Skip to main content

Advertisement

SpringerLink
Log in

Aloin Protects Against Blood–Brain Barrier Damage After Traumatic Brain Injury in Mice

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Aloin is a small-molecule drug well known for its protective actions in various models of damage. Traumatic brain injury (TBI)-induced cerebral edema from secondary damage caused by disruption of the blood–brain barrier (BBB) often leads to an adverse prognosis. Since the role of aloin in maintaining the integrity of the BBB after TBI remains unclear, we explored the protective effects of aloin on the BBB using in vivo and in vitro TBI models. Adult male C57BL/6 mice underwent controlled cortical impact injury, and mouse brain capillary endothelial bEnd.3 cells underwent biaxial stretch injury, then both received aloin treatment. In the animal experiments, we found 20 mg/kg aloin to be the optimum concentration to decrease cerebral edema, decrease disruption of the BBB, and improve neurobehavioral performance after cortical impact injury. In the cellular studies, the optimum concentration of 40 μg/mL aloin reduced apoptosis and reversed the loss of tight junctions by reducing the reactive oxygen species levels and changes in mitochondrial membrane potential after stretch injury. The mechanisms may be that aloin downregulates the phosphorylation of p38 mitogen-activated protein kinase, the activation of p65 nuclear factor-kappa B, and the ratios of B cell lymphoma (Bcl)-2-associated X protein/Bcl-2 and cleaved caspase-3/caspase-3. We conclude that aloin exhibits these protective effects on the BBB after TBI through its anti-oxidative stress and anti-apoptotic properties in mouse brain capillary endothelial cells. Aloin may thus be a promising therapeutic drug for TBI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Needham EJ, Helmy A, Zanier ER, Jones JL, Coles AJ, Menon DK. The immunological response to traumatic brain injury. J Neuroimmunol 2019, 332: 112–125.

    Article  CAS  PubMed  Google Scholar 

  2. Yang DX, Jing Y, Liu YL, Xu ZM, Yuan F, Wang ML, et al. Inhibition of transient receptor potential vanilloid 1 attenuates blood–brain barrier disruption after traumatic brain injury in mice. J Neurotrauma 2019, 36: 1279–1290.

    Article  PubMed  Google Scholar 

  3. Jiang JY, Gao GY, Feng JF, Mao Q, Chen LG, Yang XF, et al. Traumatic brain injury in China. Lancet Neurol 2019, 18: 286–295.

    Article  PubMed  Google Scholar 

  4. Zhang L, Wang H, Zhou X, Mao L, Ding K, Hu Z. Role of mitochondrial calcium uniporter-mediated Ca(2+) and iron accumulation in traumatic brain injury. J Cell Mol Med 2019, 23: 2995–3009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu YL, Yuan F, Yang DX, Xu ZM, Jing Y, Yang GY, et al. Adjudin attenuates cerebral edema and improves neurological function in mice with experimental traumatic brain injury. J Neurotrauma 2018, 35: 2850–2860.

    Article  PubMed  Google Scholar 

  6. Xu ZM, Yuan F, Liu YL, Ding J, Tian HL. Glibenclamide attenuates blood–brain barrier disruption in adult mice after traumatic brain injury. J Neurotrauma 2017, 34: 925–933.

    Article  PubMed  Google Scholar 

  7. Michinaga S, Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood–brain barrier function after brain damage. Int J Mol Sci 2019, 20: 571.

    Article  CAS  PubMed Central  Google Scholar 

  8. Liu YL, Xu ZM, Yang GY, Yang DX, Ding J, Chen H, et al. Sesamin alleviates blood–brain barrier disruption in mice with experimental traumatic brain injury. Acta Pharmacol Sin 2017, 38: 1445–1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Luissint AC, Artus C, Glacial F, Ganeshamoorthy K, Couraud PO. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS 2012, 9: 23.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hu HM, Li B, Wang XD, Guo YS, Hui H, Zhang HP, et al. Fluoxetine is neuroprotective in early brain injury via its anti-inflammatory and anti-apoptotic effects in a rat experimental subarachnoid hemorrhage model. Neurosci Bull 2018, 34: 951–962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee W, Yang S, Lee C, Park EK, Kim KM, Ku SK, et al. Aloin reduces inflammatory gene iNOS via inhibition activity and p-STAT-1 and NF-κB. Food Chem Toxicol 2019, 126: 67–71.

    Article  CAS  PubMed  Google Scholar 

  12. Zhong J, Wang F, Wang Z, Shen C, Zheng Y, Ma F, et al. Aloin attenuates cognitive impairment and inflammation induced by d-galactose via down-regulating ERK, p38 and NF-κB signaling pathway. Int Immunopharmacol 2019, 72: 48–54.

    Article  CAS  PubMed  Google Scholar 

  13. Chang R, Zhou R, Qi X, Wang J, Wu F, Yang W, et al. Protective effects of aloin on oxygen and glucose deprivation-induced injury in PC12 cells. Brain Res Bull 2016, 121: 75–83.

