This study investigated the role of spontaneous and induced spreading depression (SD) on the evolution of focal ischemia in vivo. We induced focal ischemia in 12 rats using the middle cerebral artery suture occlusion (MCAO) method. Chemical stimulation of nonischemic ipsilateral cortex by potassium chloride application (KCl group; n = 7) and saline (NaCl group; n = 5) was performed at 15, 30, 45, and 60 minutes following MCAO, and SD was detected electrophysiologically. Ischemic lesion volumes assessed over 15-minute intervals, evaluated by continuous apparent diffusion coefficient (ADC) of water mapping, demonstrated that the ischemic region increased significantly during 15-minute time epochs with a single SD episode (36.5 +/- 12.9 mm3, mean +/- SD) or multiple SD episodes (39.8 +/- 22.3) compared with those without SD (13.9 +/- 11.5) (p = 0.0009). Infarct volume at postmortem 24 hours after MCAO was significantly larger in the KCl group, with more total SDs (237.8 +/- 13.8) than the NaCl group (190.5 +/- 12.6) (p = 0.0001). This study demonstrates that ischemia-related and induced SDs increase significantly ischemic lesion volume in vivo, supporting the hypothesis for a causative role of SD in extending focal ischemic injury.

Background and Purpose:The nature of hematologic disorders in different stroke subtypes remains uncertain. The purpose of this study was to clarify the differences in the coagulation and fibrinolytic activities among ischemic stroke subtypes.Methods: We performed sequential measurements of hematologic parameters in 21 patients with acute cardioembolic stroke, 10 patients with atherothrombotic stroke, 23 patients with lacunar stroke, and 20 age-matched controls.Results: A marked elevation of plasma concentrations of the thrombin-antithrombin III complex and crosslinked D-dimer was observed only in cardioembolic stroke within 48 hours of onset (p<0.01), persisting for one month with a gradual decline. In atherothrombotic stroke, however, the level of crosslinked D-dimer was not elevated at the onset, but increased seven days after onset (p<0.01). No significant changes in these marker levels were observed in lacunar stroke.Conclusions: Our findings suggest that the nature of altered coagulation and fibrinolysis are different in various subtypes of ischemic stroke, and that an assessment of these hematologic parameters may be useful for the early classification of these subtypes. (Stroke 1992;23:194-198)

No abstract

The hematologic disorders in patients with acute cardioembolic stroke are not fully understood, and no reliable measures are available to identify patients at high risk for recurrent embolism. We analyzed coagulation and fibrinolytic functions in 22 patients with cardiogenic cerebral embolism ^24 hours after onset and in 25 age-matched controls. The levels of antithrombin HI, protein C, and a^-plasmin inhibitor were significantly lower in the patients than in the controls (/?<0.001, 0.02, and 0.05, respectively). In contrast, the plasma concentrations of thrombinantithrombin i n complex and crosslinked D-dimer were markedly higher in the patients than in the controls (p<0.01 and 0.001, respectively). At the time of admission, the plasma concentrations of thrombin-antithrombin III complex and crosslinked D-dimer in the eight patients at high risk for recurrent embolization (one with prodromal embolism, three with intracardiac thrombi, and four with recurrent embolization) were 2.8 and 3.5 times, respectively, higher than those in the 14 patients without recurrence or thrombus formation. The lowest concentration of crosslinked D-dimer in the eight patients at high risk for recurrent embolization was 600 ng/ml on admission. Our results suggest that patients with acute cardioembolic stroke have various degrees of consumption coagulopathy and that the plasma concentrations of thrombin-antithrombin HI complex and crosslinked D-dimer can be useful indicators of those who are prone to recurrent embolization during this stage. (Stroke 1991^2:12-16)

