The PI3K/Akt/FOXO3a pathway regulates regeneration following spinal cord injury in adult rats through TNF-α and p27kip1 expression

Lu,Honghui; Zhang,Li-Hai; Yang,Lin; Tang,Pei-Fu

doi:10.3892/ijmm.2018.3459

The PI3K/Akt/FOXO3a pathway regulates regeneration following spinal cord injury in adult rats through TNF-α and p27kip1 expression

Authors:
- Honghui Lu
- Li-Hai Zhang
- Lin Yang
- Pei-Fu Tang
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Affiliations: Department of Orthopaedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100853, P.R. China, Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, P.R. China, Department of Orthopaedics, The Third Hospital of Beijing Municipal Corps, Chinese People's Armed Police Forces, Beijing 100141, P.R. China
Published online on: February 6, 2018 https://doi.org/10.3892/ijmm.2018.3459
Pages: 2832-2838

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Abstract

The aim of the present study was to elucidate the expression and role of the phosphatidylinositol 3‑kinase (PI3K)/Akt/forkhead box O3 (FOXO3a) pathway in the regeneration of the spinal cord following spinal cord injury (SCI), and its regulatory effect on tumor necrosis factor (TNF)-α and cyclin-dependent kinase inhibitor 1B (p27kip1) expression. Firstly, in a Sprague-Dawley rat model of SCI, western blot analysis revealed that the protein levels of PI3K, phosphorylated Akt and FOXO3a were markedly inhibited compared with those in the sham control group. In vitro experiments were also conducted, in which primary dissociated cultures of rat dorsal spinal cord cells were induced with lipopolysaccharide (LPS; 4 µg/ml). The downregulation of PI3K using LY294002 markedly suppressed cell viability, reduced the protein levels of FOXO3a and p27kip1, and increased TNF-α protein production in the LPS-induced spinal cord cells. In addition, when the LPS-induced spinal cord cells were infected with FOXO3a adenoviral vectors, the overexpression of FOXO3 markedly promoted cell proliferation, activated p27kip1 protein levels and inhibited TNF-α protein production in the spinal cord cells. These results suggest that the PI3K/Akt/FOXO3a pathway regulates regeneration following SCI in adult rats via its modulatory effects on TNF-α and p27kip1 expression.

