Multiple mechanisms underlying neuroprotection by secretory phospholipase A2 preconditioning in a surgically induced brain injury rat model

Yuechun Wang, Prativa Sherchan, Lei Huang, Onat Akyol, Devin W. McBride, John H. Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)30-40
Number of pages11
JournalExperimental Neurology
Volume300
DOIs
StatePublished - Feb 2018

ASJC Scopus Subject Areas

  • Neurology
  • Developmental Neuroscience

Keywords

  • Brain edema
  • Intra-operative hemorrhage
  • Neuroinflammation
  • Preconditioning
  • Surgical brain injury
  • sPLA2
  • Neuroprotective Agents/administration & dosage
  • Neurosurgical Procedures/adverse effects
  • Phospholipases A2, Secretory/administration & dosage
  • Inflammation Mediators/antagonists & inhibitors
  • Rats
  • Male
  • Brain Edema/drug therapy
  • Brain Injuries/etiology
  • Rats, Sprague-Dawley
  • Animals
  • Neuroprotection/drug effects
  • Blood Glucose/drug effects

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