Fingolimod confers neuroprotection through activation of Rac1 after experimental germinal matrix hemorrhage in rat pups

William B. Rolland, Paul R. Krafft, Tim Lekic, Damon Klebe, Julia LeGrand, Abby Jones Weldon, Liang Xu, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals killed at 4 weeks post-GMH received low- or high-dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals killed at 72 h post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 h post-surgery. At 72 h post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 h post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway.

Original languageEnglish
Pages (from-to)776-786
Number of pages11
JournalJournal of Neurochemistry
Volume140
Issue number5
DOIs
StatePublished - Mar 1 2017

ASJC Scopus Subject Areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Keywords

  • behavior
  • blood–brain barrier
  • brain edema
  • fingolimod
  • germinal matrix hemorrhage
  • neuroprotection
  • Male
  • Brain Edema/drug therapy
  • Brain/pathology
  • Tight Junction Proteins/metabolism
  • Female
  • Leukocyte Count
  • Phosphoserine/analogs & derivatives
  • Pyrones/pharmacology
  • Rats
  • Thiophenes/pharmacology
  • Neuroprotective Agents/pharmacology
  • Rats, Sprague-Dawley
  • Intracranial Hemorrhages/drug therapy
  • Pregnancy
  • Quinolines/pharmacology
  • Animals
  • Body Water/metabolism
  • Fingolimod Hydrochloride/pharmacology
  • Cognition/drug effects
  • Brain Chemistry/drug effects
  • Oxadiazoles/pharmacology
  • rac1 GTP-Binding Protein/antagonists & inhibitors

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