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?

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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.

Article Information

Address reprint requests to: Jens P. Dreier, M.D., Department of Neurology, Charité Hospital, Humboldt University, 10098 Berlin, Germany. email: jens.dreier@charite.de.

© AANS, except where prohibited by US copyright law.

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    A: Traces showing that CSI originates in the cerebral cortex during superfusion of ACSF containing Hb (2 mmol/L) and K+ (35 mmol/L). The onset of CSI is indicated by the arrows. The CSI event is characterized by a sharp negative shift in DC and a steep decrease in CBF. In this case, the negative shift in the DC and the decrease in CBF lasted for more than 30 minutes. Note the waveform of DC negativity, which represents multiple CSD cycles. B: Traces showing a higher temporal resolution of the onset of CSI. Note that the negative shift in DC precedes the decrease in CBF measured by LD Probes I and II. (The DC electrode was positioned close to Probe I.) Compare also the similarity between the initial segment of the negative DC shift with that of a CSD during superfusion of ACSF with K+ (80 mmol/L) and without Hb (Fig. 8B).

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    A: Traces obtained in another animal demonstrating a shorter episode of CSI under the same conditions as those described in Fig. 1. The shorter duration is likely responsible for the lack of tissue damage in this animal. The duration of CSI was heterogeneous interindividually (compare Figs. 1 and 2) and intraindividually (compare with Fig. 6). B: Traces showing a higher temporal resolution of the onset of CSI, revealing that DC negativity and CBF decreases began almost simultaneously in this animal. The fluctuations before the CSI event represent vasomotion, which is blocked afterward.

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    Panoramic views of sections through complete rat brain demonstrating CSI after superfusion of the brain with ACSF containing Hb (2 mmol/L) and K+ (35 mmol/L) induced cortical infarction. The two panoramic photographs were obtained in two different animals, and each shows a cortical area neighboring the cranial window 48 hours after CSI was initiated. Bars indicate positions of cranial windows and asterisks focal areas of cortical necrosis. A: Sagittal section. Note that the necrosis is larger than the window. Original size of section is 1.5 cm from frontal tip of cerebrum to occipital tip of cerebrum. B: Coronal section. Cresyl violet (Nissl) staining. Original size of section is 1.4 cm from left to right.

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    Photomicrographs. A: Focal cortical necrosis 24 hours after CSI was induced by ACSF containing Hb and K+ (35 mmol/L). Note the perivascular spongiform changes and necrotic neurons with perineuronal halos. H & E. (An almost identical figure was presented in Fig. 2 of the article by Neil-Dwyer, et al., to illustrate changes after DINDs following SAH in humans.) B: Higher magnification of the tissue sample shown in A reveals shrunken, hyperchromatic, acidophilic, necrotic neurons with perineuronal halos (arrow). H & E. C: Results of staining of cells in the cortex 48 hours after CSI was induced. Positively staining neurons can represent either necrosis or apoptosis. TUNEL staining.

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    Photomicrographs Aa: Cortex at the site of the cranial window 48 hours after CSI was induced by Hb (2 mmol/L) and K+ (35 mmol/L) in ACSF. The GFAP staining reveals loss of astrocytes confined sharply to the infarcted zone (asterisk) surrounded by activated astrocytes. Ab: Activated astrocytes in the cortex at the window in a control animal (K+ [80 mmol/L] in ACSF without Hb) 48 hours after the experiment. GFAP staining. Ba: Larger numbers of phagocytic microglia and other macrophages are observed in the infarcted area 48 hours after CSI (Hb [2 mmol/L] and K+ [35 mmol/L] in ACSF). Iba1 staining. Bb: Activated microglial cells residing in cortex at the site of the cranial window in a control animal (K+ [80 mmol/L] in ACSF without Hb) 48 hours after the experiment. Iba1 staining.

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    A: Traces obtained during superfusion of Hb (2 mmol/L) combined with glucose (0.8 mmol/L) in ACSF containing a physiological concentration of K+. Data from a complete experiment are shown. Similar to Hb combined with a high concentration of K+ in ACSF, Hb and a low concentration of glucose in ACSF led to a gradual, pronounced reduction in CBF before CSIs originated in cortex at the site of the cranial window. Two CSIs are observed in this animal during the observation period of 3 hours. The first CSI event is shorter than the second. The onset of the second CSI event is indicated by the arrows. It lasted for approximately 1 hour. Note the waveform of the negative shift in DC, which represents multiple cycles of CSD (compare with Fig. 1). B: Higher temporal resolution of the second CSI event. Note that the DC shift precedes the CBF decrease.

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    A: Photomicrograph of a brain tissue sample showing CSI after superfusion of ACSF containing Hb (2 mmol/L) and glucose (0.8 mmol/L) induced cortical infarction. A coronal section including the window area demonstrates focal cortical necrosis 48 hours after CSI. H & E. B: No CSI is observed after superfusion of ACSF containing Hb (2 mmol/L) combined with physiological concentrations of K+ and glucose. Brain herniation into the cranial window is observed, similar to that seen in A, but there are no signs of necrosis 48 hours after the experiment. H & E. C: Higher-magnification photomicrograph of the window area in A demonstrating destruction of the parenchyma after CSI. Nissl staining. D: Higher-magnification photomicrograph of the window area in B revealing a normal cortical structure in the control animal, although brain herniation and a meningeal reaction are also present. Nissl staining.

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    A: Traces showing initial hypoperfusions followed by cortical spreading hyperemia induced by superfusion of ACSF with K+ (80 mmol/L) but without the NO scavenger Hb. Interestingly, similar responses to CSD with initial hypoperfusion are also known to result from lowering the concentration of NO and from physiological concentrations of K+ in ACSF.11 The arrows indicate the onset of the second CSD. B: Higher temporal resolution of the second CSD. Note that the negative shift in DC and the decrease in CBF start almost simultaneously in this experiment. Different temporal relationships between DC negativity and the CBF response within animals and between different animals result from varying initiation sites of CSD in the window. However, similar to CSI and in contrast to anoxic and periinfarction depolarizations, the CBF decrease never precedes the negative DC shift (see Discussion).

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