title: Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke.
abstract: Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD(+)/NADH ratio. In this study, we investigated whether mitochondrial NAD(+)-dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD(+)-dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway.
authors.affiliation: Department of Neurology, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Neurology, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Neurology, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Radiology, Keller Center for Imaging Innovation, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neurology, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Shi
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000627:therapeutic use; D000090:Acetoacetates / Q000627:therapeutic use; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology; D007659:Ketones / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D004856:Postural Balance / Q000187:drug effects; D061251:Primary Cell Culture; D056566:Sirtuin 3 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D000099156:Superoxide Dismutase 2
chemical_list: D020155:3-Hydroxybutyric Acid; D000090:Acetoacetates; D000255:Adenosine Triphosphate; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007659:Ketones; D018696:Neuroprotective Agents; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C474033:FoxO3 protein, mouse; C525046:Sirt3 protein, mouse; C016635:acetoacetic acid