Molecular Biology Reports

, Volume 46, Issue 2, pp 1963–1972 | Cite as

Colistin induced peripheral neurotoxicity involves mitochondrial dysfunction and oxidative stress in mice

  • Chongshan Dai
  • Shusheng Tang
  • Xiang Biao
  • Xilong Xiao
  • Chunli ChenEmail author
  • Jichang LiEmail author
Original Article


Polymyxin is a critical antibiotic against the infection caused by multidrug-resistant gram-negative bacteria. Neurotoxicity is one of main dose-limiting factors. The present study aimed to investigate the underlying molecular mechanism on colistin induced peripheral neurotoxicity using a mouse model. Forty mice were divided into control, colistin 1-, 3- and 7-day groups, the mice were intravenously injected with saline or colistin (sulfate) at the dose of 15 mg/kg/day for 1, 3 and 7 days, respectively. The results showed that, colistin treatment for 7 days markedly resulted in the demyelination, axonal degeneration and mitochondria swelling in the mice’s sciatic tissues. Colistin treatment induces oxidative stress as well as the increases of mitochondrial permeability transition, decreases of membrane potential (ΔΨm) and activities of mitochondrial respiratory chain in the mice’s sciatic nerve tissues. Furthermore, in the colistin-7 day group, adenosine-triphosphate (ATP) level Na+/K+-ATPase activity decreased to 75.2% (p < 0.01) and 80.1% (p < 0.01), respectively. Meanwhile, colistin treatment down-regulates the expression of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) mRNAs and up-regulates the expression of Bax and caspase-3 mRNAs. Our results reveal that colistin induced sciatic nerves damage involves oxidative stress, mitochondrial dysfunction and the inhibition of Akt/mTOR pathway.


Colistin Peripheral neurotoxicity Oxidative stress Mitochondrial dysfunction Akt/mTOR pathway 



