Neurotoxicity Research

, Volume 32, Issue 4, pp 535–543 | Cite as

Lithium Chloride Facilitates Autophagy Following Spinal Cord Injury via ERK-dependent Pathway

  • Peilin Liu
  • Zijuan Zhang
  • Qingde Wang
  • Rundong Guo
  • Wei Mei
ORIGINAL ARTICLE

Abstract

Spinal cord injury (SCI) is one major cause of death and results in long-term disability even in the most productive periods of human lives with few efficacious drugs. Autophagy is a potential therapeutic target for SCI. In the present study, we examined the role of lithium in functional recovery in the rat model of SCI and explored the related mechanism. Locomotion tests were employed to assess the functional recovery after SCI, Western blotting and RT-PCT to determine the level of p-ERK and LC3-II as well as p62, immunofluorescence imaging to localize LC3 and p62. Here, we found that both the expression of LC3-II and p62 were increased after SCI. However, lithium chloride enhanced the level of LC3-II while abrogated the abundance of p62. Furthermore, lithium treatment facilitated ERK activation in vivo, and inhibition of MEK/ERK signaling pathway suppressed lithium-evoked autophagy flux. Taken together, our results illustrated that lithium facilitated functional recovery by enhancing autophagy flux.

Keywords

Lithium chloride Autophagy flux Spinal cord injury ERK 

Supplementary material

12640_2017_9758_MOESM1_ESM.png (77 kb)
Supplementary Fig. 3(PNG 77 kb)
12640_2017_9758_MOESM2_ESM.png (108 kb)
DUMMY (PNG 107 kb)
12640_2017_9758_MOESM3_ESM.png (231 kb)
DUMMY (PNG 231 kb)
12640_2017_9758_MOESM4_ESM.png (94 kb)
Supplementary Fig. 4(PNG 94 kb)
12640_2017_9758_MOESM5_ESM.png (102 kb)
DUMMY (PNG 101 kb)
12640_2017_9758_MOESM6_ESM.png (120 kb)
DUMMY (PNG 119 kb)
12640_2017_9758_MOESM7_ESM.png (79 kb)
Supplementary Fig. 5(PNG 78 kb)
12640_2017_9758_MOESM8_ESM.png (171 kb)
DUMMY (PNG 171 kb)
12640_2017_9758_MOESM9_ESM.png (97 kb)
DUMMY (PNG 96 kb)
12640_2017_9758_MOESM10_ESM.png (135 kb)
Supplementary Fig. 6(PNG 134 kb)
12640_2017_9758_MOESM11_ESM.png (115 kb)
DUMMY (PNG 114 kb)
12640_2017_9758_MOESM12_ESM.png (128 kb)
DUMMY (PNG 128 kb)

