Functional activation during cerebral ischemia

描述（由申请人提供）：在正常情况下，功能性刺激导致脑血流量（CBF）的局部增加，称为“激活-流量耦合”（AFC）。虽然通常认为需要区域CBF增加来供应氧气和营养物质，但对脑功能激活的能量代谢的研究表明，区域CBF的增加是在代谢过剩的情况下增加的，而且最近的数据证实，脑血流的变化既不受糖酵解需求的调节，也不受氧化需求的调节。此外，血流效应可以从药理学上与脑激活分离，而不会损失至少电生理反应。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CBF的药理学调节（茶碱、乙酰唑胺和CO2）引起的广泛基线流量值范围内保持不变。这些数据表明，AFC可能是由一种独立的机制介导的，而不是调节基线CBF的机制。我们将在分级缺血时检查AFC，并假设AFC反应依赖于残留的神经活动，并与体感诱发电位相关。初步数据表明，对侧而非同侧刺激功能性前爪对脑缺血半球有神经保护作用。我们提出了一系列的研究来检查功能刺激对急性MCA卒中的CBF、氧代谢和缺血性损伤的影响，以更好地表征功能刺激对大鼠脑血管病理生理、脑损伤和神经预后的影响。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，超过了刺激的代谢需求。将光学监测CBF和血氧的变化，并从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，还没有证实中风的治疗方法。该项目将描述和扩展大鼠的令人兴奋的初步数据，表明缺血期间的功能刺激减少了随后对大脑的损伤。功能刺激治疗脑卒中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.