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Lanthanum Chloride Impairs the Blood-Brain Barrier Integrity by Reduction of Junctional Proteins and Upregulation of MMP-9 in Rats

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Abstract

Lanthanum could cause cognitive impairment in children and rodent animals. The normal blood-brain barrier (BBB) integrity is essential for protecting the brain from systemic toxins and maintaining the homeostasis for proper neuronal function. BBB dysfunction has been implicated as a potential mechanism of heavy metal-induced neurotoxicity. The present study was aimed to investigate effects of lanthanum on BBB integrity and endothelial junctional complexes in the cerebral cortex of young rats. Animals were exposed to lanthanum chloride (LaCl3) through drinking water under 0, 0.25, 0.5, and 1.0% concentrations from postnatal day 0 until 30 days after weaning. LaCl3-exposure increased BBB permeability, caused ultrastructure changes in cerebral capillaries, and reduced protein expression of claudin-5, occludin, and VE-cadherin. Due to the critical role of matrix metalloproteinases (MMPs) in BBB integrity, we further examined alterations in MMPs activity and expression. Enhanced gelatinase activity and upregulated MMP-9 expression were observed after LaCl3-exposure, concurrently with decreased expression of endogenous inhibitor tissue inhibitors of metalloproteinase (TIMP)-1. Taken together, this study demonstrated that postnatal lanthanum exposure caused leakage of BBB in young rats, partially attributed to upregulation of MMP-9 and reduction of junctional proteins expression.

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References

  1. Liapi C, Zarros A, Theocharis S, Al-Humadi H, Anifantaki F, Gkrouzman E, Mellios Z, Skandali N, Tsakiris S (2009) The neuroprotective role of L-cysteine towards the effects of short-term exposure to lanthanum on the adult rat brain antioxidant status and the activities of acetylcholinesterase, (Na+,K+)- and Mg2+-ATPase. Biometals: an international journal on the role of metal ions in biology, biochemistry, and medicine 22(2):329–335. https://doi.org/10.1007/s10534-008-9169-0

    Article  CAS  Google Scholar 

  2. Zhu W, Zhang H, Shao P, Wu D, Yang W, Feng J (1996) Investigation of children intelligenceauotient in REE mining area: nio-effect study of REE mining area in South Jiangxi. ChinSciBull 41:914–916

    Google Scholar 

  3. Feng L, Xiao H, He X, Li Z, Li F, Liu N, Chai Z, Zhao Y, Zhang Z (2006) Long-term effects of lanthanum intake on the neurobehavioral development of the rat. Neurotoxicol Teratol 28(1):119–124. https://doi.org/10.1016/j.ntt.2005.10.007

    Article  CAS  PubMed  Google Scholar 

  4. Zheng L, Yang J, Liu Q, Yu F, Wu S, Jin C, Lu X, Zhang L, Du Y, Xi Q, Cai Y (2013) Lanthanum chloride impairs spatial learning and memory and downregulates NF-kappaB signalling pathway in rats. Arch Toxicol 87(12):2105–2117. https://doi.org/10.1007/s00204-013-1076-7

    Article  CAS  PubMed  Google Scholar 

  5. Yang J, Liu Q, Zhang L, Wu S, Qi M, Lu S, Xi Q, Cai Y (2009) Lanthanum chloride impairs memory, decreases pCaMK IV, pMAPK and pCREB expression of hippocampus in rats. Toxicol Lett 190(2):208–214. https://doi.org/10.1016/j.toxlet.2009.07.016

    Article  CAS  PubMed  Google Scholar 

  6. Feng L, Xiao H, He X, Li Z, Li F, Liu N, Zhao Y, Huang Y, Zhang Z, Chai Z (2006) Neurotoxicological consequence of long-term exposure to lanthanum. Toxicol Lett 165(2):112–120. https://doi.org/10.1016/j.toxlet.2006.02.003

    Article  CAS  PubMed  Google Scholar 

  7. He X, Zhang Z, Zhang H, Zhao Y, Chai Z (2008) Neurotoxicological evaluation of long-term lanthanum chloride exposure in rats. Toxicological sciences: an official journal of the Society of Toxicology 103(2):354–361. https://doi.org/10.1093/toxsci/kfn046

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Pharmacol 3:46. https://doi.org/10.3389/fphar.2012.00046

    Article  PubMed  PubMed Central  Google Scholar 

  11. Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7(1). https://doi.org/10.1101/cshperspect.a020412

  12. Almutairi MM, Gong C, Xu YG, Chang Y, Shi H (2016) Factors controlling permeability of the blood-brain barrier. Cellular and molecular life sciences: CMLS 73(1):57–77. https://doi.org/10.1007/s00018-015-2050-8

    Article  CAS  PubMed  Google Scholar 

  13. Taddei A, Giampietro C, Conti A, Orsenigo F, Breviario F, Pirazzoli V, Potente M, Daly C, Dimmeler S, Dejana E (2008) Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol 10(8):923–934. https://doi.org/10.1038/ncb1752

    Article  CAS  PubMed  Google Scholar 

  14. Sandoval KE, Witt KA (2008) Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32(2):200–219. https://doi.org/10.1016/j.nbd.2008.08.005

    Article  CAS  PubMed  Google Scholar 

  15. Kim JH, Byun HM, Chung EC, Chung HY, Bae ON (2013) Loss of integrity: impairment of the blood-brain barrier in heavy metal-associated ischemic stroke. Toxicological research 29(3):157–164. https://doi.org/10.5487/tr.2013.29.3.157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bauer AT, Burgers HF, Rabie T, Marti HH (2010) Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 30(4):837–848. https://doi.org/10.1038/jcbfm.2009.248

