Ferulic acid ameliorates cerebral infarction by activating Akt/mTOR/4E‑BP1/Bcl‑2 anti‑apoptotic signaling in the penumbral cortex following permanent cerebral ischemia in rats.
The aim of the present study was to determine the effects of ferulic acid (FerA) administered immediately following the onset of permanent middle cerebral artery occlusion (MCAo) and then 7 days of ischemia, and also to explore the involvement of protein kinase B (Akt)‑induced signaling in the penumbral cortex. Immediately following the onset of MCAo, FerA was intravenously administered to rats at a dose of 60 mg/kg (FerA‑60 mg), 80 mg/kg (FerA‑80 mg), or 100 mg/kg (FerA‑100 mg). FerA‑80 mg and FerA‑100 mg effectively ameliorated cerebral infarction and neurological deficits 7 days following permanent cerebral ischemia. FerA‑80 mg and FerA‑100 mg significantly upregulated the expression of phospho‑Akt (p‑Akt), phospho‑mammalian target of rapamycin (p‑mTOR), and eukaryotic initiation factor 4E (eIF4E)‑binding protein 1 (4E‑BP1), and the phospho‑4E‑BP1 (p‑4E‑BP1)/4E‑BP1 and mitochondrial Bcl‑2/Bax ratios, and markedly downregulated the levels of cytochrome c‑, cleaved caspase‑3‑, and terminal deoxynucleotidyl transferase‑mediated dUTP‑biotin nick‑end labeling‑immunoreactive cells in the penumbral cortex at 7 days post‑ischemia. LY294002, a selective inhibitor of phosphoinositide 3‑kinase/Akt signaling, was administered 30 min prior to ischemia, which abrogated the upregulating effects of FerA‑100 mg on the expression of p‑Akt, p‑mTOR, 4E‑BP1, p‑4E‑BP1 and eIF4E, the mitochondrial Bcl‑2/Bax ratio and the ameliorating effect of FerA‑100 mg on cerebral infarction. FerA administered at doses of 80 and 100 mg/kg exerted beneficial effects against cerebral ischemia by activating Akt‑induced signaling. The effects of FerA at doses of 80 and 100 mg/kg on mitochondrial B‑cell lymphoma-2 (Bcl‑2)‑associated X protein‑related apoptosis were attributed to the activation of Akt/mTOR/4E‑BP1/Bcl‑2 anti‑apoptotic signaling, and eventually contributed to suppression of the cytochrome c/caspase‑3 activation pathway in the penumbral cortex 7 days following permanent cerebral ischemia.
['Cheng|Chin-Yi|CY|', 'Kao|Shung-Te|ST|', 'Lee|Yu-Chen|YC|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D017209:Apoptosis D002545:Brain Ischemia D002540:Cerebral Cortex D003373:Coumaric Acids D015536:Down-Regulation D008297:Male D058539:Phosphatidylinositol 3-Kinase D051057:Proto-Oncogene Proteins c-akt D019253:Proto-Oncogene Proteins c-bcl-2 D051381:Rats D017207:Rats, Sprague-Dawley D015427:Reperfusion Injury D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases D015854:Up-Regulation
ferulic acid cerebral ischemia apoptosis protein kinase B mammalian  target  of  rapamycin eukaryotic  initiation  factor 4E-binding protein 1