Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia

Yuichi Maruki, Raymond C. Koehler, Jeffrey R. Kirsch, Kathleen K. Blizzard, Richard J. Traystman

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 ± 4 ml min-1 100 g-1 and intracellular pH decreased to 5.6 ± 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 ± 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 ± 35 vs. 36 ± 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 ± 0.5 vs. 5.9 ± 0.6) and a lower intracranial pressure (18 ± 6 vs. 52 ± 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was >67% and pH was >6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia. If tirilazad acts by inhibiting lipid peroxidation, then these data are consistent with extreme acidosis limiting recovery by a mechanism involving lipid peroxidation.

Original languageEnglish (US)
Pages (from-to)88-96
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number1
StatePublished - 1995


  • Antioxidants
  • Hyperglycemia
  • Magnetic resonance spectroscopy
  • Tirilazad mesylate
  • pH

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia'. Together they form a unique fingerprint.

Cite this