References

  1. Bartholomeusz C, Rosen D, Wei C, Kazansky A, Yamasaki F, Takahashi T, Itamochi H, Kondo S, Liu J, Ueno NT (2008) PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival. Cancer res 68(22):9302–9310CrossRefPubMedPubMedCentralGoogle Scholar
  2. Beattie MS, Hermann GE, Rogers RC, Bresnahan JC (2002) Cell death in models of spinal cord injury. Prog Brain res 137:37–47CrossRefPubMedGoogle Scholar
  3. Casella GT, Bunge MB, Wood PM (2006) Endothelial cell loss is not a major cause of neuronal and glial cell death following contusion injury of the spinal cord. Exp Neurol 202(1):8–20CrossRefPubMedGoogle Scholar
  4. Chang JW, Choi H, Cotman SL, Jung YK (2011) Lithium rescues the impaired autophagy process in CbCln3(Δex7/8/Δex7/8) cerebellar cells and reduces neuronal vulnerability to cell death via IMPase inhibition. J Neurochem 116(4):659–668CrossRefPubMedPubMedCentralGoogle Scholar
  5. Clark RS, Bayir H, Chu CT, Alber SM, Kochanek PM, Watkins SC (2008) Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness. Autophagy 4(1):88–90CrossRefPubMedGoogle Scholar
  6. Cohen-Kaplan V, Ciechanover A, Livneh I (2016a) p62 at the crossroad of the ubiquitin-proteasome system and autophagy. Oncotarget 7(51):83833–83834PubMedPubMedCentralGoogle Scholar
  7. Cohen-Kaplan V, Livneh I, Avni N, Fabre B, Ziv T, Kwon YT, Ciechanover A (2016b) p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc Natl Acad Sci U S a 113(47):E7490–E7499CrossRefPubMedPubMedCentralGoogle Scholar
  8. Corcelle E, Nebout M, Bekri S, Gauthier N, Hofman P, Poujeol P, Fénichel P, Mograbi B (2006) Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Cancer res 66(13):6861–6870CrossRefPubMedGoogle Scholar
  9. Del Grosso A, Antonini S, Angella L, Tonazzini I, Signore G, Cecchini M 2016 Lithium improves cell viability in psychosine-treated MO3.13 human oligodendrocyte cell line via autophagy activation. E. R. Bongarzone, ed., J Neurosci Res, 94(11), pp.1246–1260.Google Scholar
  10. Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, Hirsch JA, Stein R, Pinkas-Kramarski R (2007) Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 3(6):561–568CrossRefPubMedGoogle Scholar
  11. Fabrizi C, Pompili E, Somma F, De Vito S, Ciraci V, Artico M, Lenzi P, Fornai F, Fumagalli L (2017) Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the concurrent autophagy impairment. Journal of Applied Toxicology: JAT 37(2):207–213CrossRefPubMedGoogle Scholar
  12. Gong X, Wang H, Ye Y, Shu Y, Deng Y, He X, Lu G, Zhang S (2016) miR-124 regulates cell apoptosis and autophagy in dopaminergic neurons and protects them by regulating AMPK/mTOR pathway in Parkinson's disease. Am J Transl res 8(5):2127–2137PubMedPubMedCentralGoogle Scholar
  13. Guttuso T (2016) Low-dose lithium adjunct therapy associated with reduced off-time in Parkinson's disease: a case series. J Neurol Sci 368:221–222CrossRefPubMedGoogle Scholar
  14. Heiseke A, Aguib Y, Riemer C, Baier M, Schätzl HM (2009) Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy. J Neurochem 109(1):25–34CrossRefPubMedGoogle Scholar
  15. Hou L, Hou L, Xiong N, Liu L, Huang J, Han C, Zhang G, Li J, Xu X, Lin Z, Wang T 2015 Lithium protects dopaminergic cells from rotenone toxicity via autophagy enhancement. BMC Neuroscience, 16(1), p.82Google Scholar
  16. Hull M, Lee E, Lee T, Anand N, LaLone V, Parameswaran N (2014) Lithium chloride induces TNFα in mouse macrophages via MEK-ERK-dependent pathway. J Cell Biochem 115(1):71–80CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kim EC, Meng H, Jun AS (2013) Lithium treatment increases endothelial cell survival and autophagy in a mouse model of Fuchs endothelial corneal dystrophy. Br J Ophthalmol 97(8):1068–1073CrossRefPubMedPubMedCentralGoogle Scholar
  18. Klionsky DJ (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12(1):1–222CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lai Y, Hickey RW, Chen Y, Bayir H, Sullivan ML, Chu CT, Kochanek PM, Dixon CE, Jenkins LW, Graham SH, Watkins SC, Clark RS (2008) Autophagy is increased after traumatic brain injury in mice and is partially inhibited by the antioxidant gamma-glutamylcysteinyl ethyl ester. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 28(3):540–550CrossRefGoogle Scholar
  20. Lenzi P, Lazzeri G, Biagioni F, Busceti CL, Gambardella S, Salvetti A, Fornai F (2016) The autophagoproteasome a novel cell clearing organelle in baseline and stimulated conditions. Front Neuroanat 10:78CrossRefPubMedPubMedCentralGoogle Scholar
  21. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477CrossRefPubMedGoogle Scholar
  22. Li Q, Li H, Roughton K, Wang X, Kroemer G, Blomgren K, Zhu C (2010) Lithium reduces apoptosis and autophagy after neonatal hypoxia-ischemia. Cell Death dis 1(7):e56CrossRefPubMedPubMedCentralGoogle Scholar
  23. Lipinski MM, Wu J, Faden AI, Sarkar C (2015) Function and mechanisms of autophagy in brain and spinal cord trauma. Antioxid Redox Signal 23(6):565–577CrossRefPubMedPubMedCentralGoogle Scholar
  24. Liu CL, Chen S, Dietrich D, Hu BR (2008) Changes in autophagy after traumatic brain injury. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 28(4):674–683CrossRefGoogle Scholar
