title: Chronic treatment with anesthetic propofol improves cognitive function and attenuates caspase activation in both aged and Alzheimer's disease transgenic mice.
abstract: There is a need to seek new treatment(s) for Alzheimer's disease (AD). A recent study showed that AD patients may have decreased levels of functional GABA receptors. Propofol, a commonly used anesthetic, is a GABA receptor agonist. We therefore set out to perform a proof of concept study to determine whether chronic treatment with propofol (50 mg/kg/week) can improve cognitive function in both aged wild-type (WT) and AD transgenic (Tg) mice. Propofol was administrated to the WT and AD Tg mice once a week for 8 or 12 weeks, respectively. Morris water maze was used to assess the cognitive function of the mice following the propofol treatment. Activation of caspase-3, caspase-9, and caspase-8 was investigated using western blot analysis at the end of the propofol treatment. In the mechanistic studies, effects of propofol, amyloid-β protein (Aβ), and GABA receptor antagonist flumazenil on caspase-3 activation and opening of the mitochondrial permeability transition pore were assessed in H4 human neuroglioma and mouse neuroblastoma cells by western blot analysis and flow cytometry. Here we showed that the propofol treatment improved cognitive function and attenuated brain caspase-3 and caspase-9 activation in both aged WT and AD Tg mice. Propofol attenuated Aβ-induced caspase-3 activation and opening of the mitochondrial permeability transition pore in the cells, and flumazenil inhibited the propofol's effects. These results suggested that propofol might improve cognitive function via attenuating the Aβ-induced mitochondria dysfunction and caspase activation, which explored the potential that anesthetic propofol could improve cognitive function in elderly and AD patients.
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.|Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Shao
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Buwei
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Veterans Affairs, Medical Research and Development Service and Geriatric Research, Education and Clinical Center, Bedford, MA, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018697:Nootropic Agents / Q000494:pharmacology*; D015742:Propofol / Q000494:pharmacology*; D011897:Random Allocation
chemical_list: D058227:Amyloidogenic Proteins; D018755:GABA Agonists; D018756:GABA Antagonists; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018697:Nootropic Agents; D005442:Flumazenil; D020169:Caspases; D015742:Propofol
keywords: Aging; Alzheimer's disease; amyloid-β protein; anesthesia; apoptosis; mitochondria; neurodegeneration; propofol