FGF-2 Attenuates Neuronal Apoptosis via FGFR3/PI3k/Akt Signaling Pathway After Subarachnoid Hemorrhage

Takeshi Okada, Budbazar Enkhjargal, Zachary D. Travis, Umut Ocak, Jiping Tang, Hidenori Suzuki, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Neuronal apoptosis is a common and critical pathology following subarachnoid hemorrhage (SAH). We investigated the anti-apoptotic property of fibroblast growth factor (FGF)-2 after SAH in rats. A total of 289 rats underwent endovascular perforation to induce SAH or sham operation. Three dosages (3, 9, or 27 μg) of recombinant FGF-2 (rFGF-2) or vehicle was administered intranasally to rats 30 min after SAH induction. The pan-FGF receptor (FGFR) inhibitor PD173074 or vehicle was administered intracerebroventricularly (i.c.v.) 1 h before modeling, in addition to rFGF-2 treatment. Small interfering ribonucleic acid (siRNA) for FGFR1 and FGFR3 or scrambled siRNA was administered i.c.v. 48 h before SAH induction in addition to rFGF-2 treatment. Anti-FGF-2 neutralizing antibody or normal mouse immunoglobulin G (IgG) was administered i.c.v. 1 h before SAH model. Neurobehavioral tests, SAH severity, brain water content, immunofluorescence, Fluoro-Jade C, TUNEL staining, and western blot were evaluated. The expression of FGF-2, FGFR1, and FGFR3 increased after SAH. FGFR1 and FGFR3 were expressed in the neurons. Nine micrograms of FGF-2 alleviated neurological impairments, brain edema, and neuronal apoptosis following SAH. A rFGF-2 treatment improved motor skill learning and spatial memory and increased the number of surviving neurons postinjury to 28 days after SAH. PD173074 abolished the anti-apoptotic effects of rFGF-2 via suppression of the expression of PI3k, phosphorylated Akt (p-Akt), and Bcl-2 leading to enhancement of the expression of Bax. FGFR3 siRNA worsened neurobehavioral function and suppressed the expression of PI3k, p-Akt, and Bcl-2 rather than FGFR1 siRNA in SAH rats treated with rFGF-2. Anti-FGF-2 neutralizing antibody suppressed the expression of PI3k and p-Akt after SAH. FGF-2 may be a promising therapy to reduce post-SAH neuronal apoptosis via activation of the FGFR3/PI3k/Akt signaling pathway.

Original languageEnglish
Pages (from-to)8203-8219
Number of pages17
JournalMolecular Neurobiology
Volume56
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus Subject Areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Keywords

  • Akt
  • Early brain injury
  • Fibroblast growth factor receptor 3
  • Fibroblast growth factor-2
  • Neuronal apoptosis
  • Subarachnoid hemorrhage
  • Injections, Intravenous
  • Apoptosis/drug effects
  • Phosphatidylinositol 3-Kinases/metabolism
  • Rats
  • Male
  • Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors
  • Neurons/drug effects
  • Random Allocation
  • Administration, Intranasal
  • Rats, Sprague-Dawley
  • Signal Transduction/drug effects
  • Dose-Response Relationship, Drug
  • Animals
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors
  • Fibroblast Growth Factor 2/administration & dosage
  • Recombinant Proteins/administration & dosage
  • Subarachnoid Hemorrhage/drug therapy

Cite this