  25. Liu S, Sarkar C, Dinizo M, Faden AI, Koh EY, Lipinski MM, Wu J (2015) Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death dis 6(1):e1582CrossRefPubMedPubMedCentralGoogle Scholar
  26. Matsuzaki T, Iwasa T, Tungalagsuvd A, Munkhzaya M, Kawami T, Yamasaki M, Murakami M, Kato T, Kuwahara A, Yasui T, Irahara M (2015) The responses of hypothalamic NPY and OBRb mRNA expression to food deprivation develop during the neonatal-prepubertal period and exhibit gender differences in rats. International Journal of Developmental Neuroscience: the Official Journal of the International Society for Developmental Neuroscience 41:63–67CrossRefGoogle Scholar
  27. Mattingly RR, Kraniak JM, Dilworth JT, Mathieu P, Bealmear B, Nowak JE, Benjamins JA, Tainsky MA, Reiners JJ Jr (2006) The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines. J Pharmacol Exp Ther 316(1):456–465CrossRefPubMedGoogle Scholar
  28. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 12(2):376–389Google Scholar
  29. O'Donovan TR, Rajendran S, O'Reilly S, O'Sullivan GC, McKenna SL 2015 Lithium modulates autophagy in esophageal and colorectal cancer cells and enhances the efficacy of therapeutic agents in vitro and in vivo. I. Ulasov, ed. PloS one, 10(8), p.e0134676Google Scholar
  30. Ogier-Denis E, Pattingre S, El Benna J, Codogno P (2000) Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem 275(50):39090–39095CrossRefPubMedGoogle Scholar
  31. Pardo R, Andreolotti AG, Ramos B, Picatoste F, Claro E (2003) Opposed effects of lithium on the MEK-ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms. J Neurochem 87(2):417–426CrossRefPubMedGoogle Scholar
  32. Raja M, Soleti F, Bentivoglio AR (2015) Lithium treatment in patients with Huntington's disease and suicidal behavior. Movement Disorders: Official Journal of the Movement Disorder Society 30(10):1438–1438CrossRefGoogle Scholar
  33. Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M, Cook LJ, Rubinsztein DC (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170(7):1101–1111CrossRefPubMedPubMedCentralGoogle Scholar
  34. Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24(18):8055–8068CrossRefPubMedPubMedCentralGoogle Scholar
  35. Shimada K, Motoi Y, Ishiguro K, Kambe T, Matsumoto SE, Itaya M, Kunichika M, Mori H, Shinohara A, Chiba M, Mizuno Y, Ueno T, Hattori N (2012) Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion. Neurobiol dis 46(1):101–108CrossRefPubMedGoogle Scholar
  36. Smith RG, Alexianu ME, Crawford G, Nyormoi O, Stefani E, Appel SH (1994) Cytotoxicity of immunoglobulins from amyotrophic lateral sclerosis patients on a hybrid motoneuron cell line. Proc Natl Acad Sci U S a 91(8):3393–3397CrossRefPubMedPubMedCentralGoogle Scholar
  37. Wang J, Whiteman MW, Lian H, Wang G, Singh A, Huang D, Denmark T (2009) A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1. J Biol Chem 284(32):21412–21424CrossRefPubMedPubMedCentralGoogle Scholar
  38. Wang C, Liu C, Gao K, Zhao H, Zhou Z, Shen Z, Guo Y, Li Z, Yao T, Mei X (2016) Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. Biochem Biophys res Commun 477(4):534–540CrossRefPubMedGoogle Scholar
  39. Wang Y, Zhu WG, Zhao Y (2017) Autophagy substrate SQSTM1/p62 regulates chromatin ubiquitination during the DNA damage response. Autophagy 13(1):212–213CrossRefPubMedGoogle Scholar
  40. Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z (2011) LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev Cell 20(4):444–454CrossRefPubMedGoogle Scholar
  41. Wong YW, Tam S, So KF, Chen JY, Cheng WS, Luk KD, Tang SW, Young W (2011) 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 49(1):94–98CrossRefPubMedGoogle Scholar
  42. Wong DJ, Robert L, Atefi MS, Lassen A, Avarappatt G, Cerniglia M, Avramis E, Tsoi J, Foulad D, Graeber TG, Comin-Anduix B, Samatar A, Lo RS, Ribas A (2014) Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma. Mol Cancer 13(1):194CrossRefPubMedPubMedCentralGoogle Scholar
  43. Yang ML, Li JJ, So KF, Chen JY, Cheng WS, Wu J, Wang ZM, Gao F, Young W (2012) Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial. Spinal Cord 50(2):141–146CrossRefPubMedGoogle Scholar
  44. Zassadowski F, Pokorna K, Ferre N, Guidez F, Llopis L, Chourbagi O, Chopin M, Poupon J, Fenaux P, Ann Padua R, Pla M, Chomienne C, Cassinat B (2015) Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent. Leukemia 29(12):2277–2284CrossRefPubMedGoogle Scholar
  45. Zhang Z, Sun S, Du C, Li W, Zhang J, Zhu Y, Liu P, Xing Y (2016a) Effects of leptin on Na+/Ca2+ exchanger in PC12 cells. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 40(6):1529–1537CrossRefGoogle Scholar
  46. Zhang D, Xuan J, Zheng BB, Zhou YL, Lin Y, Wu YS, Zhou YF, Huang YX, Wang Q, Shen LY, Mao C, Wu Y, Wang XY, Tian NF, Xu HZ, Zhang XL 2016b Metformin improves functional recovery after spinal cord injury via autophagy flux stimulation. Molecular neurobiology, pp.1–15Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Peilin Liu
    • 1
  • Zijuan Zhang
    • 2
  • Qingde Wang
    • 1
  • Rundong Guo
    • 1
  • Wei Mei
    • 1
  1. 1.Department of Spine SurgeryZhengzhou Orthopaedic HospitalZhengzhouChina
  2. 2.Experimental Teaching Center, School of Basic Medical ScienceHenan University of Chinese MedicineZhengzhouChina

Personalised recommendations