    Article  CAS  PubMed  Google Scholar 

  14. Pan Q, Pan H, Lou H, Xu Y, Tian L. Inhibition of the angiogenesis and growth of Aloin in human colorectal cancer in vitro and in vivo. Cancer Cell Int 2013, 13: 69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Silva MA, Trevisan G, Hoffmeister C, Rossato MF, Boligon AA, Walker CIB, et al. Anti-inflammatory and antioxidant effects of Aloe saponaria Haw in a model of UVB-induced paw sunburn in rats. J Photochem Photobiol B 2014, 133: 47–54.

    Article  CAS  PubMed  Google Scholar 

  16. Yuan F, Xu ZM, Lu LY, Nie H, Ding J, Ying WH, et al. SIRT2 inhibition exacerbates neuroinflammation and blood–brain barrier disruption in experimental traumatic brain injury by enhancing NF-κB p65 acetylation and activation. J Neurochem 2016, 136: 581–593.

    Article  CAS  PubMed  Google Scholar 

  17. Sarkar C, Zhao Z, Aungst S, Sabirzhanov B, Faden AI, Lipinski MM. Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury. Autophagy 2014, 10: 2208–2222.

    Article  CAS  PubMed  Google Scholar 

  18. Tang G, Liu Y, Zhang Z, Lu Y, Wang Y, Huang J, et al. Mesenchymal stem cells maintain blood–brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia. Stem Cells 2014, 32: 3150–3162.

    Article  CAS  PubMed  Google Scholar 

  19. Ni H, Yang S, Siaw-Debrah F, Hu J, Wu K, He Z, et al. Exosomes derived from bone mesenchymal stem cells ameliorate early inflammatory responses following traumatic brain injury. Front Neurosci 2019, 13: 14.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006, 1: 848–858.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jing Y, Zhang L, Xu ZM, Chen H, Ju SM, Ding J, et al. Phosphatase actin regulator-1 (PHACTR-1) knockdown suppresses cell proliferation and migration and promotes cell apoptosis in the bEnd.3 mouse brain capillary endothelial cell line. Med Sci Monit 2019, 25: 1291–1300.

  22. Xu Z, Liu Y, Yang D, Yuan F, Ding J, Chen H, et al. Sesamin protects SH-SY5Y cells against mechanical stretch injury and promoting cell survival. BMC Neurosci 2017, 18: 57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ahmed SM, Rzigalinski BA, Willoughby KA, Sitterding HA, Ellis EF. Stretch-induced injury alters mitochondrial membrane potential and cellular ATP in cultured astrocytes and neurons. J Neurochem 2000, 74: 1951–1960.

    Article  CAS  PubMed  Google Scholar 

  24. Fang J, Zhu Y, Wang H, Cao B, Fei M, Niu W, et al. Baicalin protects mice brain from apoptosis in traumatic brain injury model through activation of autophagy. Front Neurosci 2018, 12: 1006.

    Article  PubMed  Google Scholar 

  25. Bhowmick S, D’Mello V, Caruso D, Wallerstein A, Abdul-Muneer PM. Impairment of pericyte-endothelium crosstalk leads to blood–brain barrier dysfunction following traumatic brain injury. Exp Neurol 2019, 317: 260–270.

    Article  CAS  PubMed  Google Scholar 

  26. Wang ZF, Gao C, Chen W, Gao Y, Wang HC, Meng Y, et al. Salubrinal offers neuroprotection through suppressing endoplasmic reticulum stress, autophagy and apoptosis in a mouse traumatic brain injury model. Neurobiol Learn Mem 2019, 161: 12–25.

    Article  PubMed  Google Scholar 

  27. Cernak I, Wing ID, Davidsson J, Plantman S. A novel mouse model of penetrating brain injury. Front Neurol 2014, 5: 209.

    PubMed  PubMed Central  Google Scholar 

  28. Sajja VSSS, Jablonska A, Haughey N, Bulte JWM, Stevens RD, Long JB, et al. Sphingolipids and microRNA changes in blood following blast traumatic brain injury: an exploratory study. J Neurotrauma 2018, 35: 353–361.

    Article  PubMed  Google Scholar 

  29. Washington PM, Forcelli PA, Wilkins T, Zapple DN, Parsadanian M, Burns MP. The effect of injury severity on behavior: a phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J Neurotrauma 2012, 29: 2283–2296.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Huang SX, Qiu G, Cheng FR, Pei Z, Yang Z, Deng XH, et al. Berberine protects secondary injury in mice with traumatic brain injury through anti-oxidative and anti-inflammatory modulation. Neurochem Res 2018, 43: 1814–1825.

    Article  CAS  PubMed  Google Scholar 

  31. Wang D, Xu X, Wu YG, Lyu L, Zhou ZW, Zhang JN. Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms. Neural Regen Res 2018, 13: 819–826.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hao FL, Han XF, Wang XL, Zhao ZR, Guo AH, Lu XJ, et al. The neurovascular protective effect of alogliptin in murine MCAO model and brain endothelial cells. Biomed Pharmacother 2019, 109: 181–187.

    Article  CAS  PubMed  Google Scholar 

  33. Rehman SU, Ahmad A, Yoon GH, Khan M, Abid MN, Kim MO. Inhibition of c-Jun N-terminal kinase protects against brain damage and improves learning and memory after traumatic brain injury in adult mice. Cereb Cortex 2018, 28: 2854–2872.

    Article  PubMed  Google Scholar 

  34. Gao C, Qian Y, Huang J, Wang D, Su W, Wang P, et al. A three-day consecutive fingolimod administration improves neurological functions and modulates multiple immune responses of CCI mice. Mol Neurobiol 2017, 54: 8348–8360.

    Article  CAS  PubMed  Google Scholar 

  35. Xie BS, Wang YQ, Lin Y, Mao Q, Feng JF, Gao GY, et al. Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci Ther 2019, 25: 465–475.

    Article  CAS  PubMed  Google Scholar 

  36. Zhou Q, Wang YW, Ni PF, Chen YN, Dong HQ, Qian YN. Effect of tryptase on mouse brain microvascular endothelial cells via protease-activated receptor 2. J Neuroinflammation 2018, 15: 248.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Abdul-Muneer PM, Chandra N, Haorah J. Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Mol Neurobiol 2015, 51: 966–979.

    Article  CAS  PubMed  Google Scholar 

  38. Yuan F, Liu R, Hu M, Rong X, Bai L, Xu L, et al. JAX2, an ethanol extract of Hyssopus cuspidatus Boriss, can prevent bronchial asthma by inhibiting MAPK/NF-κB inflammatory signaling. Phytomedicine 2019, 57: 305–314.

    Article  CAS  PubMed  Google Scholar 

  39. Tao L, Li D, Liu H, Jiang F, Xu Y, Cao Y, et al. Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-κB and MAPK signaling pathway. Brain Res Bull 2018, 140: 154–161.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang L, Zhang L, Liu H, Jiang F, Wang H, Li D, et al. Inhibition of Epac2 attenuates neural cell apoptosis and improves neurological deficits in a rat model of traumatic brain injury. Front Neurosci 2018, 12: 263.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang X, Lan YL, Xing JS, Lan XQ, Wang LT, Zhang B. Alantolactone plays neuroprotective roles in traumatic brain injury in rats via anti-inflammatory, anti-oxidative and anti-apoptosis pathways. Am J Transl Res 2018, 10: 368–380.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Azarashvili T, Stricker R, Reiser G. The mitochondria permeability transition pore complex in the brain with interacting proteins—promising targets for protection in neurodegenerative diseases. Biol Chem 2010, 391: 619–629.

    Article  CAS  PubMed  Google Scholar 

  43. Chae IH, Park KW, Kim HS, Oh BH. Nitric oxide-induced apoptosis is mediated by Bax/Bcl-2 gene expression, transition of cytochrome c, and activation of caspase-3 in rat vascular smooth muscle cells. Clin Chim Acta 2004, 341: 83–91.

    Article  CAS  PubMed  Google Scholar 

  44. Yang J, Liu XS, Bhalla K, Kim CN, Ibrado AM, Cai J, et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 1997, 275: 5303.

    Article  Google Scholar 

  45. Knoblach SM, Nikolaeva M, Huang X, Fan L, Krajewski S, Reed JC, et al. Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome. J Neurotrauma 2002, 19: 1155–1170.

    Article  PubMed  Google Scholar 

  46. Cheng G, Kong RH, Zhang LM, Zhang JN. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 2012, 167: 699–719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang X, Li S, Ma J, Wang C, Chen A, Xin Z, et al. Effect of gastrodin on early brain injury and neurological outcome after subarachnoid hemorrhage in rats. Neurosci Bull 2019, 35: 461–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Glober NK, Sprague S, Ahmad S, Mayfield KG, Fletcher LM, Digicaylioglu MH, et al. Acetazolamide treatment prevents redistribution of astrocyte aquaporin 4 after murine traumatic brain injury. Neurosci J 2019, 2019: 1–12.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Prof. Guo-yuan Yang (School of Biomedical Engineering and Med-X Research Institute of Shanghai Jiao Tong University, Shanghai, China) for guidance in experiments. This work was supported by the National Natural Science Foundation of China (81671207, 81701895, and 81501048) and the Shanghai Jiao Tong University Medicine-Engineering Research Fund (YG2016QN20).

Author information

Author notes

  1. Yao Jing and Dian-Xu Yang have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Yao Jing, Dian-Xu Yang, Wei Wang, Fang Yuan, Hao Chen, Jun Ding & Heng-Li Tian

  2. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Zhi Geng

Authors
  1. Yao Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dian-Xu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhi Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heng-Li Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Ding, Zhi Geng or Heng-Li Tian.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jing, Y., Yang, DX., Wang, W. et al. Aloin Protects Against Blood–Brain Barrier Damage After Traumatic Brain Injury in Mice. Neurosci. Bull. 36, 625–638 (2020). https://doi.org/10.1007/s12264-020-00471-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-020-00471-0

Keywords

Search

Navigation