This study is supported by National Natural Science Foundation of China (Grant Nos. 31472240 and 31802241 To J.L.and C. C.; C. D, S.T. and X.X. was supported by the Key Projects in Chinese National Science and Technology Pillar Program during the 12th Five-year Plan Period, No. 2015BAD11B03).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Dai C et al (2017) Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress. J Antimicrob Chemother 72(6):1635–1645CrossRefGoogle Scholar
  2. 2.
    Falagas ME, Kasiakou SK (2006) Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care 10(1):R27CrossRefGoogle Scholar
  3. 3.
    Li J et al (2006) Colistin: the re-emerging antibiotic for multidrug-resistant gram-negative bacterial infections. Lancet Infect Dis 6(9):589–601CrossRefGoogle Scholar
  4. 4.
    Dai C, Li J, Li J (2013) New insight in colistin induced neurotoxicity with the mitochondrial dysfunction in mice central nervous tissues. Exp Toxicol Pathol 65(6):941–948CrossRefGoogle Scholar
  5. 5.
    Dai C et al (2012) Electrophysiology and ultrastructural changes in mouse sciatic nerve associated with colistin sulfate exposure. Toxicol Mech Methods 22(8):592–596CrossRefGoogle Scholar
  6. 6.
    Liu Y et al (2013) Ascorbic acid protects against colistin sulfate-induced neurotoxicity in PC12 cells. Toxicol Mech Methods 23(8):584–590CrossRefGoogle Scholar
  7. 7.
    Dai C et al (2018) Molecular mechanisms of neurotoxicity induced by polymyxins and chemoprevention. ACS Chem Neurosci ACS Chem Neurosci. Google Scholar
  8. 8.
    Dai C et al (2016) Colistin-induced apoptosis of neuroblastoma-2a cells involves the generation of reactive oxygen species, mitochondrial dysfunction, and autophagy. Mol Neurobiol 53(7):4685–4700CrossRefGoogle Scholar
  9. 9.
    Dai C et al (2013) In vitro toxicity of colistin on primary chick cortex neurons and its potential mechanism. Environ Toxicol Pharmacol 36(2):659–666CrossRefGoogle Scholar
  10. 10.
    Lu Z et al (2017) Colistin-induced autophagy and apoptosis involves the JNK-Bcl2-Bax signaling pathway and JNK-p53-ROS positive feedback loop in PC-12 cells. Chem Biol Interact 277:62–73CrossRefGoogle Scholar
  11. 11.
    Dai C et al (2018) Curcumin attenuates colistin-induced neurotoxicity in N2a cells via anti-inflammatory activity, suppression of oxidative stress, and apoptosis. Mol Neurobiol 55(1):421–434CrossRefGoogle Scholar
  12. 12.
    Zhang L et al (2016) p53 mediates colistin-induced autophagy and apoptosis in PC-12 Cells. Antimicrob Agents Chemother 60(9):5294–5301CrossRefGoogle Scholar
  13. 13.
    Zhang L et al (2015) Autophagy regulates colistin-induced apoptosis in PC-12 cells. Antimicrob Agents Chemother 59(4):2189–2197CrossRefGoogle Scholar
  14. 14.
    Jiang H et al (2013) Baicalin inhibits colistin sulfate-induced apoptosis of PC12 cells. Neural Regen Res 8(28):2597–2604Google Scholar
  15. 15.
    Jiang H et al (2014) Colistin-induced apoptosis in PC12 cells: involvement of the mitochondrial apoptotic and death receptor pathways. Int J Mol Med 33(5):1298–1304CrossRefGoogle Scholar
  16. 16.
    Aktay G, Tozkoparan B, Ertan M (2005) Protective effects of thiazolo[3,2-b]-1,2,4-triazoles on ethanol-induced oxidative stress in mouse brain and liver. Arch Pharm Res 28(4):438–442CrossRefGoogle Scholar
  17. 17.
    Dai C et al (2018) Rapamycin confers neuroprotection against colistin-induced oxidative stress, mitochondria dysfunction, and apoptosis through the activation of autophagy and mTOR/Akt/CREB signaling pathways. ACS Chem Neurosci 9(4):824–837CrossRefGoogle Scholar
  18. 18.
    Lu Z et al (2017) Salidroside attenuates colistin-induced neurotoxicity in RSC96 Schwann cells through PI3K/Akt pathway. Chem Biol Interact 271:67–78CrossRefGoogle Scholar
  19. 19.
    Areti A et al (2014) Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol 2:289–295CrossRefGoogle Scholar
  20. 20.
    Yang JH et al (2017) Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia. Res Rep Urol 9:93–100Google Scholar
  21. 21.
    Xin X et al (2011) Changes of mitochondrial ultrastructures and function in central nervous tissue of hens treated with tri-ortho-cresyl phosphate (TOCP). Hum Exp Toxicol 30(8):1062–1072CrossRefGoogle Scholar
  22. 22.
    Rael LT et al (2004) Lipid peroxidation and the thiobarbituric acid assay: standardization of the assay when using saturated and unsaturated fatty acids. J Biochem Mol Biol 37(6):749–752Google Scholar
  23. 23.
    Ajiboye TO (2018) Colistin sulphate induced neurotoxicity: studies on cholinergic, monoaminergic, purinergic and oxidative stress biomarkers. Biomed Pharmacother 103:1701–1707CrossRefGoogle Scholar
  24. 24.
    Ikegami K, Koike T (2003) Non-apoptotic neurite degeneration in apoptotic neuronal death: pivotal role of mitochondrial function in neurites. Neuroscience 122(3):617–626CrossRefGoogle Scholar
  25. 25.
    Dai C et al (2016) Curcumin attenuates quinocetone induced apoptosis and inflammation via the opposite modulation of Nrf2/HO-1 and NF-kB pathway in human hepatocyte L02 cells. Food Chem Toxicol 95:52–63CrossRefGoogle Scholar
  26. 26.
    Canta A, Pozzi E, Carozzi VA (2015) Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). Toxics 3(2):198–223CrossRefGoogle Scholar
  27. 27.
    Chipuk JE et al (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303(5660):1010–1014CrossRefGoogle Scholar
  28. 28.
    Castillo JP et al (2015) Mechanism of potassium ion uptake by the Na+/K+-ATPase. Nat Commun 6:7622CrossRefGoogle Scholar
  29. 29.
    Dai CS et al (2014) Effects of colistin on the sensory nerve conduction velocity and F-wave in mice. Basic Clin Pharmacol Toxicol 115(6):577–580CrossRefGoogle Scholar
  30. 30.
    Wahby K, Chopra T, Chandrasekar P (2010) Intravenous and inhalational colistin-induced respiratory failure. Clin Infect Dis 50(6):e38–e40CrossRefGoogle Scholar
  31. 31.
    Adam-Vizi V, Starkov AA (2010) Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis 20(Suppl 2):S413–S426CrossRefGoogle Scholar
  32. 32.
    Chong ZZ, Li F, Maiese K (2005) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75(3):207–246CrossRefGoogle Scholar
  33. 33.
    Domenech-Estevez E et al (2016) Akt regulates axon wrapping and myelin sheath thickness in the PNS. J Neurosci 36(16):4506–4521CrossRefGoogle Scholar
  34. 34.
    Figlia G et al (2017) Dual function of the PI3K-Akt-mTORC1 axis in myelination of the peripheral nervous system. Elife 6:e29241CrossRefGoogle Scholar
  35. 35.
    Chen W et al (2016) Rapamycin-resistant mTOR activity is required for sensory axon regeneration induced by a conditioning lesion. eNeuro 3(6):ENEURO–0358CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.College of Veterinary MedicineNortheast Agricultural UniversityHarbinPeople’s Republic of China
  2. 2.College of Veterinary MedicineChina Agricultural UniversityBeijingPeople’s Republic of China

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