title: BDNF pathway is involved in the protective effects of SS-31 on isoflurane-induced cognitive deficits in aging mice.
abstract: Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month-old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIα and CaMKIIβ. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS-31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia.
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 210093 Nanjing, PR China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 210093 Nanjing, PR China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China.
authors.forename: Xiaoru
authors.initials: X
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 210093 Nanjing, PR China.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China.
authors.forename: Muhuo
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China. Electronic address: yjyangjj@126.com.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 210093 Nanjing, PR China. Electronic address: likuanyu@nju.edu.cn.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Li
mesh_terms: D000375:Aging; D018685:Anesthetics, Inhalation / Q000633:toxicity; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure; D007530:Isoflurane / Q000633:toxicity; D008124:Locomotion / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009842:Oligopeptides / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018685:Anesthetics, Inhalation; D019208:Brain-Derived Neurotrophic Factor; D045222:Electron Transport Chain Complex Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D007530:Isoflurane
keywords: Aging; Anesthesia; Brain-derived neurotrophic factor; Cognitive deficits; Mitochondria; Synaptic plasticity