Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: A model for delayed ischemic neurological deficits after subarachnoid hemorrhage?

J. P. Dreier, N. Ebert, J. Priller, D. Megow, U. Lindauer, R. Klee, U. Reuter, Y. Imai, K. M. Einhäupl, I. Victorov, U. Dirnagl

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219 Scopus citations

Abstract

Object. The pathogenesis of delayed ischemic neurological deficits after subarachnoid hemorrhage has been related to products of hemolysis. Topical brain superfusion of artificial cerebrospinal fluid (ACSF) containing the hemolysis products K+ and hemoglobin (Hb) was previously shown to induce ischemia in rats. Superimposed on a slow vasospastic reaction, the ischemic events represent spreading depolarizations of the neuronal-glial network that trigger acute vasoconstriction. The purpose of the present study was to investigate whether such spreading ischemias in the cortex lead to brain damage. Methods. A cranial window was implanted in 31 rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry, and direct current (DC) potentials were recorded. The ACSF was superfused topically over the brain. Rats were assigned to five groups representing different ACSF compositions. Analyses included classic histochemical and immunohistochemical studies (glial fibrillary acidic protein and ionized calcium binding adaptor molecule) as well as a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Superfusion of ACSF containing Hb combined with either a high concentration of K+ (35 mmol/L, 16 animals) or a low concentration of glucose (0.8 mmol/L, four animals) reduced CBF gradually. Spreading ischemia in the cortex appeared when CBF reached 40 to 70% compared with baseline (which was deemed 100%). This spreading ischemia was characterized by a sharp negative shift in DC, which preceded a steep CBF decrease that was followed by a slow recovery (average duration 60 minutes). In 12 of the surviving 14 animals widespread cortical infarction was observed at the site of the cranial window and neighboring areas in contrast to findings in the three control groups (11 animals). Conclusions. The authors conclude that subarachnoid Hb combined with either a high K+ or a low glucose concentration leads to widespread necrosis of the cortex.

Original languageEnglish
Pages (from-to)658-666
Number of pages9
JournalJournal of Neurosurgery
Volume93
Issue number4
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Hemoglobin
  • Ischemia
  • Migraine
  • Rat
  • Vasospasm

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