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1	Pramodhyakul W, Wattanapan P, Siritaratiwat W, Eungpinichpong W and Amatachaya S: Immediate effects of obstacle crossing training in independent ambulatory patients with spinal cord injury. Spinal Cord. 51:379–383. 2013. View Article : Google Scholar : PubMed/NCBI
2	Theiss RD, Hornby TG, Rymer WZ and Schmit BD: Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human chronic spinal cord injury. J Neurophysiol. 105:2781–2790. 2011. View Article : Google Scholar : PubMed/NCBI
3	Totosy de Zepetnek JO, Pelletier CA, Hicks AL and MacDonald MJ: Following the physical activity guidelines for adults with spinal cord injury for 16 weeks does not improve vascular health: A randomized controlled trial. Arch Phys Med Rehabil. 96:1566–1575. 2015. View Article : Google Scholar : PubMed/NCBI
4	Saberi H, Derakhshanrad N and Yekaninejad MS: Comparison of neurological and functional outcomes after administration of granulocyte-colony-stimulating factor in motor-complete versus motor-incomplete postrehabilitated, chronic spinal cord injuries: A phase I/II study. Cell Transplant. 23(Suppl 1): S19–S23. 2014. View Article : Google Scholar : PubMed/NCBI
5	Jung SY, Kim DY, Yune TY, Shin DH, Baek SB and Kim CJ: Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the PI3K/Akt pathway in rats. Exp Ther Med. 7:587–593. 2014. View Article : Google Scholar : PubMed/NCBI
6	Zheng B, Ye L, Zhou Y, Zhu S, Wang Q, Shi H, Chen D, Wei X, Wang Z, Li X, et al: Epidermal growth factor attenuates blood-spinal cord barrier disruption via PI3K/Akt/Rac1 pathway after acute spinal cord injury. J Cell Mol Med. 20:1062–1075. 2016. View Article : Google Scholar : PubMed/NCBI
7	Felix MS, Bauer S, Darlot F, Muscatelli F, Kastner A, Gauthier P and Matarazzo V: Activation of Akt/FKHR in the medulla oblongata contributes to spontaneous respiratory recovery after incomplete spinal cord injury in adult rats. Neurobiol Dis. 69:93–107. 2014. View Article : Google Scholar : PubMed/NCBI
8	Guzen FP, de Araújo DP, Lucena EE, de Morais HH, Cavalcanti JR, do Nascimento ES Jr, Costa MS and Cavalcante JS: Effect of FGF-2 and sciatic nerve grafting on ChAT expression in dorsal root ganglia neurons of spinal cord transected rats. Neurosci Lett. 616:43–48. 2016. View Article : Google Scholar
9	Allodi I, Mecollari V, González-Pérez F, Eggers R, Hoyng S, Verhaagen J, Navarro X and Udina E: Schwann cells transduced with a lentiviral vector encoding Fgf-2 promote motor neuron regeneration following sciatic nerve injury. Glia. 62:1736–1746. 2014. View Article : Google Scholar : PubMed/NCBI
10	Adeeb N and Mortazavi MM: The role of FGF2 in spinal cord trauma and regeneration research. Brain Behav. 4:105–107. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zhang S, Huan W, Wei H, Shi J, Fan J, Zhao J, Shen A and Teng H: FOXO3a/p27^kip1 expression and essential role after acute spinal cord injury in adult rat. J Cell Biochem. 114:354–365. 2013. View Article : Google Scholar
12	Qin W, Pan J, Wu Y, Bauman WA and Cardozo C: Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1α. Biochem Biophys Res Commun. 403:473–478. 2010. View Article : Google Scholar : PubMed/NCBI
13	Léger B, Senese R, Al-Khodairy AW, Dériaz O, Gobelet C, Giacobino JP and Russell AP: Atrogin-1, MuRF1, and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients. Muscle Nerve. 40:69–78. 2009. View Article : Google Scholar : PubMed/NCBI
14	Xia M and Zhu Y: FOXO3a involvement in the release of TNF-α stimulated by ATP in spinal cord astrocytes. J Mol Neurosci. 51:792–804. 2013. View Article : Google Scholar : PubMed/NCBI
15	Machova Urdzikova L, Karova K, Ruzicka J, Kloudova A, Shannon C, Dubisova J, Murali R, Kubinova S, Sykova E, Jhanwar-Uniyal M, et al: The anti-inflammatory compound curcumin enhances locomotor and sensory recovery after spinal cord injury in rats by immunomodulation. Int J Mol Sci. 17:E492015. View Article : Google Scholar
16	Zhou Y, Zhang H, Zheng B, Ye L, Zhu S, Johnson NR, Wang Z, Wei X, Chen D, Cao G, et al: Retinoic acid induced-autophagic flux inhibits ER-stress dependent apoptosis and prevents disruption of blood-spinal cord barrier after spinal cord injury. Int J Biol Sci. 12:87–99. 2016. View Article : Google Scholar : PubMed/NCBI
17	Goldshmit Y, Frisca F, Pinto AR, Pébay A, Tang JK, Siegel AL, Kaslin J and Currie PD: Fgf2 improves functional recovery-decreasing gliosis and increasing radial glia and neural progenitor cells after spinal cord injury. Brain Behav. 4:187–200. 2014. View Article : Google Scholar : PubMed/NCBI
18	Kurtoglu T, Basoglu H, Ozkisacik EA, Cetin NK, Tataroglu C, Yenisey C and Discigil B: Effects of cilostazol on oxidative stress, systemic cytokine release, and spinal cord injury in a rat model of transient aortic occlusion. Ann Vasc Surg. 28:479–488. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhang HY, Wang ZG, Wu FZ, Kong XX, Yang J, Lin BB, Zhu SP, Lin L, Gan CS, Fu XB, et al: Regulation of autophagy and ubiquitinated protein accumulation by bFGF promotes functional recovery and neural protection in a rat model of spinal cord injury. Mol Neurobiol. 48:452–464. 2013. View Article : Google Scholar : PubMed/NCBI
20	Dong M, Yang G, Liu H, Liu X, Lin S, Sun D and Wang Y: Aged black garlic extract inhibits HT29 colon cancer cell growth via the PI3K/Akt signaling pathway. Biomed Rep. 2:250–254. 2014. View Article : Google Scholar : PubMed/NCBI
21	Wang Y, Wang H, Tao Y, Zhang S, Wang J and Feng X: Necroptosis inhibitor necrostatin-1 promotes cell protection and physiological function in traumatic spinal cord injury. Neuroscience. 266:91–101. 2014. View Article : Google Scholar : PubMed/NCBI
22	Li A, Wang J, Wu M, Zhang X and Zhang H: The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1 phase cell cycle arrest: Persistent p27(Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway. Eur J Pharmacol. 747:71–87. 2015. View Article : Google Scholar
23	Li CJ, Chang JK, Chou CH, Wang GJ and Ho ML: The PI3K/Akt/FOXO3a/27^Kip1 signaling contributes to anti-inflammatory drug-suppressed proliferation of human osteoblasts. Biochem Pharmacol. 79:926–937. 2010. View Article : Google Scholar
24	Pun NT, Subedi A, Kim MJ and Park PH: Globular adiponectin causes tolerance to LPS-induced TNF-α expression via autophagy induction in RAW 264.7 macrophages: Involvement of SIRT1/FoxO3A axis. PLoS One. 10:e01246362015. View Article : Google Scholar
25	Kelley K and Berberich SJ: FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway. Am J Cancer Res. 1:62–70. 2011.PubMed/NCBI
26	Pramod S and Shivakumar K: Mechanisms in cardiac fibroblast growth: An obligate role for Skp2 and FOXO3a in ERK1/2 MAPK-dependent regulation of p27^kip1. Am J Physiol Heart Circ Physiol. 306:H844–H855. 2014. View Article : Google Scholar : PubMed/NCBI