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Journal of Neurorestoratology 2023, 11(4): 100081 https://doi.org/10.1016/j.jnrt.2023.100081
Original Research | Open Access | Issue | Published: 12 October 2023

Lithium ameliorates spinal cord injury through endoplasmic reticulum stress-regulated autophagy and alleviated apoptosis through IRE1 and PERK/eIF2α signaling pathways

Show Author's Information Fang Wanga,1,  Chengyi Zhanga,1,  Qiongchi Zhanga,  Jiaxi Lia,  Yuewen Xuea,  Xijing Heb( ),  Fengtao Lia( )
Department of Orthopaedics, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
Department of Orthopaedics, Xi'an International Medical Center Hospital, Xi'an, China

1 These authors contributed to the work equally and should be regarded as cofirst authors.

Keywords:
Spinal cord injury, Lithium, Anti-apoptosis, ER stress, Anti-autophagy
Cite this article:
Wang F, Zhang C, Zhang Q, et al. Lithium ameliorates spinal cord injury through endoplasmic reticulum stress-regulated autophagy and alleviated apoptosis through IRE1 and PERK/eIF2α signaling pathways. Journal of Neurorestoratology, 2023, 11(4): 100081. https://doi.org/10.1016/j.jnrt.2023.100081
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Abstract Full text About this article
Objective

This study aims to investigate the role of apoptosis and autophagy under endoplasmic reticulum (ER) stress in a lithium-treated SCI model.

Methods

We established a rat thoracic 10 (T10) spinal cord contusion model and observed its therapeutic effect by intraperitoneal (IP) injection of lithium. Histological and behavioral recovery with or without lithium injection were evaluated after rat spinal cord injury. In addition, we employed an oxygen-glucose deprivation (OGD)-PC12 cell model to study the effects of lithium on OGD-PC12 cell apoptosis, autophagy and ER stress.

Results

We found that lithium administration to SCI rats reduced neuronal apoptosis and autophagy, restored rat locomotor function by reducing ER stress via IRE1 and PERK/eIF2α pathways. In vitro experiments confirmed that upon lithium treatment, OGD-PC12 cells resisted ER stress caused by thapsigargin (TG) via the IRE1 and PERK/eIF2α signaling pathways.

Conclusion

Lithium attenuated neuronal apoptosis and autophagy, and facilitates the recovery after spinal cord injury through ameliorating ER stress, providing a new therapeutic mechanism for lithium to treat SCI.


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Abstract
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About this article

Lithium ameliorates spinal cord injury through endoplasmic reticulum stress-regulated autophagy and alleviated apoptosis through IRE1 and PERK/eIF2α signaling pathways

Show Author's information Fang Wanga,1, Chengyi Zhanga,1, Qiongchi Zhanga, Jiaxi Lia, Yuewen Xuea, Xijing Heb( ), Fengtao Lia( )
Department of Orthopaedics, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
Department of Orthopaedics, Xi'an International Medical Center Hospital, Xi'an, China

1 These authors contributed to the work equally and should be regarded as cofirst authors.

Abstract

Objective

This study aims to investigate the role of apoptosis and autophagy under endoplasmic reticulum (ER) stress in a lithium-treated SCI model.

Methods

We established a rat thoracic 10 (T10) spinal cord contusion model and observed its therapeutic effect by intraperitoneal (IP) injection of lithium. Histological and behavioral recovery with or without lithium injection were evaluated after rat spinal cord injury. In addition, we employed an oxygen-glucose deprivation (OGD)-PC12 cell model to study the effects of lithium on OGD-PC12 cell apoptosis, autophagy and ER stress.

Results

We found that lithium administration to SCI rats reduced neuronal apoptosis and autophagy, restored rat locomotor function by reducing ER stress via IRE1 and PERK/eIF2α pathways. In vitro experiments confirmed that upon lithium treatment, OGD-PC12 cells resisted ER stress caused by thapsigargin (TG) via the IRE1 and PERK/eIF2α signaling pathways.

Conclusion

Lithium attenuated neuronal apoptosis and autophagy, and facilitates the recovery after spinal cord injury through ameliorating ER stress, providing a new therapeutic mechanism for lithium to treat SCI.

Keywords: Spinal cord injury, Lithium, Anti-apoptosis, ER stress, Anti-autophagy

References(54)

1

Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 2020;21(20):7533.
DOI Google Scholar
2

Kang Y, Ding H, Zhou HX, et al. Epidemiology of worldwide spinal cord injury: a literature review. J Neurorestoratol. 2017;6:1–9.
DOI Google Scholar
3

Huang HY, Sanberg PR, Chen L, et al. Explanation and elaboration: development of Beijing declaration of international association of neurorestoratology. J Neurorestoratol. 2023;11(2):100057.
DOI Google Scholar
4

Paquet J, Rivers CS, Kurban D, et al. The impact of spine stability on cervical spinal cord injury with respect to demographics, management, and outcome: a prospective cohort from a national spinal cord injury registry. Spine J. 2018;18(1):88–98.
DOI Google Scholar
5

Jain NB, Ayers GD, Peterson EN, et al. Traumatic spinal cord injury in the United States, 1993-2012. JAMA. 2015;313(22):2236–2243.
DOI Google Scholar
6

Huang HY, Sharma HS, Chen L, et al. Review of clinical neurorestorative strategies for spinal cord injury: exploring history and latest progresses. J Neurorestoratol. 2018;6(1):171–178.
DOI Google Scholar
7

Wojcik P, Žarković N, Gęgotek A, et al. Involvement of metabolic lipid mediators in the regulation of apoptosis. Biomolecules. 2020;10(3):402.
DOI Google Scholar
8

Celik C, Lee SYT, Yap WS, et al. Endoplasmic reticulum stress and lipids in health and diseases. Prog Lipid Res. 2023;89:101198.
DOI Google Scholar
9

Hetz C, Zhang KZ, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21(8):421–438.
DOI Google Scholar
10

Yao RQ, Ren C, Xia ZF, et al. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy. 2021;17(2):385–401.
DOI Google Scholar
11

Zhou K, Sansur CA, Xu H, et al. The temporal pattern, flux, and function of autophagy in spinal cord injury. Int J Mol Sci. 2017;18(2):E466.
DOI Google Scholar
12

Wang ZY, Zhou LQ, Zheng XT, et al. Autophagy protects against PI3K/Akt/mTOR-mediated apoptosis of spinal cord neurons after mechanical injury. Neurosci Lett. 2017;656:158–164.
DOI Google Scholar
13

Sekiguchi A, Kanno H, Ozawa H, et al. Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J Neurotrauma. 2012;29(5):946–956.
DOI Google Scholar
14

Chen HC, Fong TH, Hsu PW, et al. Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection. J Surg Res. 2013;179(1):e203–e210.
DOI Google Scholar
15

Balsa E, Soustek MS, Thomas A, et al. ER and nutrient stress promote assembly of respiratory chain super complexes through the PERK-eIF2a axis. Mol Cell. 2019;74(5):877–890.e6.
DOI Google Scholar
16

Verfaillie T, Rubio N, Garg AD, et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 2012;19(11):1880–1891.
DOI Google Scholar
17

Zhao YJ, Qiao H, Liu DF, et al. Lithium promotes recovery after spinal cord injury. Neural Regen Res. 2022;17(6):1324–1333.
DOI Google Scholar
18

Balçıkanlı Z, Culha I, Dilsiz P, et al. Lithium promotes long-term neurological recovery after spinal cord injury in mice by enhancing neuronal survival, gray and white matter remodeling, and long-distance axonal regeneration. Front Cell Neurosci. 2022;16:1012523.
DOI Google Scholar
19

Li HF, Li Q, Du XN, et al. Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells. J Cerebr Blood Flow Metabol. 2011;31(10):2106–2115.
DOI Google Scholar
20

Tong MJ, He ZL, Lin XX, et al. Lithium chloride contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by stimulating autophagic flux. Biochem Biophys Res Commun. 2018;495(4):2525–2531.
DOI Google Scholar
21

Chen ZR, Guo HH, Lu ZD, et al. Hyperglycemia aggravates spinal cord injury through endoplasmic reticulum stress mediated neuronal apoptosis, gliosis and activation. Biomed Pharmacother. 2019;112:108672.
DOI Google Scholar
22

Rivlin AS, Tator CH. Objective clinical assessment of motor function after experimental spinal cord injury in the rat. J Neurosurg. 1977;47(4):577–581.
DOI Google Scholar
23

Shi Z, Yuan S, Shi L, et al. Programmed cell death in spinal cord injury pathogenesis and therapy. Cell Prolif. 2021;54(3):e12992.
DOI Google Scholar
24

Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022;221(6):e202201159.
DOI Google Scholar
25

Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol. 2018;36:489–517.
DOI Google Scholar
26

Kesavardhana S, Malireddi RKS, Kanneganti TD. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol. 2020;38:567–595.
DOI Google Scholar
27

Tabibzadeh S. Role of autophagy in aging: the good, the bad, and the ugly. Aging Cell. 2023;22(1):e13753.
DOI Google Scholar
28

Qi FL, Hui X, Yu S, et al. Induction of inducible nitric oxide synthase by isoflurane post-conditioning via hypoxia inducible factor-1a during tolerance against ischemic neuronal injury. Brain Res. 2012;1451:1–9.
DOI Google Scholar
29

Yoshii SR, Mizushima N. Monitoring and measuring autophagy. Int J Mol Sci. 2017;18(9):1865.
DOI Google Scholar
30

Islam MA, Sooro MA, Zhang PH. Autophagic regulation of p62 is critical for cancer therapy. Int J Mol Sci. 2018;19(5):1405.
DOI Google Scholar
31

Maejima Y, Isobe M, Sadoshima J. Regulation of autophagy by beclin 1 in the heart. J Mol Cell Cardiol. 2016;95:19–25.
DOI Google Scholar
32

Lu Q, Harris VA, Kumar S, et al. Autophagy in neonatal hypoxia ischemic brain is associated with oxidative stress. Redox Biol. 2015;6:516–523.
DOI Google Scholar
33

Hagberg H, Mallard C, Rousset CI, et al. Mitochondria: hub of injury responses in the developing brain. Lancet Neurol. 2014;13(2):217–232.
DOI Google Scholar
34

Hiebert JB, Shen Q, Thimmesch AR, et al. Traumatic brain injury and mitochondrial dysfunction. Am J Med Sci. 2015;350(2):132–138.
DOI Google Scholar
35

Tobin MK, Bonds JA, Minshall RD, et al. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cerebr Blood Flow Metabol. 2014;34(10):1573–1584.
DOI Google Scholar
36

Raja M, Soleti F, Bentivoglio AR. Lithium treatment in patients with Huntington's disease and suicidal behavior. Mov Disord. 2015;30(10):1438.
DOI Google Scholar
37

Wong YW, Tam S, So KF, et al. A three-month, open-label, single-arm trial evaluating the safety and pharmacokinetics of oral lithium in patients with chronic spinal cord injury. Spinal Cord. 2011;49(1):94–98.
DOI Google Scholar
38

Zhang D, Wang F, Zhai X, et al. Lithium promotes recovery of neurological function after spinal cord injury by inducing autophagy. Neural Regen Res. 2018;13(12):2191–2199.
DOI Google Scholar
39

Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529(7586):326–335.
DOI Google Scholar
40

Iurlaro R, Munoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J. 2016;283(14):2640–2652.
DOI Google Scholar
41

Fernández A, Ordóñez R, Reiter RJ, et al. Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J Pineal Res. 2015;59(3):292–307.
DOI Google Scholar
42

Li YN, Li SJ, Wu HJ. Ubiquitination-proteasome system (UPS) and autophagy two main protein degradation machineries in response to cell stress. Cells. 2022;11(5):851.
DOI Google Scholar
43

Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78: a cell's response to stress. Life Sci. 2019;226:156–163.
DOI Google Scholar
44

Mohamed E, Cao Y, Rodriguez PC. Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. Cancer Immunol Immunother. 2017;66(8):1069–1078.
DOI Google Scholar
45

Hu H, Tian M, Ding C, et al. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 2018;9:3083.
DOI Google Scholar
46

Shoulders MD, Ryno LM, Genereux JC, et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 2013;3(4):1279–1292.
DOI Google Scholar
47

B'Chir W, Maurin AC, Carraro V, et al. The eIF2a/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41(16):7683–7699.
DOI Google Scholar
48

Hetz C, Martinon F, Rodriguez D, et al. The unfolded protein response: integrating stress signals through the stress sensor IRE1a. Physiol Rev. 2011;91(4):1219–1243.
DOI Google Scholar
49

Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102.
DOI Google Scholar
50

García de la Cadena S, Massieu L. Caspases and their role in inflammation and ischemic neuronal death. Focus on caspase-12. Apoptosis. 2016;21(7):763–777.
DOI Google Scholar
51

Zhang Q, Liu JN, Chen SL, et al. Caspase-12 is involved in stretch-induced apoptosis mediated endoplasmic reticulum stress. Apoptosis. 2016;21(4):432–442.
DOI Google Scholar
52

Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmicreticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000;403(6765):98–103.
DOI Google Scholar
53

Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29(1):42–61.
DOI Google Scholar
54

Kawada K, Mimori S, Okuma Y, et al. Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder. Neurochem Int. 2018;119:115–119.
DOI Google Scholar
Publication history
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Publication history

Received: 23 July 2023
Revised: 07 October 2023
Accepted: 08 October 2023
Published: 12 October 2023
Issue date: December 2023

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© 2023 The Authors.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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