Reducing Stroke Damage in the Brain

描述（由申请人提供）： 大量证据表明，神经通路可以调节脑血流。我们的实验室已经确定了这样一个途径，它提供了副交感神经支配脑血管。我们已经表明，激活的途径产生脑血管舒张，而中断的途径计数血管舒张，通常发生在急性高血压。其他人已经表明，这一途径的神经节纤维合成和释放一氧化氮到脑血管，我们已经表明，一氧化氮从途径eleventricular脑血管舒张。中断该通路中的副交感神经导致在脑缺血期间对脑的显著更大体积的损伤，并且电刺激该通路减少了来自中风的损伤。我们在此检验的假设是，副交感神经节神经中神经元型一氧化氮合酶的“上调”将减少梗死体积，并将提供长期的神经保护以防止中风。我们的实验室已经做好了充分的准备来追求这一假设，因为它已经开发了这样做的分子工具，并且已经开发了支持这一假设的强有力的初步证据。神经介导的中风保护已被报道与直接刺激脑深部核，但该方法需要侵入性手术或立体定向放置刺激电极到脑中的患者谁已经持续中风。通过拟议的研究可行的方法可以提供类似的保护，但通过微创方法，并有望减少受影响患者的梗死负担，从而降低康复的成本和强度以及社会的总体成本。确定脑血管的副交感神经支配中的神经传递的上调可以减少脑缺血产生的损伤，将提供补充现有治疗中风的治疗方法的新手段。这些方法的功效和应用机会都有限。负责递质合成的增强和伴随的梗死体积的减少将直接适用于老年退伍军人人群，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退伍军人人群的转化研究。

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.