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

Cheng,Chin‑Yi; Kao,Shung‑Te; Lee,Yu‑Chen

doi:10.3892/mmr.2018.9737

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

Authors:
- Chin‑Yi Cheng
- Shung‑Te Kao
- Yu‑Chen Lee
View Affiliations

Affiliations: School of Post‑Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C., School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C., Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan, R.O.C.
Published online on: December 11, 2018 https://doi.org/10.3892/mmr.2018.9737
Pages: 792-804

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Cheng CY, Tang NY, Kao ST and Hsieh CL: Ferulic acid administered at various time points protects against cerebral infarction by activating p38 MAPK/p90RSK/CREB/Bcl-2 anti-apoptotic signaling in the subacute phase of cerebral ischemia-reperfusion injury in rats. PLoS One. 11:e01557482016. View Article : Google Scholar : PubMed/NCBI
2	Huang H, Zhong R, Xia Z, Song J and Feng L: Neuroprotective effects of rhynchophylline against ischemic brain injury via regulation of the Akt/mTOR and TLRs signaling pathways. Molecules. 19:11196–11210. 2014. View Article : Google Scholar : PubMed/NCBI
3	Wang M, Li YJ, Ding Y, Zhang HN, Sun T, Zhang K, Yang L, Guo YY, Liu SB, Zhao MG and Wu YM: Silibinin prevents autophagic cell death upon oxidative stress in cortical neurons and cerebral ischemia-reperfusion injury. Mol Neurobiol. 53:932–943. 2016. View Article : Google Scholar : PubMed/NCBI
4	Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, Ruan Y and Xu A: The neuroprotection of liraglutide against ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci Rep. 6:268592016. View Article : Google Scholar : PubMed/NCBI
5	Koh PO: Melatonin prevents ischemic brain injury through activation of the mTOR/p70S6 kinase signaling pathway. Neurosci Lett. 444:74–78. 2008. View Article : Google Scholar : PubMed/NCBI
6	Xie R, Cheng M, Li M, Xiong X, Daadi M, Sapolsky RM and Zhao H: Akt isoforms differentially protect against stroke-induced neuronal injury by regulating mTOR activities. J Cereb Blood Flow Metab. 33:1875–1885. 2013. View Article : Google Scholar : PubMed/NCBI
7	Maiese K, Chong ZZ, Wang S and Shang YC: Oxidant stress and signal transduction in the nervous system with the PI 3-K, Akt, and mTOR cascade. Int J Mol Sci. 13:13830–13866. 2012. View Article : Google Scholar : PubMed/NCBI
8	Wang C, Wang Z, Zhang X, Dong L, Xing Y, Li Y, Liu Z, Chen L, Qiao H, Wang L and Zhu C: Protection by silibinin against experimental ischemic stroke: Up-regulated pAkt, pmTOR, HIF-1alpha and Bcl-2, down-regulated Bax, NF-kappaB expression. Neurosci Lett. 529:45–50. 2012. View Article : Google Scholar : PubMed/NCBI
9	Wu C, Fujihara H, Yao J, Qi S, Li H, Shimoji K and Baba H: Different expression patterns of Bcl-2, Bcl-xl, and Bax proteins after sublethal forebrain ischemia in C57Black/Crj6 mouse striatum. Stroke. 34:1803–1808. 2003. View Article : Google Scholar : PubMed/NCBI
10	Chi OZ, Barsoum S, Vega-Cotto NM, Barsoum S, Vega-Cotto NM, Jacinto E, Liu X, Mellender SJ and Weiss HR: Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia. Neuroscience. 316:321–327. 2016. View Article : Google Scholar : PubMed/NCBI
11	Xie R, Wang P, Cheng M, Sapolsky R, Ji X and Zhao H: Mammalian target of rapamycin cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke. Stroke. 45:2769–2776. 2014. View Article : Google Scholar : PubMed/NCBI
