title: Diisopropylamine dichloroacetate, a novel pyruvate dehydrogenase kinase 4 inhibitor, as a potential therapeutic agent for metabolic disorders and multiorgan failure in severe influenza.
abstract: Severe influenza is characterized by cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of diisopropylamine dichloroacetate (DADA), a new PDH kinase 4 (PDK4) inhibitor, in mice with severe influenza. Infection of mice with influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs. Oral administration of DADA at 12-h intervals for 14 days starting immediately after infection significantly restored PDH activity and ATP level in various organs, and ameliorated disorders of glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of cytokine storm, trypsin up-regulation and viral replication. These results indicate that through PDK4 inhibition, DADA effectively suppresses the host metabolic disorder-cytokine cycle, which is closely linked to the influenza virus-cytokine-trypsin cycle, resulting in prevention of multiorgan failure in severe influenza.
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamane
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Indalao
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Chida
authors.affiliation: R&D Department, Daiichi Sankyo Healthcare Co., Ltd., Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: R&D Department, Daiichi Sankyo Healthcare Co., Ltd., Tokyo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hanawa
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kido
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005947:Glucose / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D050356:Lipid Metabolism / Q000187:drug effects; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000201:enzymology / Q000821:virology; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047428:Protein Kinase Inhibitors; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; C001002:diisopropylamine dichloroacetate; D019289:Pyruvic Acid; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D005947:Glucose