Neurobiology of Disease (Nov 2017)
Crotalus helleri venom preconditioning reduces postoperative cerebral edema and improves neurological outcomes after surgical brain injury
Abstract
Introduction: 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. Materials and methods: 75 male Sprague Dawley rats (280–330 g) 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 72 h, 48 h, and 24 h prior to surgery. In Cv-PC + NS398 animals, NS398 was administered intraperitoneally 1 h 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 24 h and 72 h after SBI; COX-2 and PGE2 expression was assessed at 24 h postoperatively by Western blot and immunohistochemistry, respectively. Results: At 24 h 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 72 h post-SBI was elevated at 83.3 ± 0.2%. Cv-PC-treated animals with doses of 10% LD50 had significantly reduced brain water content of 81.92 ± 0.7% and 81.82 ± 0.3% at 24 h and 72 h, respectively, after SBI compared to that of vehicle-treated animals, while Cv-PC with 5% LD50 doses showed brain water content that trended lower but did not reach statistical significance. At 24 h and 72 h 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. Conclusion: Our findings indicate that Cv-PC may provide a promising therapy for reducing postoperative edema and improving neurological function after neurosurgical procedures.
