title: Hyperglycemia promotes tissue plasminogen activator-induced hemorrhage by Increasing superoxide production.
abstract: OBJECTIVE
  Risk of intracerebral hemorrhage is the primary factor limiting use of tissue plasminogen activator (tPA) for stroke. Clinical studies have established an association between admission hyperglycemia and the risk of hemorrhage with tPA use, independent of prior diabetes. Here we used an animal model of tPA-induced reperfusion hemorrhage to determine if this clinical association reflects a true causal relationship.
  
  
  METHODS
  Rats underwent 90 minutes of focal ischemia, and tPA infusion was begun 10 minutes prior to vessel reperfusion. Glucose was administered during ischemia to generate blood levels ranging from 5.9 ± 1.8mM (normoglycemia) to 21 ± 2.3mM. In some studies, apocynin was administered to block superoxide production by nicotinamide adenine dinucleotide phosphate (NADPH). Brains were harvested 1 hour or 3 days after reperfusion to evaluate the effects of hyperglycemia and apocynin on oxidative stress, blood-brain barrier breakdown, infarct volume, and hemorrhage volume.
  
  
  RESULTS
  Rats that were hyperglycemic during tPA infusion had diffusely increased blood-brain barrier permeability in the postischemic territory, and a 3- to 5-fold increase in intracerebral hemorrhage volumes. The hyperglycemic rats also showed increased superoxide formation in the brain parenchyma and vasculature during reperfusion. The effects of hyperglycemia on superoxide production, blood-brain barrier disruption, infarct size, and hemorrhage were all attenuated by apocynin.
  
  
  CONCLUSIONS
  These findings demonstrate a causal relationship between hyperglycemia and hemorrhage in an animal model of tPA stroke treatment, and suggest that this effect of hyperglycemia is mediated through an increase in superoxide production by NADPH oxidase.
authors: Neurology and Rehabilitation Service, San Francisco Veterans Affairs Medical Center and Department of Neurology, University of California at San Francisco, CA, USA.
authors: Seok Joon
authors: SJ
authors: Won
authors: Xian Nan
authors: XN
authors: Tang
authors: Sang Won
authors: SW
authors: Suh
authors: Midori A
authors: MA
authors: Yenari
authors: Raymond A
authors: RA
authors: Swanson
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage; D006943:Hyperglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D013481:Superoxides / Q000097:blood; D013549:Sweetening Agents / Q000008:administration & dosage; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D001786:Blood Glucose; D005343:Fibrinolytic Agents; D013549:Sweetening Agents; D013481:Superoxides; C056165:acetovanillone; D010959:Tissue Plasminogen Activator; D005947:Glucose