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RETRACTED ARTICLE: Retinoic Acid Prevents Disruption of Blood-Spinal Cord Barrier by Inducing Autophagic Flux After Spinal Cord Injury

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This article was retracted on 14 October 2020

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Abstract

Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB), which leads to infiltration of blood cells, inflammatory responses and neuronal cell death, with subsequent development of spinal cord secondary damage. Recent reports pointed to an important role of retinoic acid (RA), the active metabolite of the vitamin A, in the induction of the blood–brain barrier (BBB) during human and mouse development, however, it is unknown whether RA plays a role in maintaining BSCB integrity under the pathological conditions such as SCI. In this study, we investigated the BSCB protective role of RA both in vivo and in vitro and demonstrated that autophagy are involved in the BSCB protective effect of RA. Our data show that RA attenuated BSCB permeability and also attenuated the loss of tight junction molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in brain microvascular endothelial cells. In addition, RA administration improved functional recovery of the rat model of trauma. We also found that RA could significantly increase the expression of LC3-II and decrease the expression of p62 both in vivo and in vitro. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB and exacerbated the loss of tight junctions. Together, our studies indicate that RA improved functional recovery in part by the prevention of BSCB disruption via the activation of autophagic flux after SCI.

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References

  1. Mizee MR, de Vries HE (2013) Blood-brain barrier regulation. Tissue Barriers 1(5):26881–26886. doi:10.4161/tisb.26882/JNEUROSCI.1338-12.2013

    Article  Google Scholar 

  2. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25. doi:10.1016/j.nbd.2009.07.030

    Article  CAS  PubMed  Google Scholar 

  3. Cardoso FL, Brites D, Brito MA (2010) Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 64(2):328–363. doi:10.1016/j.brainresrev.2010.05.003

    Article  CAS  PubMed  Google Scholar 

  4. Bartanusz V, Jezova D, Alajajian B, Digicaylioglu M (2011) The blood-spinal cord barrier: morphology and clinical implications. Ann Neurol 70(2):194–206. doi:10.1002/ana.22421

    Article  PubMed  Google Scholar 

  5. Lee JY, Kim HS, Choi HY, Oh TH, Yune TY (2012) Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain J Neurol 135(Pt 8):2375–2389. doi:10.1093/brain/aws171

    Article  Google Scholar 

  6. Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822. doi:10.1038/ncb0910-814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741. doi:10.1016/j.cell.2011.10.026

    Article  CAS  PubMed  Google Scholar 

  8. Ribas VT, Schnepf B, Challagundla M, Koch JC, Bahr M, Lingor P (2015) Early and sustained activation of autophagy in degenerating axons after spinal cord injury. Brain Pathol 25(2):157–170. doi:10.1111/bpa.12170

    Article  CAS  PubMed  Google Scholar 

  9. Qin Z (2014) Changes in autophagy proteins in a rat model of spinal cord injury. Chin J Traumatol 17(4):193–197. doi:10.3760/cma.j.issn.1008-1275.2014.04.002

    Article  Google Scholar 

  10. Park Y, Liu C, Luo T, Bramlett H, Dietrich WD, Hu B (2015) Chaperone-mediated autophagy after traumatic brain injury. J Neurotrauma. doi:10.1089/neu.2014.3694

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tang P, Hou H, Zhang L, Lan X, Mao Z, Liu D, He C, Du H, Zhang L (2014) Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats. Mol Neurobiol 49(1):276–287. doi:10.1007/s12035-013-8518-3

    Article  CAS  PubMed  Google Scholar 

  12. Smith CM, Mayer JA, Duncan ID (2013) Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant. J Neurosci Off J Soc Neurosci 33(18):8088–8100. doi:10.1523/JNEUROSCI.0233-13.2013

    Article  CAS  Google Scholar 

  13. Chang CP, Su YC, Hu CW, Lei HY (2013) TLR2-dependent selective autophagy regulates NF-kappaB lysosomal degradation in hepatoma-derived M2 macrophage differentiation. Cell Death Differ 20(3):515–523. doi:10.1038/cdd.2012.146

