Background and Purpose-Both necrotic and apoptotic cell death mechanisms are activated after cerebral ischemia.However, whether they are concomitantly active in the same cell or in discrete cell populations is not known. Methods-We investigated activation of both pathways at the cellular level in mice brains subjected to transient or permanent focal ischemia. Results-Four hours after ischemia, diffuse cathepsin-B spillage into cytoplasm, suggesting lysosomal leakage, was observed within neurons immunoreactive for the active form of caspase-3 (p20). Ischemic neurons with a leaky plasma membrane (positive for propidium iodide) were colabeled with caspase-cleaved actin fragment and exhibited TUNEL-positive nuclei having apoptotic morphology. At 72 hours, up to 27% of cells with caspase activity displayed morphological features suggestive of secondary necrosis. Conclusions-These data, demonstrating an early and concurrent increase in caspase-3 and cathepsin-B activities followed by appearance of caspase-cleavage products, DNA fragmentation, and membrane disintegration, suggest that subroutines of necrotic and apoptotic cell death are concomitantly activated in ischemic neurons and that the dominant cell death phenotype is determined by the relative speed of each process.
BackgroundMigraine is a common headache disorder that may be associated with vascular disease and cerebral white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) scan. High sensitivity C-reactive protein (hs-CRP) is a marker of inflammation that may predict subclinical atherosclerosis. However, the relation between migraine, vascular risks, and WMHs is unknown. We evaluated hs-CRP levels and the relation between hs-CRP level and WMHs in adult migraine patients.MethodsThis case–control study included 432 subjects (216 migraine patients [without aura, 143 patients; with aura, 73 patients]; 216 healthy control subjects without migraine; age range 18–50 y). Migraine diagnosis was determined according to the International Classification of Headache Disorders II diagnostic criteria. The migraine patients and control subjects had no known vascular risk factors, inflammatory disease, or comorbid disease. The presence and number of WMHs on MRI scans were determined, and serum hs-CRP levels were measured by latex-enhanced immunoturbidimetry.ResultsMean hs-CRP level was significantly greater in migraine patients (1.94 ± 2.03 mg/L) than control subjects (0.82 ± 0.58 mg/L; P ≤ .0001). The mean number of WMHs per subject and the presence of WMHs was significantly greater in migraine patients (69 patients [31.9%]; 1.68 ± 3.12 mg/dL) than control subjects (21 subjects [9.7%]; 0.3 ± 1.3; P ≤ .001). However, there was no correlation between hs-CRP level and WMHs in migraine patients (r = 0.024; not significant). The presence of WMHs was increased 4.35-fold in migraine patients (odds ratio 4.35, P ≤ .001).ConclusionsHigh hs-CRP level may be a marker of the proinflammatory state in migraine patients. However, the absence of correlation between hs-CRP level and WMHs suggests that hs-CRP is not causally involved in the pathogenesis of WMHs in migraine patients. The WMHs were located mostly in the frontal lobe and subcortical area.
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