autophagy is regulated by carnosine, an endogenous pleiotropic dipeptide which has robust neuroprotective activity against ischemic brain damage. We examined the effect of carnosine on mitochondrial dysfunction and autophagic processes in rat focal ischemia and in neuronal cultures. Autophagic pathways such as reduction of phosphorylated mTOR/p70S6K and the conversion of LC3-I to LC3-II were enhanced in the ischemic brain. However, treatment with carnosine significantly attenuated autophagic signaling in the ischemic brain, with improvement of brain mitochondrial function and mitophagy signaling. The protective effect of carnosine against autophagy was also confirmed in primary cortical neurons. Taken together, our data suggest that the neuroprotective effect of carnosine is at least partially mediated by mitochondrial protection, and attenuation of deleterious autophagic processes. Our findings shed new light on the mechanistic pathways that this exciting neuroprotective agent influences.