title: Aminophylline, administered at usual doses for rodents in pharmacological studies, induces hippocampal neuronal cell injury under low tidal volume hypoxic conditions in guinea-pigs.
abstract: OBJECTIVE
  To establish whether aminophylline, administered at usual doses for rodents in pharmacological studies, induces brain injury in systemic hypoxaemia in guinea-pigs.
  
  
  METHODS
  A hypoxaemia (partial oxygen tension of arterial blood (PaO₂) = 40-60 mmHg) model was developed by low tidal volume mechanical ventilation in guinea-pigs.
  
  
  RESULTS
  Under hypoxic conditions, aminophylline significantly increased the concentration of brain-specific creatine kinase in the serum in a dose- and time-dependent manner. A reduced number of hippocampal neuronal cells in the CA1 region, an increase in the concentration of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF), an increase in lipid hydroperoxides and a decrease in the ratio of glutathione to glutathione disulfide in the brain tissues were also observed. These effects were not observed when aminophylline at the same doses was administered under normoxic conditions (PaO₂ = 80-100 mmHg). There was no difference in either serum or CSF concentrations of theophylline between normoxic and hypoxic conditions. Another methylxanthine, caffeine, did not increase the concentration of NSE in CSF.
  
  
  CONCLUSIONS
  Aminophylline potentially induces brain damage under hypoxic conditions. We suggest that aminophylline treatment has adverse effects in patients with hypoxaemia subsequent to respiratory disorders such as asthma.
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Somekawa-Kondo
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ito
authors.forename: Kaori
authors.initials: K
authors.lastname: Tanaka
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Irikura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moriuchi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Toshio
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
mesh_terms: D000628:Aminophylline / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D052276:Creatine Kinase, BB Form / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D002534:Hypoxia, Brain / Q000503:physiopathology*; D007262:Infusions, Intravenous; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000097:blood / Q000134:cerebrospinal fluid; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D010751:Phosphopyruvate Hydratase / Q000134:cerebrospinal fluid; D058915:Purinergic P1 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D013806:Theophylline / Q000097:blood / Q000134:cerebrospinal fluid
chemical_list: D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D000628:Aminophylline; D013806:Theophylline; D052276:Creatine Kinase, BB Form; D010751:Phosphopyruvate Hydratase; D005978:Glutathione; D000077553:Edaravone; D000983:Antipyrine