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?

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.

[1]  R. Macdonald,et al.  A review of hemoglobin and the pathogenesis of cerebral vasospasm. , 1991, Stroke.

[2]  G. V. van Melle,et al.  Migraine stroke , 1988, Neurology.

[3]  T. Wieloch,et al.  Intracerebral microdialysis of glutamate and aspartate in two vascular territories after aneurysmal subarachnoid hemorrhage. , 1996, Neurosurgery.

[4]  O. Manzoni,et al.  Nitric oxide-induced blockade of NMDA receptors , 1992, Neuron.

[5]  K. Welch,et al.  Bilateral posterior cerebral artery strokes in a young migraine sufferer. , 1988, Stroke.

[6]  M. Avoli,et al.  Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro , 1991, Annals of neurology.

[7]  S. Bracard,et al.  Vasospasm After Subarachnoid Hemorrhage: Interest in Diffusion-Weighted MR Imaging , 2001, Stroke.

[8]  Ulrich Dirnagl,et al.  Nitric Oxide Scavenging by Hemoglobin or Nitric Oxide Synthase Inhibition by N-Nitro-L-Arginine Induces Cortical Spreading Ischemia When K+ Is Increased in the Subarachnoid Space , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  U. Dirnagl,et al.  Continuous Measurement of Cerebral Cortical Blood Flow by Laser—Doppler Flowmetry in a Rat Stroke Model , 1989, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  V. Grutta,et al.  Nitric Oxide and Glutamate Interaction in the Control of Cortical and Hippocampal Excitability , 1999, Epilepsia.

[11]  H. Adams,et al.  The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. , 1990, Journal of neurosurgery.

[12]  Y. Imai,et al.  A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. , 1996, Biochemical and biophysical research communications.

[13]  E. Oldfield,et al.  Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage. , 1998, Journal of neurosurgery.

[14]  N. Gorelova,et al.  Ketamine blockade of cortical spreading depression in rats. , 1987, Electroencephalography and clinical neurophysiology.

[15]  K. Hosoki,et al.  Modulation of extraluminally induced vasoconstrictions by endothelium-derived nitric oxide in the canine basilar artery. , 1995, Arzneimittel-Forschung.

[16]  Robert B. Duckrow,et al.  A brief hypoperfusion precedes spreading depression if nitric oxide synthesis is inhibited , 1993, Brain Research.

[17]  D. Warner,et al.  Cortical negative DC deflections following middle cerebral artery occlusion and KCl-induced spreading depression: effect on blood flow, tissue oxygenation, and electroencephalogram. , 1994 .

[18]  M. Lauritzen,et al.  The Effect of Glutamate Receptor Blockade on Anoxic Depolarization and Cortical Spreading Depression , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[19]  A. Gjedde,et al.  Relationship between local changes in cortical blood flow and extracellular K+ during spreading depression. , 1980, Acta physiologica Scandinavica.

[20]  O B Paulson,et al.  Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? , 1987, Science.

[21]  I. T. Demchenko,et al.  Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. , 1997, Science.

[22]  M. Chopp,et al.  Ultrastructural and light microscopic evidence of apoptosis after middle cerebral artery occlusion in the rat. , 1995, The American journal of pathology.

[23]  U. Ungerstedt,et al.  Bedside detection of brain ischemia using intracerebral microdialysis: subarachnoid hemorrhage and delayed ischemic deterioration. , 1999, Neurosurgery.

[24]  Joseph Loscalzo,et al.  A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds , 1993, Nature.

[25]  A. Betz,et al.  Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model. , 1992, Neurosurgery.

[26]  Charles Nicholson,et al.  Quisqualate, kainate and NMDA can initiate spreading depression in the turtle cerebellum , 1988, Brain Research.

[27]  J. Garcìa,et al.  Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. , 1995, Stroke.

[28]  G. Kreutzberg,et al.  Calcitonin gene‐related peptide and ATP induce immediate early gene expression in cultured rat microglial cells , 1995, Glia.

[29]  G. Somjen,et al.  Hypotonic exposure enhances synaptic transmission and triggers spreading depression in rat hippocampal tissue slices , 1995, Brain Research.

[30]  M. Lauritzen,et al.  Influence of MK-801 on Brain Extracellular Calcium and Potassium Activities in Severe Hypoglycemia , 1990, Journal of Cerebral Blood Flow and Metabolism.

[31]  M. Lauritzen,et al.  Pathophysiology of the migraine aura. The spreading depression theory. , 1994, Brain : a journal of neurology.

[32]  T. M. Griffith,et al.  The effect of chronic subarachnoid hemorrhage on basal endothelium-derived relaxing factor activity in intrathecal cerebral arteries. , 1992, Journal of neurosurgery.

[33]  D. Pelligrino,et al.  NO synthase inhibition modulates NMDA-induced changes in cerebral blood flow and EEG activity. , 1996, The American journal of physiology.

[34]  J Astrup,et al.  Infarct Rim: Effect of Hyperglycemia on Direct Current Potential and [14C]2-Deoxyglucose Phosphorylation , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[35]  A Villringer,et al.  Nitric Oxide Modulates the CBF Response to Increased Extracellular Potassium , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  E. Wijdicks,et al.  Hyponatremia is associated with cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage , 1990, Annals of neurology.

[37]  W. Spielmeyer.  Histopathologie des Nervensystems: Erster Band Allgemeiner Teil , 1922 .

[38]  J. Astrup,et al.  Potassium activity in cerebral cortex in rats during progressive severe hypoglycemia , 1976, Brain Research.

[39]  R. Lillie,et al.  Histopathologic Technic and Practical Histochemistry , 1954 .

[40]  R. Macleod,et al.  Evaluation of the role hemoglobin in cerebrospinal fluid plays in producing contractions of cerebral arteries. , 1987, Surgical neurology.

[41]  K. Someda,et al.  Cerebral vasospasm and hemoglobins--clinical and experimental studies. , 1979, Neurologia medico-chirurgica.

[42]  J. Broderick.  Stroke and Migraine , 1997 .