    Article  CAS  Google Scholar 

  17. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 27(4):697–709. https://doi.org/10.1038/sj.jcbfm.9600375

    Article  CAS  Google Scholar 

  18. Rosenberg GA (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. The Lancet Neurology 8(2):205–216. https://doi.org/10.1016/s1474-4422(09)70016-x

    Article  CAS  PubMed  Google Scholar 

  19. Mukherjee A, Swarnakar S (2015) Implication of matrix metalloproteinases in regulating neuronal disorder. Mol Biol Rep 42(1):1–11. https://doi.org/10.1007/s11033-014-3752-y

    Article  CAS  PubMed  Google Scholar 

  20. Zhao H, Cheng Z, Hu R, Chen J, Hong M, Zhou M, Gong X, Wang L, Hong F (2011) Oxidative injury in the brain of mice caused by lanthanid. Biol Trace Elem Res 142(2):174–189. https://doi.org/10.1007/s12011-010-8759-1

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Huang B, Krafft PR, Ma Q, Rolland WB, Caner B, Lekic T, Manaenko A, Le M, Tang J, Zhang JH (2012) Fibroblast growth factors preserve blood-brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice. Neurobiol Dis 46(1):204–214. https://doi.org/10.1016/j.nbd.2012.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gu Y, Zheng G, Xu M, Li Y, Chen X, Zhu W, Tong Y, Chung SK, Liu KJ, Shen J (2012) Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood-brain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem 120(1):147–156. https://doi.org/10.1111/j.1471-4159.2011.07542.x

    Article  CAS  PubMed  Google Scholar 

  24. Luissint AC, Artus C, Glacial F, Ganeshamoorthy K, Couraud PO (2012) Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids and barriers of the CNS 9(1):23. https://doi.org/10.1186/2045-8118-9-23

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161(3):653–660. https://doi.org/10.1083/jcb.200302070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yen LF, Wei VC, Kuo EY, Lai TW (2013) Distinct patterns of cerebral extravasation by Evans blue and sodium fluorescein in rats. PLoS One 8(7):e68595. https://doi.org/10.1371/journal.pone.0068595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Song Y, Xue Y, Liu X, Wang P, Liu L (2008) Effects of acute exposure to aluminum on blood-brain barrier and the protection of zinc. Neurosci Lett 445(1):42–46. https://doi.org/10.1016/j.neulet.2008.08.081

    Article  CAS  PubMed  Google Scholar 

  28. Song H, Zheng G, Shen XF, Liu XQ, Luo WJ, Chen JY (2014) Reduction of brain barrier tight junctional proteins by lead exposure: role of activation of nonreceptor tyrosine kinase Src via chaperon GRP78. Toxicol Sci 138(2):393–402. https://doi.org/10.1093/toxsci/kfu007

    Article  CAS  PubMed  Google Scholar 

  29. Dejana E, Tournier-Lasserve E, Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16(2):209–221. https://doi.org/10.1016/j.devcel.2009.01.004

    Article  CAS  Google Scholar 

  30. Brkic M, Balusu S, Libert C, Vandenbroucke RE (2015) Friends or foes: matrix metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediat Inflamm 2015:620581. https://doi.org/10.1155/2015/620581

    Article  CAS  Google Scholar 

  31. Martins T, Baptista S, Goncalves J, Leal E, Milhazes N, Borges F, Ribeiro CF, Quintela O, Lendoiro E, Lopez-Rivadulla M, Ambrosio AF, Silva AP (2011) Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: role of tight junction proteins and matrix metalloproteinase-9. Brain Res 1411:28–40. https://doi.org/10.1016/j.brainres.2011.07.013

    Article  CAS  PubMed  Google Scholar 

  32. Xu L, Cao F, Xu F, He B, Dong Z (2015) Bexarotene reduces blood-brain barrier permeability in cerebral ischemia-reperfusion injured rats. PLoS One 10(4):e0122744. https://doi.org/10.1371/journal.pone.0122744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wallez Y, Huber P (2008) Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochim Biophys Acta Biomembr 1778(3):794–809. https://doi.org/10.1016/j.bbamem.2007.09.003

    Article  CAS  Google Scholar 

  34. Wei H, Wang S, Zhen L, Yang Q, Wu Z, Lei X, Lv J, Xiong L, Xue R (2015) Resveratrol attenuates the blood-brain barrier dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. Journal of molecular neuroscience: MN 55(4):872–879. https://doi.org/10.1007/s12031-014-0441-1

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China; Grant Numbers are 81502837, 81673220, and 81273117.

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Authors and Affiliations

  1. Department of Toxicology, School of Public Health, China Medical University, #77 Puhe Road, Shenyang, 110122, People’s Republic of China

    Jie Wu, Jinghua Yang, Xiaobo Lu, Cuihong Jin, Shengwen Wu, Lijin Zhang, Xiaoyu Hu & Yuan Cai

  2. Department of Occupational and Environmental Health, School of Public Health, Jinzhou Medical University, #40 Section Three Songpo Road, Jinzhou, 121001, People’s Republic of China

    Jie Wu & Honglin Ma

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  1. Jie Wu
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  9. Yuan Cai
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Correspondence to Yuan Cai.

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Ethical approval for all animals involved in this study was from the Institutional Animal Care and Use Committee of China Medical University.

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Wu, J., Yang, J., Lu, X. et al. Lanthanum Chloride Impairs the Blood-Brain Barrier Integrity by Reduction of Junctional Proteins and Upregulation of MMP-9 in Rats. Biol Trace Elem Res 187, 482–491 (2019). https://doi.org/10.1007/s12011-018-1402-2

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  • DOI: https://doi.org/10.1007/s12011-018-1402-2

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