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Protective Effect of Mild Hypothermia on Spinal Cord Ischemia-Induced Delayed Paralysis and Spinal Cord Injury

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Abstract

To explore the mechanism regarding the regulation of spinal cord ischemia (SCI) in rats by mild hypothermia. A SCI rat model was established through aorta occlusion, and in some cases, the rats were intervened with mild hypothermia, after which motor function, microglia activation, and M1/M2 polarization in rats were measured. Also, the expression of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and neuronal apoptosis were examined. Lipopolysaccharide (LPS)-induced M1 microglia and IL-4-induced M2 microglia were intrathecally injected into rats to evaluate the effect of microglial polarization on SCI. In in vitro experiments, primary microglial cells were treated under hypothermic condition, in which M1/M2 polarization and microglia apoptosis, the levels of iNOS, CD86, CD206, Arg-1 and inflammatory cytokines were assessed. Western blot analysis detected the activation of the TLR4/NF-κB pathway to investigate the role of this pathway in M1/M2 polarization. SCI treatment impaired motor function, induced higher M1 microglia proportion, and increased the levels of pro-inflammatory cytokines in rats, and mild hypothermic treatment attenuated these trends. Moreover, injection of M1 microglia increased M1 microglia proportion and increased the levels of pro-inflammatory cytokines, while injection of M2 microglia induced the reverse results, i.e. decreased M1 microglia proportion and reduced pro-inflammatory cytokine levels. In LPS-induced microglial cells, mild hypothermia treatment increased M2 microglia proportion and decreased pro-inflammatory cytokine levels, relative to normothermia. Mild hypothermia inactivated the TLR4/NF-κB pathway in LPS-treated microglia. TLR4 overexpression reversed the function of mild hypothermia in LPS-stimulated microglia, and under normal condition, TLR4/NF-κB pathway suppressed microglial M2 polarization. Mild hypothermia inhibits TLR4/NF-κB pathway and promotes microglial M2 polarization, thus attenuating SCI-induced injury and inflammation.

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Data Availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. He L, Xu JM, Li H et al (2016) Moderate hypothermia increased the incidence of delayed paralysis through activation of the spinal microglia in an aortic cross-clamping rat model. Int J Cardiol 220:454–461

    Article  PubMed  Google Scholar 

  2. Nguyen BN, Albadawi H, Oklu R et al (2016) Ethyl pyruvate modulates delayed paralysis following thoracic aortic ischemia reperfusion in mice. J Vasc Surg 64(5):1433–1443

    Article  PubMed  Google Scholar 

  3. Kim H, Hwang J, Park S et al (2014) A peroxisome proliferator-activated receptor gamma agonist attenuates neurological deficits following spinal cord ischemia in rats. J Vasc Surg 59(4):1084–1089

    Article  PubMed  Google Scholar 

  4. Nardone R, Pikija S, Mutzenbach JS et al (2016) Current and emerging treatment options for spinal cord ischemia. Drug Discov Today 21(10):1632–1641

    Article  PubMed  Google Scholar 

  5. Bell MT, Agoston VA, Freeman KA et al (2014) Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia. J Vasc Surg 59(4):1090–1097

    Article  PubMed  Google Scholar 

  6. Chen CH, Huang SY, Chen NF et al (2013) Intrathecal granulocyte colony-stimulating factor modulate glial cell line-derived neurotrophic factor and vascular endothelial growth factor A expression in glial cells after experimental spinal cord ischemia. Neuroscience 242:39–52

    Article  CAS  PubMed  Google Scholar 

  7. Awad H, Ankeny DP, Guan Z et al (2010) A mouse model of ischemic spinal cord injury with delayed paralysis caused by aortic cross-clamping. Anesthesiology 113(4):880–891

    Article  PubMed  Google Scholar 

  8. Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflamm 11:98

    Article  Google Scholar 

  9. Zheng Y, He R, Wang P et al (2019) Exosomes from LPS-stimulated macrophages induce neuroprotection and functional improvement after ischemic stroke by modulating microglial polarization. Biomater Sci 7(5):2037–2049

    Article  CAS  PubMed  Google Scholar 

  10. Tian DS, Li CY, Qin C et al (2016) Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke. J Neurochem 139(1):96–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao R, Ying M, Gu S et al (2019) Cysteinyl leukotriene receptor 2 is involved in inflammation and neuronal damage by mediating microglia M1/M2 polarization through NF-kappaB pathway. Neuroscience 422:99–118

    Article  CAS  PubMed  Google Scholar 

  12. Mongardon N, Kohlhauer M, Lidouren F et al (2018) Targeted temperature management with total liquid ventilation after ischemic spinal cord injury. Ann Thorac Surg 106(6):1797–1803

    Article  PubMed  Google Scholar 

  13. Awad H, Elgharably H, Popovich PG (2012) Role of induced hypothermia in thoracoabdominal aortic aneurysm surgery. Ther Hypoth Temp Manag 2(3):119–137

    Article  Google Scholar 

  14. Saito T, Saito S, Yamamoto H et al (2013) Neuroprotection following mild hypothermia after spinal cord ischemia in rats. J Vasc Surg 57(1):173–181

    Article  PubMed  Google Scholar 

  15. Lee JH, Wei ZZ, Cao W et al (2016) Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice. Neurobiol Dis 96:248–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mestre C, Pelissier T, Fialip J et al (1994) A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods 32(4):197–200

    Article  CAS  PubMed  Google Scholar 

  17. Lin X, Zhao T, Walker M et al (2016) Transplantation of pro-oligodendroblasts, preconditioned by LPS-stimulated microglia, promotes recovery after acute contusive spinal cord injury. Cell Transplant 25(12):2111–2128

    Article  PubMed  Google Scholar 

  18. Gaojian T, Dingfei Q, Linwei L et al (2020) Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-kappaB and STAT 1/3 signaling pathway. Cell Death Discov 6(1):97

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhou Q, Lin L, Li H et al (2021) Melatonin reduces neuroinflammation and improves axonal hypomyelination by modulating M1/M2 microglia polarization via JAK2-STAT3-telomerase pathway in postnatal rats exposed to lipopolysaccharide. Mol Neurobiol 58(12):6552–6576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhou J, Wu JS, Yan Y et al (2020) MiR-199a modulates autophagy and inflammation in rats with cerebral infarction via regulating mTOR expression. Eur Rev Med Pharmacol Sci 24(11):6338–6345

    CAS  PubMed  Google Scholar 

  21. Lee JC, Tae HJ, Cho JH et al (2019) Therapeutic hypothermia attenuates paraplegia and neuronal damage in the lumbar spinal cord in a rat model of asphyxial cardiac arrest. J Therm Biol 83:1–7

    Article  PubMed  Google Scholar 

  22. Motomatsu Y, Sakurai M, Onitsuka H et al (2020) Hypothermia inhibits the expression of receptor interacting protein kinases 1 and 3 after transient spinal cord ischaemia in rabbits. Eur J Vasc Endovasc Surg 59(5):824–833

    Article  PubMed  Google Scholar 

  23. Takeda M, Kawaguchi M, Kumatoriya T et al (2011) Effects of minocycline on hind-limb motor function and gray and white matter injury after spinal cord ischemia in rats. Spine (Phila Pa 1976) 36(23):1919–1924

    Article  Google Scholar 

  24. Sun YJ, Zhang ZY, Fan B et al (2019) Neuroprotection by therapeutic hypothermia. Front Neurosci 13:586

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dai W, Wang X, Teng H et al (2019) Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats. Int Immunopharmacol 66:215–223

    Article  CAS  PubMed  Google Scholar 

  26. Wang L, Feng D, Liu Y et al (2017) Autophagy plays a protective role in motor neuron degeneration following spinal cord ischemia/reperfusion-induced spastic paralysis. Am J Transl Res 9(9):4261–4270

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu C, Xu H, Li J et al (2020) Baicalein attenuates pyroptosis and endoplasmic reticulum stress following spinal cord ischemia-reperfusion injury via autophagy enhancement. Front Pharmacol 11:1076

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang F, Dong H, Lv T et al (2018) Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway. J Neuroinflamm 15(1):273

    Article  Google Scholar 

  29. Tu Y, Guo C, Song F et al (2019) Mild hypothermia alleviates diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis. Brain Res Bull 150:1–12

    Article  PubMed  Google Scholar 

  30. Graeber MB (2010) Changing face of microglia. Science 330(6005):783–788

    Article  CAS  PubMed  Google Scholar 

  31. Liu X, Wen S, Yan F et al (2018) Salidroside provides neuroprotection by modulating microglial polarization after cerebral ischemia. J Neuroinflamm 15(1):39

    Article  Google Scholar 

  32. Smith PD, Bell MT, Puskas F et al (2013) Preservation of motor function after spinal cord ischemia and reperfusion injury through microglial inhibition. Ann Thorac Surg 95(5):1647–1653

    Article  PubMed  Google Scholar 

  33. Hu X, Li P, Guo Y et al (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43(11):3063–3070

    Article  CAS  PubMed  Google Scholar 

  34. Kigerl KA, Gensel JC, Ankeny DP et al (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29(43):13435–13444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kroner A, Greenhalgh AD, Zarruk JG et al (2014) TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83(5):1098–1116

    Article  CAS  PubMed  Google Scholar 

  36. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173(4):649–665

    Article  CAS  PubMed  Google Scholar 

  37. Kerr N, Dietrich DW, Bramlett HM et al (2019) Sexually dimorphic microglia and ischemic stroke. CNS Neurosci Ther 25(12):1308–1317

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ahn JH, Lee TK, Kim B et al (2020) Therapeutic hypothermia improves hind limb motor outcome and attenuates oxidative stress and neuronal damage in the lumbar spinal cord following cardiac arrest. Antioxidants (Basel) 9(1):38

    Article  CAS  Google Scholar 

  39. Ye Y, Jin T, Zhang X et al (2019) Meisoindigo protects against focal cerebral ischemia-reperfusion injury by inhibiting NLRP3 inflammasome activation and regulating microglia/macrophage polarization via TLR4/NF-kappaB signaling pathway. Front Cell Neurosci 13:553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Litak J, Grochowski C, Litak J et al (2020) TLR-4 signaling vs. immune checkpoints, miRNAs molecules, cancer stem cells, and wingless-signaling interplay in glioblastoma multiforme-future perspectives. Int J Mol Sci 21(9):3114

    Article  CAS  PubMed Central  Google Scholar 

  41. Bell MT, Puskas F, Agoston VA et al (2013) Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury. Circulation 128(11 Suppl 1):S152-156

    CAS  PubMed  Google Scholar 

  42. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Thanks for all the contributors and participants.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81860239); the Guangxi Natural Science Foundation (Grant Nos. 2018GXNSFBA050062 and AD19110125); and the Guangxi Medical and Health Key Cultivation Discipline Construction Project.

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Authors and Affiliations

  1. Department of Pediatrics, Fifth Affiliated Hospital of Southern Medical University, Guangzhou, 510900, Guangdong, People’s Republic of China

    Dan Fu

  2. Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541000, Guangxi, People’s Republic of China

    Cai Chen & Aiguo Li

  3. Department of Anesthesiology, Fifth Affiliated Hospital of Southern Medical University, No.566, Congcheng Avenue, Conghua District, Guangzhou, 510900, Guangdong, People’s Republic of China

    Liang He

  4. Department of Anesthesia, Graduate College, Guilin Medical University, Guilin, 541000, Guangxi, People’s Republic of China

    Jingjuan Li

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  1. Dan Fu
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  3. Liang He
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Correspondence to Liang He.

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Fu, D., Chen, C., He, L. et al. Protective Effect of Mild Hypothermia on Spinal Cord Ischemia-Induced Delayed Paralysis and Spinal Cord Injury. Neurochem Res 47, 1212–1225 (2022). https://doi.org/10.1007/s11064-021-03515-7

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  • DOI: https://doi.org/10.1007/s11064-021-03515-7

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