Yuechun Wang1, Prativa Sherchan2, Lei Huang3, Onat Akyol2, Devin W McBride2, John H Zhang4. 1. Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Physiology, Jinan University School of Medicine, Guangzhou, Guangdong Province, China. 2. Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. 3. Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. 4. Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. Electronic address: jhzhang@llu.edu.
Abstract
BACKGROUND: Intra-operative bleeding, post-operative brain edema and neuroinflammation are major complications in patients with surgical brain injury (SBI). Phospholipase A2 (PLA2) is the upstream enzyme which initiates the PLA2, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4) inflammatory pathway. We hypothesized PLA2preconditioning (PPC) prior to SBI can activate endogenous anti-inflammatory responses to protect against SBI. This study evaluated if PPC can ameliorate neurosurgical complications and elucidated PPC-mediated possible protective mechanisms in a rat SBI model. METHODS: Total 105 adult male Sprague Dawley rats were used for this study. SBI was induced by partial resection of the right frontal lobe. PLA2 or 0.9% NaCl was injected via rats' tail vein for 3 consecutive days prior to SBI. For mechanism study, a selective PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton were injected intravenously with PPC to elucidate the role of PLA2 and 5-LOX in PPC-mediated anti-inflammatory effects. Brain water content (BWC) and lung water content, neurological tests, ELISA, western blot, immunohistochemistry, white blood cells (WBC) count, and spectrophotometric assay for intra-operative hemorrhage volume were evaluated. RESULTS: First, PPC reduced brain water content, intra-operative bleeding, and improved neurological function after SBI. Second, PPC decreased 5-LOX expression and brain leukocyte infiltration, while increasing glial fibrillary acidic protein (GFAP) expression in the peri-resection brain tissue after SBI. Third, PPC induced peripheral inflammation represented by mild pulmonary inflammation and increased peripheral blood WBC count and LTB4 level. Lastly, PPC increased blood glucose concentration and glucocorticoid levels after SBI. In addition, PPC mediated above-mentioned changes were partially reversed by administration of PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton. CONCLUSIONS: PPC conferred neuroprotection against SBI via multi-target involvement induced anti-inflammatory mechanisms.
BACKGROUND:Intra-operative bleeding, post-operative brain edema and neuroinflammation are major complications in patients with surgical brain injury (SBI). Phospholipase A2 (PLA2) is the upstream enzyme which initiates the PLA2, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4) inflammatory pathway. We hypothesized PLA2preconditioning (PPC) prior to SBI can activate endogenous anti-inflammatory responses to protect against SBI. This study evaluated if PPC can ameliorate neurosurgical complications and elucidated PPC-mediated possible protective mechanisms in a ratSBI model. METHODS: Total 105 adult male Sprague Dawley rats were used for this study. SBI was induced by partial resection of the right frontal lobe. PLA2 or 0.9% NaCl was injected via rats' tail vein for 3 consecutive days prior to SBI. For mechanism study, a selective PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton were injected intravenously with PPC to elucidate the role of PLA2 and 5-LOX in PPC-mediated anti-inflammatory effects. Brain water content (BWC) and lung water content, neurological tests, ELISA, western blot, immunohistochemistry, white blood cells (WBC) count, and spectrophotometric assay for intra-operative hemorrhage volume were evaluated. RESULTS: First, PPC reduced brain water content, intra-operative bleeding, and improved neurological function after SBI. Second, PPC decreased 5-LOX expression and brain leukocyte infiltration, while increasing glial fibrillary acidic protein (GFAP) expression in the peri-resection brain tissue after SBI. Third, PPC induced peripheral inflammation represented by mild pulmonary inflammation and increased peripheral blood WBC count and LTB4 level. Lastly, PPC increased blood glucose concentration and glucocorticoid levels after SBI. In addition, PPC mediated above-mentioned changes were partially reversed by administration of PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton. CONCLUSIONS:PPC conferred neuroprotection against SBI via multi-target involvement induced anti-inflammatory mechanisms.
Authors: F C Barone; L M Hillegass; M N Tzimas; D B Schmidt; J J Foley; R F White; W J Price; G Z Feuerstein; R K Clark; D E Griswold Journal: Mol Chem Neuropathol Date: 1995-01
Authors: E Caldenhoven; J Liden; S Wissink; A Van de Stolpe; J Raaijmakers; L Koenderman; S Okret; J A Gustafsson; P T Van der Saag Journal: Mol Endocrinol Date: 1995-04