Background and Purpose-Endothelins (ETs) are potent vasoconstrictors. Plasma ET levels increase during acute brain ischemia and may worsen the ischemic damage. Diffusion-weighted MRI (DWI) and perfusion imaging (PI) are powerful tools for evaluation of acute cerebral ischemia. We studied the effects of A-127722, a novel ET A -selective ET antagonist, on cerebral ischemic lesion size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem, on acute ischemic lesion development with DWI, and on the cerebral circulation using PI. Methods-Twenty male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (nϭ10 per group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral artery occlusion (MCAO). Whole-brain DWI and single-slice PI were done before initiation of treatment and repeated frequently thereafter up to 4 hours after MCAO. The animals were reperfused in the MRI scanner 90 minutes after the onset of MCAO. At 24 hours the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal. Results-Physiological parameters, body weight, neurological scores, and premature mortality (2 versus 2) did not differ between the two groups. No hypotension, abnormal behavior, or other adverse effects were seen. TTC-derived %HLV was 25.3Ϯ5.6% for controls and 16.2Ϯ9.6% for treated animals (36% reduction, PϽ.02). Six animals in each group had successful reperfusion as shown by PI. Among these animals, %HLV was 23.2Ϯ3.1% for controls and 9.3Ϯ4.4% for treated animals (60% reduction, Pϭ.0001). The beneficial effect of A-127722 was limited to animals in which successful reperfusion was demonstrated. No difference in PI-detected perfusion deficit size was observed between the groups. DWI did not demonstrate significant in vivo lesion size differences. Conclusions-A-127722 significantly reduced ischemic lesion size in rats without observable adverse effects. It is not clear whether the effect was due to vasodilatation of collateral arterioles not detectable by PI or whether A-127722 has neuroprotective properties that are independent of vascular effects. (Stroke. 1998;29:850-858.)

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Background and Purpose-Brain ischemia is associated with a marked increase in extracellular adenosine levels. This results in activation of cell surface adenosine receptors and some degree of neuroprotection. Adenosine kinase is a key enzyme controlling adenosine metabolism. Inhibition of this enzyme enhances the levels of endogenous brain adenosine already elevated as a result of the ischemic episode. We studied a novel adenosine kinase inhibitor (AKI), GP683, in a rat focal ischemia model. Methods-Four groups of 10 adult Sprague-Dawley rats were exposed to 90 minutes of temporary middle cerebral artery (MCA) occlusion. Animals were injected intraperitoneally with vehicle, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of GP683 30, 150, and 270 minutes after the induction of ischemia by a researcher blinded to treatment group. The animals were euthanatized 24 hours after MCA occlusion, and brains were stained with 2,3,5-triphenyltetrazolium chloride. We measured brain temperatures in a separate group of 6 rats before and after administration of 1.0 mg/kg GP683. Results-All treated groups showed a reduction in infarct volumes, but a significant effect was observed only in the 1.0 mg/kg-dose group (44% reduction, Pϭ0.0077). Body weight, physiological parameters, neurological scores, and mortality did not differ among the 4 groups. No apparent behavioral side effects were observed. Brain temperatures did not change after drug injection. Conclusions-Our

Multispectral (MS) analysis was used to determine the ischemic lesion volume in the rat brain after permanent middle cerebral arterial occlusion. MS analysis used a four-dimensional MS model consisting of an estimate of the average apparent diffusion coefficient of water (ADC(av)), T2, proton density, and perfusion. Four classification methods were investigated: (a) multivariate gaussian (MVG); (b) k-nearest neighbor (k-NN); (c) k-means (KM); and (d) fuzzy c-means (FCM). MVG and k-NN classifiers are supervised methods requiring labeled training data to characterize the stroke lesion. Unsupervised classifiers (KM, FCM) do not require previous statistics or labeled training data, resulting in potentially greater clinical usefulness. All MS methods provided significant correlation with postmortem findings beyond the use of ADC(av) alone (partial correlation given the ADC(av) estimate: MVG, .66; k-NN, .75; KM, .68; FCM, .70). This study demonstrates that MS analysis provides an improved estimate of ischemic lesion volume over that obtained from ADC alone.