title: Crotalus helleri venom preconditioning reduces postoperative cerebral edema and improves neurological outcomes after surgical brain injury.
abstract: BACKGROUND
  Postoperative cerebral edema is a devastating complication in neurosurgical patients. Loss of blood-brain barrier integrity has been shown to lead to the development of brain edema following neurosurgical procedures. The aim of this study was to evaluate preconditioning with Crotalus helleri venom (Cv-PC) as a potential preventive therapy for reducing postoperative brain edema in the rodent SBI model. C. helleri venom is known to contain phospholipase A2 (PLA2), an enzyme upstream to cyclooxygenase-2 (COX-2) in the inflammatory cascade, acts to increase the production of inflammatory mediators, such as prostaglandins. We hypothesize that Cv-PC will downregulate the response of the COX-2 pathway to injury, thereby reducing the inflammatory response and the development of brain edema after SBI.
  
  
  METHODS
  75 male Sprague Dawley rats (280-330g) were divided to the following groups-naïve+vehicle, naïve+Cv-PC, sham, vehicle, Cv-PC, Cv-PC+NS398 (COX-2 inhibitor). Vehicle preconditioned and Cv-PC animals received either three daily subcutaneous doses of saline or C. helleri venom at 72h, 48h, and 24h prior to surgery. In Cv-PC+NS398 animals, NS398 was administered intraperitoneally 1h prior to each Cv-PC injection. Sham-operated animals received craniotomy only, whereas SBI animals received a partial right frontal lobectomy. Neurological testing and brain water content were assessed at 24h and 72h after SBI; COX-2 and PGE2expression was assessed at 24h postoperatively by Western blot and immunohistochemistry, respectively.
  
  
  RESULTS
  At 24h after SBI, the vehicle-treated animals were observed to have increased brain water content (83.1±0.2%) compared to that of sham animals (80.2±0.1%). The brain water content of vehicle-treated animals at 72h post-SBI was elevated at 83.3±0.2%. Cv-PC-treated animals with doses of 10% LD50had significantly reduced brain water content of 81.92±0.7% and 81.82±0.3% at 24h and 72h, respectively, after SBI compared to that of vehicle-treated animals, while Cv-PC with 5% LD50doses showed brain water content that trended lower but did not reach statistical significance. At 24h and 72h post-SBI, Cv-PC-treated animals had significantly higher neurological score than vehicle-treated animals. The COX-2 over-expression characterized in SBI was attenuated in Cv-PC-treated animals; NS398 reversed the protective effect of Cv-PC on COX-2 expression. Cv-PC tempered the over-expression of the inflammatory marker PGE2.
  
  
  CONCLUSIONS
  Our findings indicate that Cv-PC may provide a promising therapy for reducing postoperative edema and improving neurological function after neurosurgical procedures.
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Cherine H
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Devin W
authors.initials: DW
authors.lastname: McBride
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Prativa
authors.initials: P
authors.lastname: Sherchan
authors.affiliation: Department of Earth and Biological Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Person
authors.affiliation: Department of Earth and Biological Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Eric C K
authors.initials: ECK
authors.lastname: Gren
authors.affiliation: Department of Earth and Biological Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Kelln
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.affiliation: Department of Earth and Biological Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Hayes
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: jhzhang@llu.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001834:Body Water / Q000187:drug effects; D001921:Brain / Q000601:surgery*; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017839:Crotalus; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005625:Frontal Lobe / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000601:surgery; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007431:Intraoperative Complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D019635:Neurosurgical Procedures; D009578:Nitrobenzenes / Q000494:pharmacology; D011183:Postoperative Complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D012910:Snake Venoms / Q000008:administration & dosage*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D012910:Snake Venoms; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone
keywords: Brain edema; Cerebral edema; Crotalus helleri; Preconditioning; Rattlesnake venom; Surgical brain injury