Functional activation during cerebral ischemia

脑缺血期间的功能激活

• 批准号: 7772310
• 负责人: JOEL H GREENBERG
• 金额: $ 34.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772310
• 关键词: Acetazolamide; Acute; Address; Anesthetics; Animal Model; Animals; Blood; Blood flow; Brain; Brain Injuries; Carbon Dioxide; Cerebral Ischemia; Cerebrovascular Circulation; Clinical; Contralateral; Corpus striatum structure; Coupling; Data; Distal; Energy Metabolism; Exhibits; Filament; Functional disorder; Grant; Halothane; Infarction; Injury; Ipsilateral; Ischemia; Isoflurane; Laboratories; Lesion; Mediating; Metabolic; Metabolism; Modeling; Monitor; Neurological outcome; Nutrient; Outcome; Oxygen; Prosencephalon; Protocols documentation; Rattus; Research; Residual state; Series; Severities; Somatosensory Evoked Potentials; Source; Stroke; Suggestion; Theophylline; Translating; cerebrovascular; improved; neuroprotection; public health relevance; relating to nervous system; response

DESCRIPTION (provided by applicant): Under normal circumstances, functional stimulation results in a regional increase in cerebral blood flow (CBF) termed "activation-flow coupling" (AFC). While it is often assumed that a regional CBF increase is required to supply oxygen and nutrients, studies of brain energy metabolism in response to functional activation have demonstrated that regional CBF increases in excess of metabolism, and more recent data confirm that cerebral blood flow changes are not regulated by either glycolytic or oxidative demands. Additionally, blood flow effects can be pharmacologically decoupled from brain activation without loss of at least electrophysiological responses. Studies from our laboratory have demonstrated that the AFC response is preserved over a broad range of baseline flow values caused by a variety of pathophysiological conditions including mild and severe ischemia and pharmacological modulation of CBF with theophylline, acetazolamide, and CO2. This data suggest that AFC may be mediated by an independent mechanism than that which regulates baseline CBF. We will examine AFC during graded ischemia, and hypothesize that the AFC response is dependent on residual neural activity and is correlated with the somatosensory evoked potential. Preliminary data demonstrate a neuroprotective effect of functional forepaw stimulation contralateral but not ipsilateral to the ischemic hemisphere in the rat filament model of MCA stroke. We propose a series of studies to examine the effects of functional stimulation on CBF, oxygen metabolism, and ischemic injury in acute MCA stroke to better characterize the effects of functional stimulation on cerebrovascular pathophysiology, brain injury, and neurological outcome in rats. It is hypothesized that functional forepaw stimulation improves outcome from focal forebrain ischemia because the AFC response produces an incremental CBF increase through collateral flow sources that exceeds the metabolic demands of stimulation. Changes in CBF and blood oxygenation will be monitored optically, and changes in oxygen metabolism will be calculated from these parameters. PUBLIC HEALTH RELEVANCE: Despite many years of research, there are no proven treatments for stroke. This project will characterize and extend exciting preliminary data in the rat showing that functional stimulation during the period of ischemia reduces the subsequent damage to the brain. The use of functional stimulation as treatment for stroke has obvious translational potential.

描述（由申请人提供）：在正常情况下，功能刺激导致称为“激活流耦合”（AFC）的脑血流（CBF）的区域增加。虽然通常假定需要增加区域CBF来供应氧气和养分，但对响应功能激活的脑能量代谢的研究表明，局部CBF的代谢过量过多，并且最近的数据证实，脑血流变化均不受糖溶液或氧化性需求调节。另外，血流作用可以在药理学上与脑激活脱钩，而不会至少失去电生理反应。我们实验室的研究表明，在由多种病理生理条件引起的广泛基线流动值中，AFC反应保留了，包括轻度和严重的缺血和使用茶碱，乙酰唑胺和CO2对CBF的药理调节。该数据表明，与调节基线CBF的独立机制可以通过独立的机制介导。我们将在分级缺血期间检查AFC，并假设AFC反应取决于残留的神经活动，并且与体感诱发的潜力相关。初步数据表明，在MCA中风大鼠丝模型中，功能性前尾刺激对侧的功能性前尾刺激的神经保护作用。我们提出了一系列研究，以检查急性MCA中风中功能刺激对CBF，氧代谢和缺血性损伤的影响，以更好地表征大鼠功能刺激对脑血管病理生理学，脑损伤和神经系统结果的影响。假设功能性前言刺激可以改善局灶性前脑缺血的结果，因为AFC响应通过侧支流源超过刺激的代谢需求而产生的CBF增加。 CBF和血液氧合的变化将通过光学监测，氧代谢的变化将从这些参数中计算出来。公共卫生相关性：尽管进行了多年的研究，但仍未对中风进行可靠的治疗方法。该项目将表征和扩展大鼠中令人兴奋的初步数据，表明缺血期间功能刺激减少了随后对大脑的损害。使用功能刺激作为中风的治疗具有明显的翻译潜力。