Lanthanum Chloride Impairs the Blood-Brain Barrier Integrity by Reduction of Junctional Proteins and Upregulation of MMP-9 in Rats
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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.
KeywordsLanthanum Blood-brain barrier Tight junctions Matrix metalloproteinases
This work was supported by the National Natural Science Foundation of China; Grant Numbers are 81502837, 81673220, and 81273117.
Compliance with Ethical Standards
Ethical approval for all animals involved in this study was from the Institutional Animal Care and Use Committee of China Medical University.
Conflict of Interest
The authors declare that there are no conflicts of interest.
- 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 CrossRefGoogle 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 41:914–916Google 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
- 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar