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

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 ?g) 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.

SUBMITTER: Okada T

PROVIDER: S-EPMC6842096 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Okada Takeshi T Enkhjargal Budbazar B Travis Zachary D ZD Ocak Umut U Tang Jiping J Suzuki Hidenori H Zhang John H JH

Molecular neurobiology 20190615 12

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 intra ...[more]

PMID: 31203572

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Project description:Numerous studies have elucidated the neuroprotective effect of 6-gingerol in central nervous system diseases. However, the potential role and mechanism of 6-gingerol on early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains poorly understood. Here, we report that 6-gingerol exerts a neuroprotective effect on SAH-induced EBI through the GBP2/PI3K/AKT pathway. A SAH rat model was established by injecting femoral artery blood into the cisterna magna. 6-gingerol or vehicle was injected intraperitoneally one hour post-SAH induction. We found that the neurological function score and brain edema of SAH rats were significantly improved after 6-gingerol treatment, as well as neuronal apoptosis was attenuated in SAH rats by Nissl staining assay and TUNEL assay. To further explore potential molecular mechanisms associated with 6-gingerol, RNA sequencing was implemented to investigate the differences in transcriptomes between SAH rats with and without 6-gingerol treatment; and found that the expression of guanylate-binding protein 2 (GBP2) evidently was suppressed with 6-gingerol treatment compared to vehicle group. In addition, dual immunofluorescence was also employed to investigate changes in neurons, astrocytes, and microglia after 6-gingerol treatment. The results showed that GBP2 was expressed in neurons but not astrocytes or microglia. Western blotting analysis results demonstrated that the PI3K/AKT pathway was activated in the SAH rats treated with 6-gingerol. Furthermore, recombinant GBP2 protein and LY294002 (PI3K inhibitor) treatment reversed the effects of 6-gingerol treatment in SAH rats. These results indicate that 6-gingerol suppressed the expression of GBP2 to activate the PI3K/AKT pathway, improve neurologic outcomes, reduce brain edema and neuronal apoptosis. In summary, our findings suggest that 6-gingerol could attenuate EBI post-SAH in rats, and 6-gingerol may serve as a novel candidate neuroprotective drug for SAH-induced EBI.

Dataset Information

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

Publications

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

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