Low-level Laser Therapy in Global Cerebral Ischemia

低强度激光治疗全球性脑缺血

• 批准号: 8816362
• 负责人: Quanguang Zhang
• 金额: $ 33.05万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816362
• 关键词: Affect; American; Animal Model; Animals; Area; Brain; Cause of Death; Cerebral Ischemia; Cerebrum; Cessation of life; Cognitive deficits; Dose; Gene Expression; Goals; Heart Arrest; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; In Vitro; Inflammatory; Injury; Ischemic Brain Injury; Lasers; Lead; Light; Low-Level Laser Therapy; Membrane Potentials; Mitochondria; Neurons; Nitric Oxide; Pathway interactions; Phototherapy; Procedures; Production; Proteins; Reperfusion Therapy; SOD2 gene; Signal Transduction; Testing; Therapeutic; Time; United States; Work; base; cranium; disability; functional outcomes; improved; in vivo; interest; meetings; neuroprotection; oxidative damage; preclinical study; prevent; public health relevance

DESCRIPTION (provided by applicant): Transient global cerebral ischemia (GCI) during cardiac arrest affects 300,000 Americans each year, and in many cases, results in delayed death of hippocampal CA1 neurons and severe cognitive deficits. Current therapies are ineffective and only offer a short therapeutic window. Low-level Laser/Light Therapy (LLLT) is widely practiced by directly applying a low energy laser or light emitting diodes (LED) to a specific area of interest on the body. As a noninvasive procedure, the laser/light can penetrate the animal skull and brain to a depth of 2.5-3 cm. Our preliminary work in the GCI animal model has shown that LLLT 3 h after GCI strongly protects the CA1 pyramidal regions. This exciting observation has led to hope that further studies on the mechanisms underlying LLLT neuroprotection following GCI could potentially lead to new therapies in humans, which would allow rescue of hippocampal CA1 neurons in the human brain following cardiac arrest with an extended therapeutic window. The overall goal of the current proposal is to delineate the optimal wavelengths, doses, and time window of LLLT benefits, and to elucidate how LLLT protects the brain following GCI. We hypothesize that cerebral ischemic reperfusion induces ROS production and ATP overloading from dysfunctional mitochondria in neurons. This leads to subsequent enhanced oxidative damage and NLRP3 inflammasome cascade signaling, resulting in delayed CA1 neuronal death and cognitive deficits. LLLT is able to preserve mitochondrial integrity and membrane potential, blocking ROS production and ATP overloading. We propose that LLLT stimulates mitochondria-derived nitric oxide (NO) release to inhibit the activation of NLRP3 inflammasome (via S-nitrosylation of NLRP3) and to activate Nrf2 (via S-nitrosylation of Keap1 and Nrf2 release). We further hypothesize that LLLT can exert its beneficial actions by boosting Nrf2-regulated gene expression (e.g. Trx and SOD2) to counteract the NLRP3 inflammasome cascade and the oxidative damage induced by dysfunctional mitochondria after GCI. The proposed preclinical studies would advance the field by being the first to determine the potential efficacy of LLLT for protection of the brain following GCI. Specific Aim 1 would test the hypothesis that LLLT exerts neuroprotection and improves functional outcome after GCI. Specific Aim 2 would test the hypothesis that LLLT reduces ischemic oxidative damage and functional deficits via the activation of the Nrf2 pathway following GCI. Specific Aim 3 would test the hypothesis that LLLT prevents NLRP3 inflammasome activation by preserving mitochondrial integrity and promoting Nrf2-regulated gene expression.

描述（由申请人提供）：心脏骤停期间的短暂性脑缺血（GCI）每年影响30万美国人，在许多情况下，导致海马CA1神经元延迟死亡和严重的认知缺陷。目前的治疗方法是无效的，只提供一个短的治疗窗口。低能量激光/光疗（LLLT）是通过直接将低能量激光或发光二极管（LED）应用于身体的特定区域而广泛实践的。作为一种非侵入性手术，激光/光可以穿透动物的头骨和大脑2.5-3厘米的深度。我们在GCI动物模型中的初步工作表明，GCI后3小时LLLT对CA1锥体区域有很强的保护作用。这一令人兴奋的观察结果带来了希望，对GCI后LLLT神经保护机制的进一步研究可能会导致人类的新疗法，这将允许在心脏骤停后延长治疗窗口期来拯救人类大脑中的海马CA1神经元。当前提案的总体目标是描述LLLT益处的最佳波长，剂量和时间窗口，并阐明LLLT如何保护GCI后的大脑。我们假设脑缺血再灌注诱导神经元功能失调线粒体产生ROS和ATP超载。这导致随后氧化损伤和NLRP3炎性小体级联信号的增强，导致延迟的CA1神经元死亡和认知缺陷。LLLT能够保持线粒体完整性和膜电位，阻断ROS的产生和ATP过载。我们提出，LLLT刺激线粒体来源的一氧化氮（NO）释放，以抑制NLRP3炎性体的激活（通过NLRP3的s -亚硝基化），并激活Nrf2（通过Keap1的s -亚硝基化和Nrf2释放）。我们进一步假设，LLLT可以通过促进nrf2调控的基因表达（如Trx和SOD2）来抵消NLRP3炎性体级联反应和GCI后功能失调线粒体诱导的氧化损伤，从而发挥其有益作用。拟议的临床前研究将通过首次确定LLLT对GCI后大脑保护的潜在功效来推进该领域。特异性目的1将检验LLLT发挥神经保护作用并改善GCI后功能结局的假设。特异性目的2将验证低脂低脂通过激活GCI后Nrf2通路减少缺血性氧化损伤和功能缺陷的假设。具体目标3将测试