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HLY78 Attenuates Neuronal Apoptosis via the LRP6/GSK3β/β-Catenin Signaling Pathway After Subarachnoid Hemorrhage in Rats

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Abstract

Neuronal apoptosis is one of the essential mechanisms of early brain injury after subarachnoid hemorrhage (SAH). Recently, HLY78 has been shown to inhibit apoptosis in tumor cells and embryonic cells caused by carbon ion radiation through activation of the Wnt/β-catenin pathway. This study was designed to explore the anti-apoptotic role of HLY78 in experimental SAH. The results demonstrated that HLY78 attenuated neuronal apoptosis and the neurological deficits after SAH through the activation of low-density lipoprotein receptor-related protein 6 (LRP6), which subsequently increased the level of phosphorylated glycogen synthesis kinase 3 beta (p-GSK3β) (Ser9), β-catenin, and Bcl-2, accompanied by a decrease of p-β-catenin, Bax, and cleaved caspase 3. An LRP6 small-interfering ribonucleic acid reversed the effects of HLY78. In conclusion, HLY78 attenuates neuronal apoptosis and improves neurological deficits through the LRP6/GSK3β/β-catenin signaling pathway after SAH in rats. HLY78 is a promising therapeutic agent to attenuate early brain injury after SAH.

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References

  1. Lawton MT, Vates GE. Subarachnoid hemorrhage. N Engl J Med 2017, 377: 257–266.

    Article  Google Scholar 

  2. Nath S, Koziarz A, Badhiwala JH, Almenawer SA. Predicting outcomes in aneurysmal subarachnoid haemorrhage. BMJ 2018, 360: k102.

    Article  Google Scholar 

  3. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet 2017, 389: 655–666.

    Article  Google Scholar 

  4. Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res 2013, 4: 432–446.

    Article  Google Scholar 

  5. 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  Google Scholar 

  6. Joiner DM, Ke J, Zhong Z, Xu HE, Williams BO. LRP5 and LRP6 in development and disease. Trends Endocrinol Metab 2013, 24: 31–39.

    Article  CAS  Google Scholar 

  7. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 2000, 407: 530–535.

    Article  CAS  Google Scholar 

  8. Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 2005, 438: 873–877.

    Article  CAS  Google Scholar 

  9. Wang S, Yin J, Chen D, Nie F, Song X, Fei C, et al. Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5 interaction. Nat Chem Biol 2013, 9:579–585.

    Article  CAS  Google Scholar 

  10. Li H, Yue L, Xu H, Li N, Li J, Zhang Z, et al. Curcumin suppresses osteogenesis by inducing miR-126a-3p and subsequently suppressing the WNT/LRP6 pathway. Aging (Albany NY) 2019, 11: 6983–6998.

    Article  CAS  Google Scholar 

  11. Ren DN, Chen J, Li Z, Yan H, Yin Y, Wo D, et al. LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumor metastasis. Nat Commun 2015, 6: 6906.

    Article  CAS  Google Scholar 

  12. Wang Z, Li B, Zhou L, Yu S, Su Z, Song J, et al. Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells. Proc Natl Acad Sci U S A 2016, 113: 13150–13155.

    Article  CAS  Google Scholar 

  13. Wang Y, Bao DJ, Xu B, Cheng CD, Dong YF, Wei XP, et al. Neuroprotection mediated by the Wnt/Frizzled signaling pathway in early brain injury induced by subarachnoid hemorrhage. Neural Regen Res 2019, 14: 1013–1024.

    Article  Google Scholar 

  14. Si J, Zhou R, Zhao B, Xie Y, Gan L, Zhang J, et al. Effects of ionizing radiation and HLY78 on the zebrafish embryonic developmental toxicity. Toxicology 2019, 411: 143–153.

    Article  CAS  Google Scholar 

  15. Guo X, Zhang L, Fan Y, Zhang D, Qin L, Dong S, et al. Oxysterol-binding protein-related protein 8 inhibits gastric cancer growth through induction of ER stress, inhibition of Wnt signaling, and activation of apoptosis. Oncol Res 2017, 25: 799–808.

    Article  Google Scholar 

  16. Xie Z, Huang L, Enkhjargal B, Reis C, Wan W, Tang J, et al. Recombinant netrin-1 binding UNC5B receptor attenuates neuroinflammation and brain injury via PPARγ/NFκB signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun 2018, 69: 190–202.

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

  18. Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 2008, 167: 327–334.

    Article  Google Scholar 

  19. Zhang T, Wu P, Budbazar E, Zhu Q, Sun C, Mo J, et al. Mitophagy reduces oxidative stress via Keap1 (Kelch-Like Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related Factor 2)/PHB2 (Prohibitin 2) pathway after subarachnoid hemorrhage in rats. Stroke 2019, 50: 978–988.

    Article  CAS  Google Scholar 

  20. Li P, Zhao G, Ding Y, Wang T, Flores J, Ocak U, et al. Rh-IFN-α attenuates neuroinflammation and improves neurological function by inhibiting NF-κB through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model. Brain Behav Immun 2019, 79: 174–185.

    Article  CAS  Google Scholar 

  21. Xie Z, Huang L, Enkhjargal B, Reis C, Wan W, Tang J, et al. Intranasal administration of recombinant Netrin-1 attenuates neuronal apoptosis by activating DCC/APPL-1/AKT signaling pathway after subarachnoid hemorrhage in rats. Neuropharmacology 2017, 119: 123–133.

    Article  CAS  Google Scholar 

  22. Yu J, Li X, Matei N, McBride D, Tang J, Yan M, et al. Ezetimibe, an NPC1L1 inhibitor, attenuates neuronal apoptosis through AMPK dependent autophagy activation after MCAO in rats. Exp Neurol 2018, 307: 12–23.

    Article  CAS  Google Scholar 

  23. Ostrowski RP, Colohan AR, Zhang JH. Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 2006, 28: 399–414.

    Article  CAS  Google Scholar 

  24. Cahill J, Calvert JW, Zhang JH. Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 2006, 26: 1341–1353.

    Article  CAS  Google Scholar 

  25. Ayer RE, Zhang JH. Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl 2008, 104: 33–41.

    Article  CAS  Google Scholar 

  26. Zheng H, Jia L, Liu CC, Rong Z, Zhong L, Yang L, et al. TREM2 promotes microglial survival by activating Wnt/β-catenin pathway. J Neurosci 2017, 37: 1772–1784.

    Article  CAS  Google Scholar 

  27. Gao K, Shen Z, Yuan Y, Han D, Song C, Guo Y, et al. Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/β-catenin signaling pathway after spinal cord injury. J Neurochem 2016, 138: 139–149.

    Article  CAS  Google Scholar 

  28. Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, Maqueda A, Arenas E, Rodriguez FJ. Differential expression of Wnts after spinal cord contusion injury in adult rats. PLoS One 2011, 6: e27000.

    Article  CAS  Google Scholar 

  29. Hassan MQ, Maeda Y, Taipaleenmaki H, Zhang W, Jafferji M, Gordon JA, et al. MiR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem 2012, 287: 42084–42092.

    Article  CAS  Google Scholar 

  30. Yakisich JS, Azad N, Kaushik V, O’Doherty GA, Iyer AK. Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides. Tumour Biol 2017, 39: 1010428317694310.

    Article  CAS  Google Scholar 

  31. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 2012, 149: 1192–1205.

    Article  CAS  Google Scholar 

  32. Abe T, Zhou P, Jackman K, Capone C, Casolla B, Hochrainer K, et al. Lipoprotein receptor-related protein-6 protects the brain from ischemic injury. Stroke 2013, 44: 2284–2291.

    Article  CAS  Google Scholar 

  33. Endo H, Nito C, Kamada H, Yu F, Chan PH. Akt/GSK3beta survival signaling is involved in acute brain injury after subarachnoid hemorrhage in rats. Stroke 2006, 37: 2140–2146.

    Article  CAS  Google Scholar 

  34. Ma J, Wang Z, Liu C, Shen H, Chen Z, Yin J, et al. Pramipexole-induced hypothermia reduces early brain injury via PI3K/AKT/GSK3β pathway in subarachnoid hemorrhage rats. Sci Rep 2016, 6: 23817.

    Article  CAS  Google Scholar 

  35. Li X, Peng J, Pang J, Wu Y, Huang X, Li Y, et al. Apolipoprotein E-mimetic peptide COG1410 promotes autophagy by phosphorylating GSK-3β in early brain injury following experimental subarachnoid hemorrhage. Front Neurosci 2018, 12: 127.

    Article  Google Scholar 

  36. Min JK, Park H, Choi HJ, Kim Y, Pyun BJ, Agrawal V, et al. The Wnt antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells. J Clin Invest 2011, 121: 1882–1893.

    Article  CAS  Google Scholar 

  37. Lee SH, Ko HM, Kwon KJ, Lee J, Han SH, Han DW, et al. tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells. Mol Neurobiol 2014, 49: 199–215.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81771961 and 81401505) and the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (201959).

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Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China

    Xu Luo, Yuan Cheng & Zongyi Xie

  2. Department of Nephrology, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, 401120, China

    Lina Li

  3. Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Weilin Xu

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  1. Xu Luo
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  2. Lina Li
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  3. Weilin Xu
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  4. Yuan Cheng
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Correspondence to Yuan Cheng or Zongyi Xie.

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Luo, X., Li, L., Xu, W. et al. HLY78 Attenuates Neuronal Apoptosis via the LRP6/GSK3β/β-Catenin Signaling Pathway After Subarachnoid Hemorrhage in Rats. Neurosci. Bull. 36, 1171–1181 (2020). https://doi.org/10.1007/s12264-020-00532-4

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  • DOI: https://doi.org/10.1007/s12264-020-00532-4

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