title: Effects of hyperthermia on hypoxic-ischemic brain damage in the immature rat: its influence on caspase-3-like protease.
abstract: OBJECTIVE
  Recent clinical studies suggested that intrapartum maternal fever is a strong independent risk factor for neonatal encephalopathy. With use of a well-studied rat model of neonatal hypoxic-ischemic encepalopathy, this study investigated the hypothesis that intraischemic hyperthermia accelerates and worsens brain injury in immature animals and examined whether apoptotic cell death machinery is involved in the underlying mechanisms.
  
  
  METHODS
  Seven-day-old rats underwent a combination of left common carotid artery ligation and exposure to 8% oxygen for 15 minutes (n = 32 rats). During the 15-minute hypoxic insult, body temperature was elevated to 40 degrees C in 16 animals (hyperthermic hypoxic insult group), and was maintained at 37 degrees C in 16 animals (normothermic hypoxic insult group). Then both groups were placed in the same chamber in a water bath at 37 degrees C for 24 hours and finally returned to the mothers. Caspase-3-like activity was assessed 36 hours after the hypoxic-ischemic insult. One week later, microtubule-associated protein-2 immunostaining was used to examine neuronal damage.
  
  
  RESULTS
  Intraischemic hyperthermia was shown to activate the caspase-3 activity 36 hours after hypoxia-ischemia while caspase-3 was activated insignificantly in the normothermic hypoxic insult group at that time. The hyperthermic hypoxic insult group also showed a reduced microtubule-associated protein-2-positive area 7 days after hypoxia-ischemia compared with that in the normothermia group.
  
  
  CONCLUSIONS
  Hyperthermia during hypoxia-ischemia makes the immature brain inordinately susceptible to hypoxic-ischemic insult and causes brain injury, even if hypoxic-ischemic insult is so mild that it causes no or little injury by itself. This effect may be mediated by the escalation of the apoptotic cell death pathway in the immature animal.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, Japan. tomimatu@gyne.med.osaka-u.ac.jp
authors.forename: Takuji
authors.initials: T
authors.lastname: Tomimatsu
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Fukuda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanagawa
authors.forename: Junwu
authors.initials: J
authors.lastname: Mu
authors.forename: Toru
authors.initials: T
authors.lastname: Kanzaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Murata
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001925:Brain Damage, Chronic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006979:Hyperthermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D007150:Immunohistochemistry; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013997:Time Factors
chemical_list: D008869:Microtubule-Associated Proteins; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases