AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Article Link
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Research | Open Access

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

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.

Show Author Information

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.

References

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.

2

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

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.

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.

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.

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.

7

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

8

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

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.

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.

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.

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.

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.

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.

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.

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.

17

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

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.

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.

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.

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.

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.

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.

24

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

25

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

26

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

27

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

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.

29

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

30

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

31

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

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.

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.

34

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

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.

36

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

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.

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.

39

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

40

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

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.

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.

43

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

53

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

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.

Journal of Neurorestoratology
Article number: 100081
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

857

Views

3

Crossref

2

Web of Science

3

Scopus

Altmetrics

Received: 23 July 2023
Revised: 07 October 2023
Accepted: 08 October 2023
Published: 12 October 2023
© 2023 The Authors.

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

Return