Reducing Stroke Damage in the Brain

描述(由申请人提供)： 大量证据表明，神经通路可能调节大脑血流量。我们的实验室已经定义了一种这样的通路，它为脑血管提供副交感神经支配。我们已经证明，激活该通路会产生脑血管扩张，而阻断该通路则会对抗通常发生在急性高血压期间的血管扩张。其他研究表明，这条通路的神经节纤维合成并向脑血管释放一氧化氮，我们已经证明，来自该通路的一氧化氮可以引起脑血管扩张。阻断这一通路中的副交感神经会在脑缺血期间对大脑造成明显更大的损害，而电刺激这一通路可以减少中风造成的损害。我们在这里测试的假设是，副交感神经节神经中神经元型一氧化氮合酶的上调将缩小脑梗塞体积，并将提供对中风的长期神经保护。我们的实验室已经做好了充分准备来探索这一假说，因为它已经开发出了这样做的分子工具，并已经开发出强有力的初步证据来支持这一假说。据报道，通过直接刺激大脑深部核团，神经介导的中风保护作用，但这种方法需要侵入性手术或在中风患者的大脑中立体定向放置刺激电极。拟议的研究将使方法可行，可以提供类似的保护，但方法将是微创的，并有望减少受影响患者的梗塞负担，从而降低康复的成本和强度，以及社会的总体成本。证实上调脑血管副交感神经支配的神经传递可以减少脑缺血造成的损害，将为补充现有的治疗中风的方法提供一种新的手段。这些办法的效力有限，应用的机会也有限。增强负责任递质的合成和随之而来的梗死体积的减少将直接适用于老年老兵人口，这增加了中风的风险。我们预计，拟议研究的成功结果将导致包括这一老兵群体的转化性研究。

DESCRIPTION (provided by applicant): Considerable evidence suggests that neural pathways may modulate cerebral blood flow. Our laboratory has defined one such pathway, which provides parasympathetic innervation to cerebral vessels. We have shown that activation of the pathway produces cerebral vasodilatation while interruption of the pathway counters vasodilatation that normally occurs during acute hypertension. Others have shown that ganglionic fibers of this pathway synthesize and release nitric oxide onto cerebral vessels and we have shown that nitric oxide from the pathway elicits cerebral vasodilatation. Interrupting parasympathetic nerves in this pathway leads to significantly greater volumes of damage to the brain during cerebral ischemia and electrically stimulating the pathway reduces damage from stroke. The hypothesis we test here is that "upregulation" of neuronal nitric oxide synthase in the parasympathetic ganglionic nerves will attenuate infarct volume and will provide long-lasting neuroprotection from stroke. Our laboratory is well poised to pursue this hypothesis in its having developed molecular tools to do so and in having developed strong preliminary evidence that supports the hypothesis. Neurally mediated protection from stroke has been reported with direct stimulation of deep brain nuclei but that approach requires either invasive surgery or stereotactic placement of stimulating electrodes into the brain in patients who have sustained a stroke. The approach that would be made feasible by the proposed studies could afford similar protection but through an approach that would be minimally invasive and holds promise to reduce infarct burden to affected patients thus reducing costs and intensity of rehabilitation and overall costs to society. Establishing that upregulation of neurotransmission in the parasympathetic innervation of cerebral vessels may reduce damage produced by cerebral ischemia would provide a novel means of complementing existing therapeutic approaches to the treatment of stroke. Those approaches are limited in their efficacy and in the window of opportunity for their application. Enhanced synthesis of responsible transmitters and attendant reduction in infarct volume would be directly applicable in the aging Veteran population, which carries increased risk of stroke. We anticipate that successful results from the proposed studies will lead to translational studies that would include that Veteran population.