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 language | English |
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Pages (from-to) | 8203-8219 |
Number of pages | 17 |
Journal | Molecular Neurobiology |
Volume | 56 |
Issue number | 12 |
DOIs | |
State | Published - 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