Crotalus Snake Venom Preconditioning to Prevent Surgical Brain Injury

响尾蛇蛇毒预处理可预防外科脑损伤

• 批准号: 8809374
• 负责人: John H Zhang
• 金额: $ 34.56万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8809374
• 关键词: Adverse effects; Anabolism; Applications Grants; Arachidonic Acids; Attenuated; Biochemical; Brain; Brain Edema; Brain Injuries; Brain hemorrhage; Cleaved cell; Clinic; Coagulation Process; Crotalus; Data; Diagnostic; Disease; Dose; Edema; Electrocoagulation; Enzymes; Fibrinogen; Functional disorder; Generations; Goals; Health Care Costs; Hemorrhage; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Measures; Mediating; Medical; Membrane; Metalloproteases; Modeling; Molecular; Nature; Nervous System Physiology; Neurologic; Neurological outcome; Neurosurgical Procedures; Operative Surgical Procedures; Outcome; PTGS2 gene; Patients; Perioperative Care; Phospholipase; Phospholipids; Plasma; Postoperative Period; Prevention; Property; Prostaglandins; Proteins; Rattus; Reactive Oxygen Species; Severities; Signal Pathway; Snake Venoms; Stimulus; Surgical incisions; Therapeutic Effect; Time; Tissues; Toxic effect; Trauma; Venoms; Water; cost; cytokine; improved; interest; preconditioning; prevent; public health relevance; response; treatment effect

DESCRIPTION (provided by applicant): Over 200 million major elective surgeries are performed worldwide per year. With the rising costs of healthcare, preventative measures grow increasingly relevant to medical practice. Preconditioning (PC), a preemptive therapy in which mildly harmful stimuli are administered to induce endogenous protective mechanisms prior to major injury, has shown to be protective in many injury models. Given the elective nature of most neurosurgical procedures, the surgical brain injury (SBI) model is an ideal platform for PC. In SBI, collateral damage to healthy tissue caused by neurosurgical maneuvers-incision, retraction, and electrocoagulation-result in brain edema and hemorrhage. We propose PC with small doses of Crotalus snake venom, known for their inflammatory and hemorrhagic effects, to increase tolerance to SBI. Crotalus venoms contain two proteins of interest to SBI PC: phospholipase 2 (PLA2), an enzyme upstream to COX-2 in the inflammatory cascade, and snake venom metalloproteinase (sMMP), an enzyme with hemorrhagic effects. Crotalus venoms have been studied for diagnostic capabilities as well as therapeutic effects in coagulative disorders; and will soon be a new avenue of therapy for SBI by utilizing their toxic properties to preemptively upregulate the endogenous response to inflammatory and hemorrhagic injury. Our central hypothesis is that PC with Crotalus venom (CV-PC) will temper the severity of SBI by inducing innate tolerance to injury. This premise is supported by our preliminary data, which demonstrate that CV-PC reduces brain edema and hemorrhage, and improves neurological function 24 hrs after SBI in rats. We propose to systematically examine the effects of and investigate the molecular mechanisms for CV-PC. In our first aim, we will evaluate brain edema and hemorrhage for CV-PC, and determine optimal dosing and toxicity of CV-PC. We expect that CV-PC will reduce the brain edema, hemorrhage, and neurological deficits that result from SBI. In our second aim, we will examine the expression of inflammatory mediators after SBI, evaluate the effects of antagonizing PLA2 and COX-2 while administering CV-PC, and administer PLA2 as a preconditioning treatment in SBI. We expect that CV-PC produces neuroprotective effects for SBI through the PLA2/COX-2 inflammatory signaling pathway. In our third aim, we will measure plasma fibrinogen and fibrinogen degradation products, determine coagulative parameters, and evaluate the effects of antagonizing sMMP in CV-PC. We expect CV- PC reduces hemorrhage in SBI via its fibrinogenolytic activity. Our long-term goal is to develop an effective, preemptive therapy for SBI. Our proposal aims to establish a better mechanistic understanding of SBI that will facilitate the application of preconditioning therapies in the clinic. If successful, this proposal will improve patient outcome and decrease costs of perioperative care for neurosurgical patients and could prove beneficial in other major elective surgeries as well.

描述（由申请人提供）：全世界每年进行超过 2 亿例大型择期手术。随着医疗保健成本的不断上升，预防措施与医疗实践的相关性越来越大。预处理（PC）是一种先发制人的疗法，在严重损伤之前给予轻微有害的刺激以诱导内源性保护机制，已证明在许多损伤模型中具有保护作用。鉴于大多数神经外科手术的选择性性质，外科脑损伤 (SBI) 模型是 PC 的理想平台。在 SBI 中，神经外科操作（切开、牵开和电凝）对健康组织造成附带损伤，导致脑水肿和出血。我们建议在 PC 中加入小剂量的响尾蛇蛇毒（以其炎症和出血作用而闻名），以增加对 SBI 的耐受性。响尾蛇毒液含有 SBI PC 感兴趣的两种蛋白质：磷脂酶 2 (PLA2)（炎症级联中 COX-2 上游的一种酶）和蛇毒金属蛋白酶 (sMMP)（一种具有出血作用的酶）。人们已经研究了响尾蛇毒液的诊断能力以及对凝血障碍的治疗作用。通过利用其毒性特性先发制人地上调对炎症和出血性损伤的内源性反应，很快将成为 SBI 治疗的新途径。我们的中心假设是含有响尾蛇毒液的 PC (CV-PC) 会通过诱导对损伤的先天耐受来减轻 SBI 的严重程度。我们的初步数据支持了这一前提，这些数据表明 CV-PC 可以减少大鼠 SBI 后 24 小时的脑水肿和出血，并改善神经功能。我们建议系统地检查 CV-PC 的影响并研究其分子机制。我们的第一个目标是评估 CV-PC 的脑水肿和出血，并确定 CV-PC 的最佳剂量和毒性。我们预计 CV-PC 将减少 SBI 引起的脑水肿、出血和神经​​功能缺损。在我们的第二个目标中，我们将检查 SBI 后炎症介质的表达，评估在施用 CV-PC 时拮抗 PLA2 和 COX-2 的效果，并在 SBI 中施用 PLA2 作为预处理治疗。我们预计 CV-PC 通过 PLA2/COX-2 炎症信号通路对 SBI 产生神经保护作用。在我们的第三个目标中，我们将测量血浆纤维蛋白原和纤维蛋白原降解产物，确定凝血参数，并评估 CV-PC 中拮抗 sMMP 的效果。我们预计 CV-PC 通过其纤维蛋白原溶解活性减少 SBI 出血。我们的长期目标是开发一种有效的、先发制人的 SBI 治疗方法。我们的建议旨在建立对 SBI 更好的机制理解，这将有助于预处理疗法在临床中的应用。如果成功，该提议将改善患者的治疗效果并降低神经外科患者的围手术期护理成本，并且也可能对其他主要择期手术有益。