eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 15
Experimental research

Matrix metalloproteinase-9 and p53 involved in chronic fluorosis induced blood-brain barrier damage and neurocyte changes

Shen Qing-Feng, Xia Ying-Peng, Xu Tian-Tong

Arch Med Sci 2019; 15, 2: 457–466
Online publish date: 2019/03/04
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
A large number of basic and clinical studies have confirmed that fluoride produces toxic effects on multiple organ systems in the body including the nervous system.

Material and methods
One hundred twenty Wistar rats were randomly divided into 4 groups with 30 in each group: a high fluoride group (drinking 200 mg/l fluoridated water, 24 weeks); a high fluoride control group (drinking distilled water, 24 weeks); a fluo­ride removal group (drinking fluoridated water, 12 W; then distilled water, 12 W) and a defluorination control group (drinking distilled water, 24 weeks).

The high fluoride and fluoride removal groups had spinal cord astrocyte edema. The apoptosis rate of spinal nerve cells in the high fluoride group and fluoride removal group were significantly higher (p < 0.01) than in the fluoride control and defluorination control group. The Evans blue (EB) content, matrix metalloproteinase-9 (MMP-9) and p53 expression in the high fluoride group and fluoride removal group were higher (p < 0.01) than in the fluoride control and defluorination control group.

The apoptosis of spinal cord nerve cells is obviously higher in rats with chronic fluoride exposure. Chronic fluoride exposure leads to high expression of MMP-9, and results in increased damage of the blood-spinal cord barrier. Increased p53 may be one of the factors causing damage. Short-term removal of fluoride has no obvious recovery in apoptosis of spinal cord nerve cells; highly expressed MMP-9 and p53 may be one of the reasons for unrecovered function.


fluorosis, blood-brain barrier, nerve cells, rats, matrix metallo­pro­tei­nase-9, p53

