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: 8901321
• 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/8901321
• 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; 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; 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）：全球每年进行超过2亿例重大择期手术。随着医疗保健成本的上升，预防措施与医疗实践的相关性越来越大。预处理（PC）是一种先发制人的治疗方法，在严重损伤之前给予轻度有害的刺激以诱导内源性保护机制，已被证明在许多损伤模型中具有保护作用。考虑到大多数神经外科手术的选择性，外科脑损伤（SBI）模型是PC的理想平台。在SBI中，神经外科手术（切开、牵开和电凝）对健康组织造成的附带损害导致脑水肿和出血。我们建议PC与小剂量的响尾蛇蛇毒，其炎症和出血作用，以增加耐受性SBI。响尾蛇毒液含有两种SBI PC感兴趣的蛋白质：磷脂酶2（PLA 2），一种炎症级联反应中考克斯-2上游的酶，和蛇毒金属蛋白酶（sMMP），一种具有出血作用的酶。响尾蛇毒液已被研究的诊断能力，以及在凝血功能障碍的治疗效果，并将很快成为一个新的途径，治疗SBI的利用其毒性，预先上调内源性反应的炎症和出血性损伤。我们的中心假设是，PC与响尾蛇毒液（CV-PC）将缓和SBI的严重性，诱导先天性耐受损伤。这一前提得到了我们初步数据的支持，这些数据表明CV-PC减少了脑水肿和出血，并改善了大鼠SBI后24小时的神经功能。我们建议系统地检查CV-PC的影响，并探讨其分子机制。在我们的第一个目标中，我们将评估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将减少脑水肿，出血和神经功能缺损，由SBI。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的同时拮抗PLA 2和考克斯-2的效果，并施用PLA 2作为SBI的预处理。我们预期CV-PC通过PLA 2/考克斯-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。我们认为CV-PC可能通过其纤溶活性减少SBI的出血.我们的长期目标是开发一种有效的，先发制人的治疗SBI。我们的建议旨在建立一个更好的机制的理解SBI，将促进预处理治疗在临床上的应用。如果成功的话，这一建议将改善患者的预后，降低神经外科患者围手术期护理的成本，并可能证明在其他重大择期手术中也是有益的。