12	Koh PO: Gingko biloba extract (EGb 761) prevents cerebral ischemia-induced p70S6 kinase and S6 phosphorylation. Am J Chin Med. 38:727–734. 2010. View Article : Google Scholar : PubMed/NCBI
13	Koh PO, Cho JH, Won CK, Lee HJ, Sung JH and Kim MO: Estradiol attenuates the focal cerebral ischemic injury through mTOR/p70S6 kinase signaling pathway. Neurosci Lett. 436:62–66. 2008. View Article : Google Scholar : PubMed/NCBI
14	Chong ZZ, Yao Q and Li HH: The rationale of targeting mammalian target of rapamycin for ischemic stroke. Cell Signal. 25:1598–1607. 2013. View Article : Google Scholar : PubMed/NCBI
15	Ayuso MI, Hernández-Jiménez M, Martin ME, Salinas M and Alcázar A: New hierarchical phosphorylation pathway of the translational repressor eIF4E-binding protein 1 (4E-BP1) in ischemia-reperfusion stress. J Biol Chem. 285:34355–34363. 2010. View Article : Google Scholar : PubMed/NCBI
16	Ayuso MI, Martinez-Alonso E, Cid C, Alonso de Leciñana M and Alcázar A: The translational repressor eIF4E-binding protein 2 (4E-BP2) correlates with selective delayed neuronal death after ischemia. J Cereb Blood Flow Metab. 33:1173–1181. 2013. View Article : Google Scholar : PubMed/NCBI
17	Xie R, Wang P, Ji X and Zhao H: Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats. J Neurochem. 127:723–732. 2013. View Article : Google Scholar : PubMed/NCBI
18	Koh PO: Ferulic acid modulates nitric oxide synthase expression in focal cerebral ischemia. Lab Anim Res. 28:273–278. 2012. View Article : Google Scholar : PubMed/NCBI
19	Zhang L, Wang H, Wang T, Jiang N, Yu P, Chong Y and Fu F: Ferulic acid ameliorates nerve injury induced by cerebral ischemia in rats. Exp Ther Med. 9:972–976. 2015. View Article : Google Scholar : PubMed/NCBI
20	Wu YC and Hsieh CL: Pharmacological effects of radix angelica sinensis (Danggui) on cerebral infarction. Chin Med. 6:322011. View Article : Google Scholar : PubMed/NCBI
21	Cheng CY, Ho TY, Lee EJ, Su SY, Tang NY and Hsieh CL: Ferulic acid reduces cerebral infarct through its antioxidative and anti-inflammatory effects following transient focal cerebral ischemia in rats. Am J Chin Med. 36:1105–1119. 2008. View Article : Google Scholar : PubMed/NCBI
22	Cheng CY, Su SY, Tang NY, Ho TY, Chiang SY and Hsieh CL: Ferulic acid provides neuroprotection against oxidative stress-related apoptosis after cerebral ischemia/reperfusion injury by inhibiting ICAM-1 mRNA expression in rats. Brain Res. 1209:136–150. 2008. View Article : Google Scholar : PubMed/NCBI
23	Koh PO: Ferulic acid prevents the cerebral ischemic injury-induced decrease of Akt and Bad phosphorylation. Neurosci Lett. 507:156–160. 2012. View Article : Google Scholar : PubMed/NCBI
24	Koh PO: Ferulic acid prevents the cerebral ischemic injury-induced decreases of astrocytic phosphoprotein PEA-15 and its two phosphorylated forms. Neurosci Lett. 511:101–105. 2012. View Article : Google Scholar : PubMed/NCBI
25	Longa EZ, Weinstein PR, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar : PubMed/NCBI
26	Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J and Chopp M: Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 32:2682–2688. 2001. View Article : Google Scholar : PubMed/NCBI
27	Hsiang CY, Wu SL and Ho TY: Morin inhibits 12-O-tetradecanoylphorbol-13-acetate-induced hepatocellular transformation via activator protein 1 signaling pathway and cell cycle progression. Biochem Pharmacol. 69:1603–1611. 2005. View Article : Google Scholar : PubMed/NCBI