    Article  CAS  PubMed  Google Scholar 

  14. Kanno H, Ozawa H, Sekiguchi A, Yamaya S, Itoi E (2011) Induction of autophagy and autophagic cell death in damaged neural tissue after acute spinal cord injury in mice. Spine 36(22):E1427–E1434. doi:10.1097/BRS.0b013e3182028c3a

    Article  PubMed  Google Scholar 

  15. Niederreither K, Dolle P (2008) Retinoic acid in development: towards an integrated view. Nat Rev Genet 9(7):541–553. doi:10.1038/nrg2340

    Article  CAS  PubMed  Google Scholar 

  16. Kornyei Z, Gocza E, Ruhl R, Orsolits B, Voros E, Szabo B, Vagovits B, Madarasz E (2007) Astroglia-derived retinoic acid is a key factor in glia-induced neurogenesis. FASEB J 21(10):2496–2509. doi:10.1096/fj.06-7756com

    Article  CAS  PubMed  Google Scholar 

  17. Shearer KD, Fragoso YD, Clagett-Dame M, McCaffery PJ (2012) Astrocytes as a regulated source of retinoic acid for the brain. Glia 60(12):1964–1976. doi:10.1002/glia.22412

    Article  PubMed  Google Scholar 

  18. Paschaki M, Lin SC, Wong RL, Finnell RH, Dolle P, Niederreither K (2012) Retinoic acid-dependent signaling pathways and lineage events in the developing mouse spinal cord. PLoS One 7(3):e32447. doi:10.1371/journal.pone.0032447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mizee MR, Wooldrik D, Lakeman KA, van het Hof B, Drexhage JA, Geerts D, Bugiani M, Aronica E, Mebius RE, Prat A, de Vries HE, Reijerkerk A (2013) Retinoic acid induces blood-brain barrier development. J Neurosci 33(4):1660–1671. doi:10.1523/JNEUROSCI.1338-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lippmann ES, Al-Ahmad A, Azarin SM, Palecek SP, Shusta EV (2014) A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep 4:4160. doi:10.1038/srep04160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, Shen Y, Wang RR, Wang X, Hu WW, Wang G, Chen Z (2013) Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy 9(9):1321–1333. doi:10.4161/auto.25132

    Article  CAS  PubMed  Google Scholar 

  22. Zhang X, Yuan Y, Jiang L, Zhang J, Gao J, Shen Z, Zheng Y, Deng T, Yan H, Li W, Hou WW, Lu J, Shen Y, Dai H, Hu WW, Zhang Z, Chen Z (2014) Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: involvement of PARK2-dependent mitophagy. Autophagy 10(10):1801–1813. doi:10.4161/auto.32136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang H, Wu F, Kong X, Yang J, Chen H, Deng L, Cheng Y, Ye L, Zhu S, Zhang X, Wang Z, Shi H, Fu X, Li X, Xu H, Lin L, Xiao J (2014) Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury. J Transl Med 12:130. doi:10.1186/1479-5876-12-130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van Neerven S, Mey J, Joosten EA, Steinbusch HW, van Kleef M, Marcus MA, Deumens R (2010) Systemic but not local administration of retinoic acid reduces early transcript levels of pro-inflammatory cytokines after experimental spinal cord injury. Neurosci Lett 485(1):21–25. doi:10.1016/j.neulet.2010.08.051

    Article  CAS  PubMed  Google Scholar 

  25. Wang HL, Lai TW (2014) Optimization of Evans blue quantitation in limited rat tissue samples. Sci Rep 4:6588. doi:10.1038/srep06588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201. doi:10.1016/j.neuron.2008.01.003

    Article  CAS  PubMed  Google Scholar 

  27. Lee JY, Kim HS, Choi HY, Oh TH, Ju BG, Yune TY (2012) Valproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury. J Neurochem 121(5):818–829. doi:10.1111/j.1471-4159.2012.07731.x

    Article  CAS  PubMed  Google Scholar 

  28. Fassbender JM, Saraswat-Ohri S (2012) Deletion of endoplasmic reticulum stress-induced CHOP protects microvasculature post-spinal cord injury. Curr Neurovasc Res 9(1875–5739):274–281

