Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
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J. Cereb. Blood Flow Metab. · May 2010
Absence of the alpha v beta 3 integrin dictates the time-course of angiogenesis in the hypoxic central nervous system: accelerated endothelial proliferation correlates with compensatory increases in alpha 5 beta 1 integrin expression.
Cerebral angiogenesis is an important adaptive response to hypoxia. As the alpha v beta 3 integrin is induced on angiogenic vessels in the ischemic central nervous system (CNS), and the suggested angiogenic role for this integrin in other systems, it is important to determine whether the alpha v beta 3 integrin is an important mediator of cerebral angiogenesis. alpha v beta 3 integrin expression was examined in a model of cerebral hypoxia, in which mice were subject to hypoxia (8% O(2)) for 0, 4, 7, or 14 days. Immunofluorescence and western blot analysis revealed that in the hypoxic CNS, alpha v beta 3 integrin was strongly induced on angiogenic brain endothelial cells (BEC), along with its ligand vitronectin. ⋯ However, early in the angiogenic process, BEC in these mice showed an increased mitotic index that correlated closely with increased alpha 5 integrin expression. In vitro experiments confirmed alpha 5 integrin upregulation on beta 3 integrin-null BEC, which also correlated with increased BEC proliferation on fibronectin. These studies confirm hypoxic induction of alpha v beta 3 integrin on angiogenic vessels, but suggest distinct roles for the BEC integrins alpha v beta 3 and alpha 5 beta 1 in cerebral angiogenesis, with alpha v beta 3 having a nonessential role, and alpha 5 beta 1 promoting BEC proliferation.
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J. Cereb. Blood Flow Metab. · May 2010
Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents.
Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. ⋯ The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.
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J. Cereb. Blood Flow Metab. · Apr 2010
Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice.
Cerebral inflammation involves molecular cascades contributing to progressive damage after traumatic brain injury (TBI). The chemokine CC ligand-2 (CCL2) (formerly monocyte chemoattractant protein-1, MCP-1) is implicated in macrophage recruitment into damaged parenchyma after TBI. This study analyzed the presence of CCL2 in human TBI, and further investigated the role of CCL2 in physiological and cellular mechanisms of secondary brain damage after TBI. ⋯ We found that CCL2-/- mice showed altered production of multiple cytokines acutely (2 to 24 h); however, this did not affect lesion size or cell death within the first week after CHI. In contrast, by 2 and 4 weeks, a delayed reduction in lesion volume, macrophage accumulation, and astrogliosis were observed in the injured cortex and ipsilateral thalamus of CCL2-/- mice, corresponding to improved functional recovery as compared with wild-type mice after CHI. Our findings confirm the significant role of CCL2 in mediating post-traumatic secondary brain damage.
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J. Cereb. Blood Flow Metab. · Apr 2010
ReviewGenetic determinants of cerebral vasospasm, delayed cerebral ischemia, and outcome after aneurysmal subarachnoid hemorrhage.
Despite extensive effort to elucidate the cellular and molecular bases for delayed cerebral injury after aneurysmal subarachnoid hemorrhage (aSAH), the pathophysiology of these events remains poorly understood. Recently, much work has focused on evaluating the genetic underpinnings of various diseases in an effort to delineate the contribution of specific molecular pathways as well as to uncover novel mechanisms. The majority of subarachnoid hemorrhage genetic research has focused on gene expression and linkage studies of these markers as they relate to the development of intracranial aneurysms and their subsequent rupture. ⋯ The suspected genes are diverse and encompass multiple functional systems including fibrinolysis, inflammation, vascular reactivity, and neuronal repair. To this end, we present a systematic review of 21 studies suggesting a genetic basis for clinical outcome after aSAH, with a special emphasis on the pathogenesis of cerebral vasospasm and delayed cerebral ischemia. In addition, we highlight potential pitfalls in the interpretation of genetic association studies, and call for uniformity of design of larger multicenter studies in the future.
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J. Cereb. Blood Flow Metab. · Apr 2010
Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury.
Chronic brain atrophy after traumatic brain injury (TBI) is a well-known phenomenon, the causes of which are unknown. Early nonischemic reduction in oxidative metabolism is regionally associated with chronic brain atrophy after TBI. A total of 32 patients with moderate-to-severe TBI prospectively underwent positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) within the first week and at 6 months after injury. ⋯ The extent of regional brain atrophy correlated best with CMRO(2) and CBF. Lobar values of OEF were not in the ischemic range and did not correlate with chronic brain atrophy. Chronic brain atrophy is regionally specific and associated with regional reductions in oxidative brain metabolism in the absence of irreversible ischemia.