Progranulin reduced neuronal cell death by activation of sortilin 1 signaling pathways after subarachnoid hemorrhage in rats

Bo Li, Yue He, Liang Xu, Qin Hu, Junjia Tang, Yujie Chen, Jiping Tang, Hua Feng, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Progranulin has been reported to have neuroprotective actions in cultured neurons. This study investigated the effect of recombinant rat progranulin on early brain injury after subarachnoid hemorrhage. Design: Controlled in vivo laboratory study. Setting: Animal research laboratory. Subjects: Two hundred thirty adult male Sprague-Dawley rats weighing 280-320 g. Interventions: Subarachnoid hemorrhage was induced in rats by endovascular perforation. Rat recombinant progranulin (1 and 3 ng) was administrated intracerebroventricularly at 1.5 hours after subarachnoid hemorrhage. Progranulin small interfering RNA was administrated by intracerebroventricularly at 1 day before subarachnoid hemorrhage induction. Subarachnoid hemorrhage grade, neurologic score, and brain water content were measured at 24 and 72 hours after subarachnoid hemorrhage. Neural apoptosis was evaluated by double immunofluorescence staining using terminal deoxynucleotidyl transferase-mediated uridine 5?-triphosphate-biotin nick-end labeling and neuronal nuclei. For mechanistic study, the expression of progranulin, phosphorylated Akt, Akt, p-Erk, Erk, Bcl-2, and cleaved caspase-3 were analyzed by Western blot at 24 hours after subarachnoid hemorrhage. siRNA for sortilin 1 (a progranulin receptor) was used to intervene the downstream pathway. Measurements and Main Results: The expression of progranulin decreased and reached the lowest point at 24 hours after subarachnoid hemorrhage. Administration of rat recombinant progranulin decreased brain water content and improved neurologic functions at both 24 and 72 hours after subarachnoid hemorrhage, while knockdown of endogenous progranulin aggravated neurologic deficits after subarachnoid hemorrhage. Rat recombinant progranulin treatment reduced neuronal apoptosis, while progranulin deficiency promoted neuronal apoptosis at 24 hours after subarachnoid hemorrhage. Rat recombinant progranulin promoted Akt activation, increased Bcl-2 level, but reduced caspase-3 level. Knockdown of progranulin binding factor sortilin 1 abolished the beneficial effects of rat recombinant progranulin at 24 hours after subarachnoid hemorrhage. Conclusion: Rat recombinant progranulin alleviated neuronal death via sortilin 1-mediated and Akt-related antiapoptosis pathway. Rat recombinant progranulin may have potentials to ameliorate early brain injury for subarachnoid hemorrhage patients.

Original languageEnglish
Pages (from-to)e304-e311
JournalCritical Care Medicine
Volume43
Issue number8
DOIs
StatePublished - Aug 2015

ASJC Scopus Subject Areas

  • Critical Care and Intensive Care Medicine

Keywords

  • Akt
  • Early brain injury
  • Progranulin
  • Sortilin 1
  • Subarachnoid hemorrhage
  • Neurons/pathology
  • Signal Transduction
  • Apoptosis/drug effects
  • Rats
  • Male
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Neuroprotective Agents/pharmacology
  • Adaptor Proteins, Vesicular Transport/biosynthesis
  • Rats, Sprague-Dawley
  • Blotting, Western
  • Subarachnoid Hemorrhage/physiopathology
  • Animals
  • Cell Death/drug effects

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