title: Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Controlled in vivo laboratory study.
  
  
  METHODS
  Animal research laboratory.
  
  
  METHODS
  Two hundred thirty adult male Sprague-Dawley rats weighing 280-320 g.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.|Department of Neurosurgery, Jinan General Military Hospital, Jinan, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.|Department of Neurosurgery, Tongji Hospital, Wuhan, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.|Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.|Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Junjia
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.|Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, CA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D000099183:Sortilin