    Article  CAS  PubMed  Google Scholar 

  29. Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43(4):348–364. doi:10.1080/10715760902751902

    Article  CAS  PubMed  Google Scholar 

  30. Olmez I, Ozyurt H (2012) Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int 60(2):208–212. doi:10.1016/j.neuint.2011.11.009

    Article  CAS  PubMed  Google Scholar 

  31. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19(12):1584–1596. doi:10.1038/nm.3407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li XQ, Lv HW (2014) Role of the TLR4 pathway in blood spinal cord barrier dysfunction during the bimodal stage after ischemiareperfusion injury in rats. J Neuroinflammation 2014(7):28–42

    Google Scholar 

  33. Xiao-Qian Li JW (2014) Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperf usion injury in rats. Mol Brain 2014(7):28

    Google Scholar 

  34. Xanthos DN, Pungel I, Wunderbaldinger G, Sandkuhler J (2012) Effects of peripheral inflammation on the blood-spinal cord barrier. Mol Pain 8:44. doi:10.1186/1744-8069-8-44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fan ZK, Lv G, Wang YF, Li G, Yu DS, Wang YS, Zhang YQ, Mei XF, Cao Y (2013) The protective effect of salvianolic acid B on blood-spinal cord barrier after compression spinal cord injury in rats. J Mol Neurosc 51(3):986–993. doi:10.1007/s12031-013-0083-8

    Article  CAS  Google Scholar 

  36. Rajawat Y, Hilioti Z, Bossis I (2010) Autophagy A target for retinoic acids. Autophagy 6(8):1224–1226. doi:10.4161/auto.6.8.13793/ars.2010.3491

    Article  CAS  PubMed  Google Scholar 

  37. Niapour N, Niapour A, Sheikhkanloui Milan H, Amani M, Salehi H, Najafzadeh N, Gholami MR (2015) All trans retinoic acid modulates peripheral nerve fibroblasts viability and apoptosis. Tissue Cell 47(1):61–65. doi:10.1016/j.tice.2014.11.004

    Article  CAS  PubMed  Google Scholar 

  38. Wang Y, He PC, Qi J, Liu YF, Zhang M (2015) Tetra-arsenic tetra-sulfide induces cell cycle arrest and apoptosis in retinoic acid-resistant acute promyelocytic leukemia cells. Biomed Rep 3(4):583–587. doi:10.3892/br.2015.466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liang C, Yang L, Guo S (2015) All- retinoic acid inhibits migration, invasion and proliferation, and promotes apoptosis in glioma cells. Oncol Lett 9(6):2833–2838. doi:10.3892/ol.2015.3120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schrage K, Koopmans G, Joosten EA, Mey J (2006) Macrophages and neurons are targets of retinoic acid signaling after spinal cord contusion injury. Eur J Neurosci 23(2):285–295. doi:10.1111/j.1460-9568.2005.04534.x

    Article  PubMed  Google Scholar 

  41. Mey J, Morassutti DJ, Brook G, Liu RH, Zhang YP, Koopmans G, McCaffery P (2005) Retinoic acid synthesis by a population of NG2-positive cells in the injured spinal cord. Eur J Neurosci 21(6):1555–1568. doi:10.1111/j.1460-9568.2005.03928.x

    Article  PubMed  Google Scholar 

  42. Yip PK, Wong LF, Pattinson D, Battaglia A, Grist J, Bradbury EJ, Maden M, McMahon SB, Mazarakis ND (2006) Lentiviral vector expressing retinoic acid receptor beta2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord. Hum Mol Genet 15(21):3107–3118. doi:10.1093/hmg/ddl251

    Article  CAS  PubMed  Google Scholar 

  43. Mizee MR, Nijland PG, van der Pol SM, Drexhage JA, van Het Hof B, Mebius R, van der Valk P, van Horssen J, Reijerkerk A, de Vries HE (2014) Astrocyte-derived retinoic acid: a novel regulator of blood-brain barrier function in multiple sclerosis. Acta Neuropathol 128(5):691–703. doi:10.1007/s00401-014-1335-6

    Article  CAS  PubMed  Google Scholar 

  44. Alirezaei M, Kemball CC, Whitton JL (2011) Autophagy, inflammation and neurodegenerative disease. Eur J Neurosci 33(2):197–204. doi:10.1111/j.1460-9568.2010.07500.x

    Article  PubMed  Google Scholar 

  45. Nixon RA (2006) Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci 29(9):528–535. doi:10.1016/j.tins.2006.07.003

    Article  CAS  PubMed  Google Scholar 

  46. Xie Y, You SJ, Zhang YL, Han Q, Cao YJ, Xu XS, Yang YP, Li J, Liu CF (2011) Protective role of autophagy in AGE-induced early injury of human vascular endothelial cells. Mol Med Rep 4(3):459–464. doi:10.3892/mmr.2011.460

    Article  CAS  PubMed  Google Scholar 

  47. Li H, Gao A, Feng D, Wang Y, Zhang L, Cui Y, Li B, Wang Z, Chen G (2014) Evaluation of the protective potential of brain microvascular endothelial cell autophagy on blood-brain barrier integrity during experimental cerebral ischemia-reperfusion injury. Transl Stroke Res 5(5):618–626. doi:10.1007/s12975-014-0354-x

    Article  PubMed  Google Scholar 

  48. Nighot PK, Hu CA, Ma TY (2015) Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation. J Biol Chem 290(11):7234–7246. doi:10.1074/jbc.M114.597492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhao H, Ji Z, Tang D, Yan C, Zhao W, Gao C (2013) Role of autophagy in early brain injury after subarachnoid hemorrhage in rats. Mol Biol Rep 40(2):819–827. doi:10.1007/s11033-012-2120-z

    Article  CAS  PubMed  Google Scholar 

  50. van Vliet EA, Forte G, Holtman L, den Burger JC, Sinjewel A, de Vries HE, Aronica E, Gorter JA (2012) Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia 53(7):1254–1263. doi:10.1111/j.1528-1167.2012.03513.x

    Article  CAS  PubMed  Google Scholar 

  51. Yu F, Wang Z, Tanaka M, Chiu CT, Leeds P, Zhang Y, Chuang DM (2013) Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury. J Neurosurg 119(3):766–773. doi:10.3171/2013.6.JNS13135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zeng M, Zhou JN (2008) Roles of autophagy and mTOR signaling in neuronal differentiation of mouse neuroblastoma cells. Cell Signal 20(4):659–665. doi:10.1016/j.cellsig.2007.11.015

    Article  CAS  PubMed  Google Scholar 

  53. Trocoli A, Mathieu J, Priault M, Reiffers J, Souquere S, Pierron G, Besancon F, Djavaheri-Mergny M (2011) ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells. Autophagy 7(10):1108–1114. doi:10.4161/auto.7.10.16623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was partially supported by a research Grant from the National Natural Science Funding of China (81302775, 81472165, 81200958, 81372112), Zhejiang Provincial Natural Science Foundation of China (LY14H090013, LY14H150010, LY14H170002), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents (to J.X.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China

    Yulong Zhou, Binbin Zheng, Sipin Zhu, Zili He, Qingqing Wang & Huazi Xu

  2. School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China

    Yulong Zhou, Binbin Zheng, Libing Ye, Hongyu Zhang, Sipin Zhu, Xiaomeng Zheng, Qinghai Xia, Zili He, Qingqing Wang & Jian Xiao

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  1. Yulong Zhou
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This article has been retracted. Please see the retraction notice for more detail:https://doi.org/10.1007/s41980-020-00472-9

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11064_2015_1756_MOESM1_ESM.tif

RA inhibits apoptosis protein caspase-12 expression after SCI. Representative western blots and quantification data of Cle-caspase-12 in each group rats. *P < 0.01, versus SCI group. Data represent mean values ± SEM, n = 4 (TIFF 347 kb)

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Zhou, Y., Zheng, B., Ye, L. et al. RETRACTED ARTICLE: Retinoic Acid Prevents Disruption of Blood-Spinal Cord Barrier by Inducing Autophagic Flux After Spinal Cord Injury. Neurochem Res 41, 813–825 (2016). https://doi.org/10.1007/s11064-015-1756-1

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