title: Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage.
abstract: OBJECTIVE
  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.
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Republic of Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Baek
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Ah Reum
authors.initials: AR
authors.lastname: Noh
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Kyeong-A
authors.initials: KA
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akram
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea.
authors.forename: Seong Woon
authors.initials: SW
authors.lastname: Yu
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, SHEFFIELD S10 2HQ, England.
authors.forename: Arshad
authors.initials: A
authors.lastname: Majid
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002336:Carnosine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D002336:Carnosine; D058570:TOR Serine-Threonine Kinases
keywords: autophagy; carnosine; mitochondria