Functional activation during cerebral ischemia

描述（由申请人提供）：在正常情况下，功能刺激导致脑血流量（CBF）局部增加，称为“激活-流量耦合”（AFC）。虽然人们通常认为需要局部CBF增加来提供氧气和营养，但对功能激活响应的大脑能量代谢的研究表明，局部CBF的增加超过了代谢，而且最近的数据证实，脑血流变化不受糖酵解或氧化需求的调节。另外，血流效应可以与脑激活解耦，而不会损失至少电生理响应。我们实验室的研究表明，AFC反应在由各种病理生理条件（包括轻度和重度缺血）和茶碱、乙酰唑胺和CO2对CBF的药理学调节引起的广泛基线流量值范围内保持不变。这些数据表明，AFC可能是由一个独立的机制比调节基线CBF介导的。我们将在分级缺血期间检查AFC，并假设AFC反应依赖于残余神经活动，并与体感诱发电位相关。初步数据表明，在MCA卒中的大鼠细丝模型中，功能性前爪刺激对侧而非同侧缺血半球具有神经保护作用。我们提出了一系列的研究，以检查功能刺激对脑血流，氧代谢和缺血性损伤的影响，在急性大脑中动脉卒中，以更好地表征功能刺激对脑血管病理生理学，脑损伤和神经功能的影响，在大鼠。假设功能性前爪刺激改善局灶性前脑缺血的结果，因为AFC反应通过侧支血流源产生增量CBF增加，超过刺激的代谢需求。将光学监测CBF和血氧的变化，并根据这些参数计算氧代谢的变化。公共卫生相关性：尽管经过多年的研究，中风的治疗方法还没有得到证实。该项目将表征和扩展大鼠中令人兴奋的初步数据，这些数据表明在缺血期间的功能刺激减少了随后对大脑的损伤。使用功能性刺激治疗中风具有明显的转化潜力。

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.