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Stroke. 2014 Aug;45(8):2438-2443. doi: 10.1161/STROKEAHA.114.005183. Epub 2014 Jun 17.

Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage.

Author information

1
College of Pharmacy, Ajou University, Suwon, Republic of Korea.
2
College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
3
Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea.
4
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, SHEFFIELD S10 2HQ, England.
#
Contributed equally

Abstract

BACKGROUND AND PURPOSE:

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.

METHODS:

We examined the effect of carnosine on mitochondrial dysfunction and autophagic processes in rat focal ischemia and in neuronal cultures.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

autophagy; carnosine; mitochondria

PMID:
24938837
PMCID:
PMC4211270
DOI:
10.1161/STROKEAHA.114.005183
[Indexed for MEDLINE]
Free PMC Article

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