28	Cheng CY, Lin JG, Tang NY, Kao ST and Hsieh CL: Electroacupuncture-like stimulation at the Baihui (GV20) and Dazhui (GV14) acupoints protects rats against subacute-phase cerebral ischemia-reperfusion injuries by reducing S100B-mediated neurotoxicity. PLoS One. 9:e914262014. View Article : Google Scholar : PubMed/NCBI
29	Cheng CY, Lin JG, Su SY, Tang NY, Kao ST and Hsieh CL: Electroacupuncture-like stimulation at Baihui and Dazhui acupoints exerts neuroprotective effects through activation of the brain-derived neurotrophic factor-mediated MEK1/2/ERK1/2/p90RSK/bad signaling pathway in mild transient focal cerebral ischemia in rats. BMC Complement Altern Med. 14:922014. View Article : Google Scholar : PubMed/NCBI
30	Matsui T, Mori T, Tateishi N, Kagamiishi Y, Satoh S, Katsub N, Morikawa E, Morimoto T, Ikuta F and Asano T: Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part I: Enhanced astrocytic synthesis of s-100beta in the periinfarct area precedes delayed infarct expansion. J Cereb Blood Flow Metab. 22:711–722. 2002. View Article : Google Scholar : PubMed/NCBI
31	Mori T, Town T, Kobayashi M, Tan J, Fujita SC and Asano T: Augmented delayed infarct expansion and reactive astrocytosis after permanent focal ischemia in apolipoprotein E4 knock-in mice. J Cereb Blood Flow Metab. 24:646–656. 2004. View Article : Google Scholar : PubMed/NCBI
32	Koh PO: Ferulic acid attenuates the injury-induced decrease of protein phosphatase 2A subunit B in ischemic brain injury. PLoS One. 8:e542172013. View Article : Google Scholar : PubMed/NCBI
33	Tateishi N, Mori T, Kagamiishi Y, Satoh S, Katsube N, Morikawa E, Morimoto T, Matsui T and Asano T: Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: Suppression of astrocytic activation by a novel agent (R)-(−)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J Cereb Blood Flow Metab. 22:723–734. 2002. View Article : Google Scholar : PubMed/NCBI
34	Tang Q, Han R, Xiao H, Shen J, Luo Q and Li J: Neuroprotective effects of tanshinone IIA and/or tetramethylpyrazine in cerebral ischemic injury in vivo and in vitro. Brain Res. 1488:81–91. 2012. View Article : Google Scholar : PubMed/NCBI
35	Shi J, Gu JH, Dai CL, Gu J, Jin X, Sun J, Iqbal K, Liu F and Gong CX: O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling. Sci Rep. 5:145002015. View Article : Google Scholar : PubMed/NCBI
36	Wu J, Li J, Hu H, Liu P, Fang Y and Wu D: Rho-kinase inhibitor, fasudil, prevents neuronal apoptosis via the Akt activation and PTEN inactivation in the ischemic penumbra of rat brain. Cell Mol Neurobiol. 32:1187–1197. 2012. View Article : Google Scholar : PubMed/NCBI
37	Ishrat T, Sayeed I, Atif F, Hua F and Stein DG: Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway. Neuroscience. 210:442–450. 2012. View Article : Google Scholar : PubMed/NCBI
38	Bracho-Valdés I, Moreno-Alvarez P, Valencia-Martinez I, Robles-Molina E, Chavez-Vargas L and Vázquez-Prado J: mTORC1- and mTORC2-interacting proteins keep their multifunctional partners focused. IUBMB Life. 63:896–914. 2011. View Article : Google Scholar : PubMed/NCBI
39	Li W, Yang Y, Hu Z, Ling S and Fang M: Neuroprotective effects of DAHP and Triptolide in focal cerebral ischemia via apoptosis inhibition and PI3K/Akt/mTOR pathway activation. Front Neuroanat. 9:482015. View Article : Google Scholar : PubMed/NCBI
40	Josse L, Xie J, Proud CG and Smales CM: mTORC1 signalling and eIF4E/4E-BP1 translation initiation factor stoichiometry influence recombinant protein productivity from GS-CHOK1 cells. Biochem J. 473:4651–4664. 2016. View Article : Google Scholar : PubMed/NCBI
41	Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004. View Article : Google Scholar : PubMed/NCBI
42	Koh PO: Ferulic acid attenuates focal cerebral ischemia-induced decreases in p70S6 kinase and S6 phosphorylation. Neurosci Lett. 555:7–11. 2013. View Article : Google Scholar : PubMed/NCBI
43	Attar-Schneider O, Pasmanik-Chor M, Tartakover-Matalon S, Drucker L and Lishner M: eIF4E and eIF4GI have distinct and differential imprints on multiple myeloma's proteome and signaling. Oncotarget. 6:4315–4329. 2015. View Article : Google Scholar : PubMed/NCBI
44	Li S, Perlman DM, Peterson MS, Burrichter D, Avdulov S, Polunovsky VA and Bitterman PB: Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis. J Biol Chem. 279:21312–21317. 2004. View Article : Google Scholar : PubMed/NCBI
45	Fan S, Li Y, Yue P, Khuri FR and Sun SY: The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP Down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation. Neoplasia. 12:346–356. 2010. View Article : Google Scholar : PubMed/NCBI
46	Cao G, Minami M, Pei W, Yan C, Chen D, O'Horo C, Graham SH and Chen J: Intracellular Bax translocation after transient cerebral ischemia: Implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cereb Blood Flow Metab. 21:321–333. 2001. View Article : Google Scholar : PubMed/NCBI
47	Noshita N, Sugawara T, Fujimura M, Morita-Fujimura Y and Chan PH: Manganese superoxide dismutase affects cytochrome c release and caspase-9 activation after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 21:557–567. 2001. View Article : Google Scholar : PubMed/NCBI
48	Li L, Peng L and Zuo Z: Isoflurane preconditioning increases B-cell lymphoma-2 expression and reduces cytochrome c release from the mitochondria in the ischemic penumbra of rat brain. Eur J Pharmacol. 586:106–113. 2008. View Article : Google Scholar : PubMed/NCBI
49	Liu D, Lu C, Wan R, Auyeung WW and Mattson MP: Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. J Cereb Blood Flow Metab. 22:431–443. 2002. View Article : Google Scholar : PubMed/NCBI
50	Lee HK, Jang JY, Yoo HS and Seong YH: Neuroprotective effect of phytoceramide against transient focal ischemia-induced brain damage in rats. Arch Pharm Res. 38:2241–2350. 2015. View Article : Google Scholar : PubMed/NCBI
51	Zheng L, Ding J, Wang J, Zhou C and Zhang W: Effects and mechanism of action of inducible nitric oxide synthase on apoptosis in a rat model of cerebral ischemia-reperfusion injury. Anat Rec. 299:246–255. 2016. View Article : Google Scholar
52	Cheng CY, Su SY, Tang NY, Ho TY, Lo WY and Hsieh CL: Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABA(B1) receptor expression in transient focal cerebral ischemia in rats. Acta Pharmacol Sin. 31:889–899. 2010. View Article : Google Scholar : PubMed/NCBI
53	Yao RQ, Qi DS, Yu HL, Liu J, Yang LH and Wu XX: Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem Res. 37:2777–2786. 2012. View Article : Google Scholar : PubMed/NCBI
54	Qi D, Ouyang C, Wang Y, Zhang S, Ma X, Song Y, Yu H, Tang J, Fu W, Sheng L, et al: HO-1 attenuates hippocampal neurons injury via the activation of BDNF-TrkB-PI3K/Akt signaling pathway in stroke. Brain Res. 1577:69–76. 2014. View Article : Google Scholar : PubMed/NCBI
55	Zhao H, Shimohata T, Wang JQ, Sun G, Schaal DW, Sapolsky RM and Steinberg GK: Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci. 25:9794–9806. 2005. View Article : Google Scholar : PubMed/NCBI