Yamamoto G, Yoshitake K, Sato T, Kimura T, Ando T. Distribution and forms of fluorine in whole blood of human male. Anal Biochem 1989; 182: 371-6.
Clifford H, Olszowy H, Young M, Hegarty J, Cross M. Fluoride content of powdered infant formula meets Australian Food Safety Standards. Aust N Z J Public Health 2009; 33: 573-6.
Singh N, Verma KG, Verma P, Sidhu GK, Sachdeva S. A comparative study of fluoride ingestion levels, serum thyroid hormone & TSH level derangements, dental fluorosis status among school children from endemic and non-endemic fluorosis areas. Springerplus 2014; 3: 7.
Abdel-Gawad FA, Ashmawy MH, Zaki SM, Abdel-Fatah GH. Lung damage after long-term exposure of adult rats to sodium fluoride. Arch Med Sci 2014; 10: 1035-40.
Adali MK, Varol E, Aksoy F, et al. Impaired heart rate recovery in patients with endemic fluorosis. Biol Trace Elem Res 2013; 152: 310-5.
Zhang J, Zhu WJ, Xu XH, Zhang ZG. Effect of fluoride on calcium ion concentration and expression of nuclear transcription factor kappa-B rho65 in rat hippocampus. Exp Toxicol Pathol 2011; 63: 407-11.
Li M, Gao Y, Cui J, et al. Cognitive impairment and risk factors in elderly people living in fluorosis areas in China. Biol Trace Elem Res 2016; 172: 53-60.
Song GH, Gao JP, Wang CF, et al. Sodium fluoride induces apoptosis in the kidney of rats through caspase-mediated pathways and DNA damage. J Physiol Biochem 2014; 70: 857-68.
Haimanot RT. Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy. Paraplegia 1990; 28: 244-51.
Choi AL, Zhang Y, Sun G, et al. Comment on “Severe dental fluorosis and cognitive deficits”. Neurotoxicol Teratol 2015; 50: 32.
Chakraborti D, Rahman MM, Chatterjee A, et al. Fate of over 480 million inhabitants living in arsenic and fluoride endemic Indian districts: magnitude, health, socio-economic effects and mitigation approaches. J Trace Elem Med Biol 2016; 38: 33-45.
Richter H, Kierdorf U, Richards A, Kierdorf H. Dentin abnormalities in cheek teeth of wild red deer and roe deer from a fluoride-polluted area in Central Europe. Ann Anat 2010; 192: 86-95.
Khan SA, Singh RK, Navit S, et al. Relationship between dental fluorosis and intelligence quotient of school going children in and around lucknow district: a cross-sectional study. J Clin Diagn Res 2015; 9: ZC10-5.
Das K, Mondal NK. Dental fluorosis and urinary fluoride concentration as a reflection of fluoride exposure and its impact on IQ level and BMI of children of Laxmisagar, Simlapal Block of Bankura District, W.B., India. Environ Monit Assess 2016; 188: 218.
Sun Z, Liu F, Yang H, et al. Observations of the supra-micro-structure of the brain hippocampus in mice exposed to high fluoride in drinking water. Chin J Endemiol 2000; 19: 78-81.
Mohamed NE. Erratum to: The role of calcium in ameliorating the oxidative stress of fluoride in rats. Biol Trace Elem Res 2016; 170: 145.
Yadav SS, Kumar R, Khare P, Tripathi M. Oxidative stress biomarkers in the freshwater fish, heteropneustes fossilis (Bloch) exposed to sodium fluoride: antioxidant defense and role of ascorbic acid. Toxicol Int 2015; 22: 71-6.
Dittrich S, Sunyakumthorn P, Rattanavong S, et al. Blood-brain barrier function and biomarkers of central nervous system injury in rickettsial versus other neurological infections in Laos. Am J Trop Med Hyg 2015; 93: 232-7.
Martins T, Baptista S, Goncalves J, et al. Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: role of tight junction proteins and matrix metalloproteinase-9. Brain Res 2011; 1411: 28-40.
Chiu TH, Lan KY, Yang MD, et al. Diallyl sulfide promotes cell-cycle arrest through the p53 expression and triggers induction of apoptosis via caspase- and mitochondria-dependent signaling pathways in human cervical cancer Ca Ski cells. Nutr Cancer 2013; 65: 505-14.
Foster KA, Colditz PB, Lingwood BE, Burke C, Dunster KR, Roberts MS. An improved survival model of hypoxia/ischaemia in the piglet suitable for neuroprotection studies. Brain Res 2001; 919: 122-31.
Kurdi MS. Chronic fluorosis: the disease and its anaesthetic implications. Indian J Anaesth 2016; 60: 157-62.
Lou DD, Guan ZZ, Liu YJ, et al. The influence of chronic fluorosis on mitochondrial dynamics morphology and distribution in cortical neurons of the rat brain. Arch Toxicol 2013; 87: 449-57.
Zhang KL, Lou DD, Guan ZZ. Activation of the AGE/RAGE system in the brains of rats and in SH-SY5Y cells exposed to high level of fluoride might connect to oxidative stress. Neurotoxicol Teratol 2015; 48: 49-55.
Ma J, Liu F, Liu P, et al. Impact of early developmental fluoride exposure on the peripheral pain sensitivity in mice. Int J Dev Neurosci 2015; 47: 165-71.
Ke L, Zheng X, Sun Y, Ouyang W, Zhang Z. Effects of sodium fluoride on lipid peroxidation and PARP, XBP-1 expression in PC12 cell. Biol Trace Elem Res 2016; 173: 161-7.
Ugarte-Berzal E, Vandooren J, Bailon E, Opdenakker G, Garcia-Pardo A. Inhibition of MMP-9-dependent degradation of gelatin, but not other MMP-9 substrates, by the MMP-9 hemopexin domain blades 1 and 4. J Biol Chem 2016; 291: 11751-60.
Chen J, Luo M, Wang W, et al. Altered proteolytic activity and expression of MMPs and aggrecanases and their inhibitors in Kashin-Beck disease. J Orthop Res 2015; 33: 47-55.
Zwierzchowski TJ, Stasikowska-Kanicka O, Janus J, Konecki W, Danilewicz M, Fabis J. Assessment of apoptosis, MMP-1, MMP-3, TIMP-2 expression and mechanical and biochemical properties of fresh rabbit’s medial meniscus stored two weeks under tissue culture conditions. Arch Med Sci 2014; 10: 167-73.
Hou H, Zhang G, Wang H, Gong H, Wang C, Zhang X. High matrix metalloproteinase-9 expression induces angiogenesis and basement membrane degradation in stroke-prone spontaneously hypertensive rats after cerebral infarction. Neural Regen Res 2014; 9: 1154-62.
Miyazaki K, Ohta Y, