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.

Public Health Relevance

Surgical brain injury (SBI) is the inevitable injury to the normal, yet susceptible brain that occurs during neurosurgical procedures. In this grant proposal, our objective is to reduce injury and improve neurological outcomes following SBI by eliciting the body's endogenous protective response with the administration of Crotalus snake venom prior to surgery.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Loma Linda University
Other Basic Sciences
Schools of Medicine
Loma Linda
United States
Zip Code
Sherchan, Prativa; Huang, Lei; Wang, Yuechun et al. (2016) Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model. Neurobiol Dis 85:164-73
Chen, Yujie; Li, Qiang; Tang, Jiping et al. (2015) The evolving roles of pericyte in early brain injury after subarachnoid hemorrhage. Brain Res 1623:110-22
McBride, Devin W; Wang, Yuechun; Sherchan, Prativa et al. (2015) Correlation between subacute sensorimotor deficits and brain water content after surgical brain injury in rats. Behav Brain Res 290:161-71
Chen, Yujie; Zhang, Yang; Tang, Junjia et al. (2015) Norrin protected blood-brain barrier via frizzled-4/β-catenin pathway after subarachnoid hemorrhage in rats. Stroke 46:529-36
Huang, Lei; Sherchan, Prativa; Wang, Yuechun et al. (2015) Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury. J Neurosci 35:10390-401
Tang, Junjia; Hu, Qin; Chen, Yujie et al. (2015) Neuroprotective role of an N-acetyl serotonin derivative via activation of tropomyosin-related kinase receptor B after subarachnoid hemorrhage in a rat model. Neurobiol Dis 78:126-33
Chen, Sheng; Chen, Yujie; Xu, Liang et al. (2015) Venous system in acute brain injury: Mechanisms of pathophysiological change and function. Exp Neurol 272:4-10
Chen, Sheng; Li, Qian; Wu, Haijian et al. (2014) The harmful effects of subarachnoid hemorrhage on extracerebral organs. Biomed Res Int 2014:858496