College of Pharmacy, Ajou University, Suwon, Republic of Korea.
College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
Stroke. 2014 Aug;45(8):2438-2443. doi: 10.1161/STROKEAHA.114.005183. Epub 2014 Jun 17.
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 that 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 mammalian target of rapamycin (mTOR)/p70S6K and the conversion of microtubule-associated protein 1 light chain 3 (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.
尽管缺血性中风的全球负担迅速增加，但目前尚无针对中风的神经保护治疗选择。最近的研究表明，自噬在缺血性神经元死亡中起关键作用，针对自噬的治疗可能代表神经保护的一种新策略。我们研究了肌肽是否通过调节自噬来发挥作用，肌肽是一种内源性多功能二肽，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物中线粒体功能障碍和自噬过程的影响。
在缺血性大脑中，自噬途径如磷酸化哺乳动物雷帕霉素靶蛋白（mTOR）/p70S6K 的减少和微管相关蛋白 1 轻链 3（LC3）-I 向 LC3-II 的转化增强。然而，肌肽治疗显著减弱了缺血性大脑中的自噬信号，改善了脑线粒体功能和噬线粒体信号。肌肽对自噬的保护作用在原代皮质神经元中也得到了证实。
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通过线粒体保护和减轻有害自噬过程来介导的。我们的研究结果为这种令人兴奋的神经保护剂影响的机制途径提供了新的见解。
