A series of 14 patients with intracerebral hemorrhage after carotid endarterectomy is reviewed. This complication occurred in 0.6% of 2362 consecutive carotid endarterectomies performed at the Mayo Clinic from 1972 through 1986. All hemorrhages occurred within the first 2 weeks after operation and were ipsilateral to the side of the operation. Eight patients died, and only two made a good recovery. Significant risk factors are hypertension and chronic hemispheric hypoperfusion with impaired autoregulation. The "normal pressure-hyperperfusion breakthrough" syndrome was considered to be operative in 12 of the 14 patients. Nine patients had documented hyperperfusion (at least 100% increase of baseline cerebral blood flow) at the time of surgery. In an additional three patients, normal perfusion-pressure breakthrough was inferred by the clinical course and radiological findings, as well as by the absence of alternative explanations. Patients at risk for postendarterectomy intracerebral hemorrhage include those who have a clinical history suggestive of hemodynamic cerebral ischemia, severe carotid stenosis with limited hemispheric collateral flow, and postendarterectomy hyperperfusion, as measured by intraoperative cerebral blood flow. To minimize the risk of hemorrhage in these patients, strict maintenance of blood pressure at normotensive or even relatively hypotensive levels during the intraoperative and early postoperative periods is advised.
Although accumulating evidence indicates that cAMP response element-binding protein (CREB) phosphorylation mediates not only synaptic plasticity but also survival of certain neurons, it remains uncertain whether CREB phosphorylation induced after metabolic insult leads to CRE-mediated gene transcription and is involved in cell survival or not. In the present study, we clarified that (1) CREB phosphorylation and ischemic tolerance induced after preconditioning ischemia in the hippocampal neurons was abolished by MK801 administration in gerbil global ischemia model, (2) CREB phosphorylation induced after exposure to glutamate in cultured neurons was inhibited by removal of extracellular calcium, by MK801 and by an inhibitor of calcium-calmodulin-dependent protein kinase (CaMK) II and IV, (3) inhibitor of CaMK II-IV or CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression and accelerated neuronal damage after exposure to glutamate, and (4) CREB phosphorylation induced in the hippocampal neurons after ischemia and in cultured neurons after exposure to glutamate was followed by CRE-mediated gene transcription in transgenic mice with a CRE-LacZ reporter. Our results suggest that CREB phosphorylation in neurons after ischemia and exposure to glutamate is induced by NMDA receptor-gated calcium influx and subsequent activation of CaMK II-IV and that CREB phosphorylation after metabolic stress might show a neuroprotective response through CRE-mediated gene induction.
Summary: Cerebral ischemia models using mice have drawn increasing attention, particularly because of the availability of transgenic animals, However, the variability of intracranial vas culature at the circle of Willis in mice can influence the degree of ischemia in both the bilateral common carotid artery (CCA) occlusion and intraluminal suture occlusion models, We have developed a method to predict the extent of the anastomosis between carotid and vertebrobasilar circulation in three mouse strains (C57BLl6, CBA, and DBAl2) by measuring cortical microperfusion with laser Doppler flowmetry during a 1-minute occlusion of both CCA, When animals showed residual cortical microperfusion of less than 12% during bilateral CCA occlusion, the mice showed absence of functional anastomosis, developed ATP depletion in the frontal cortex during occlusion,The patency of the posterior communicating artery (PComA) has been regarded as a crucial factor in the development of forebrain ischemia after bilateral com mon carotid artery (CCA) occlusion in gerbils (Levine and Sohn, 1969;Kahn, 1972; Berry et aI., 1975), In mice, strain differences have been observed regarding the pa tency of the PComA at the circle of Willis (Barone et a!., 1993; Yang et aI., 1997), Although the territory supplied by the posterior cerebral artery (PCA), including the hip pocampus and thalamus, is expected to experience isch- emia using the intraluminal suture occlusion model in the absence of collateral circulation through a patent PComA (Fig. 1), the importance of the PComA has not been critically evaluated in the context of an intraluminal su ture occlusion model to produce occlusion of the middle cerebral artery (MCA), In the current study, we provide evidence that patency of the PComA is a crucial deter minant of the development of bilateral forebrain isch emia after bilateral CCA occlusion as well as ischemia in the PCA territory using the intraluminal suture occlusion model in three murine strains, including C57BL/6, CBA, and DBA12. We therefore developed a procedure to pre dict the patency of the PComA and found that this pro cedure would be useful for the reproducible induction of cerebral ischemia in transgenic mice. MATERIALS AND METHODSThree mouse strains were obtained from Charles River, Inc.(Yokohama, Kanagawa, Japan): C57BLl6NCrj (C57BLl6), CBAljNCrj (CBA), and DBAl2NCrj (DBAl2). All mice were mature males aged 8 to 16 weeks, weighing 22.5 ± 0.4 g (C57BLl6, n = 46), 21.8 ± 0.6 g (CBA, n = 27), and 22.8 ±
Background and Purpose-The purpose of this study was (1) to examine the contribution of microglia and macrophages with their interleukin-1 production and (2) to assess the vulnerability and response of oligodendrocytes in cerebral infarction. Methods-Male Wistar rats were subjected to permanent occlusion of the left middle cerebral artery. Expansion of ischemic infarction and response of oligodendrocytes were investigated together with accumulation of inflammatory cells, production of interleukin-1, and disruption of the blood-brain barrier. Apoptotic cell death was inferred from fragmented DNA and the expression of proapoptotic Bax protein. Results-During expansion of infarction, amoeboid microglia and extravasation of serum albumin were observed not only in the infarcted area but also in the adjacent surviving area, whereas macrophages accumulated along the boundary and granulocytes migrated into the center of the infarction. Both amoeboid microglia and macrophages produced interleukin-1, an inflammatory cytokine, during an early ischemic period. Furthermore, macrophages within the infarcted tissue expressed Bax protein and subsequently showed fragmented nuclear DNA. Oligodendrocytes were detected in the infarcted area even after 24 hours following middle cerebral artery occlusion, but they subsequently developed fragmented DNA. A week after onset of ischemia, oligodendrocytes were found to be accumulated in the intact area bordered with the infarct together with reactive astrocytes. Conclusions--Our results suggest the importance of amoeboid microglia, macrophages, and their interleukin-1 production in gradual expansion of cerebral infarction. Resident oligodendrocytes may be resistant to ischemic insults, and oligodendrocytes accumulated at the border of the infarction may participate in tissue repair after cerebral infarction.
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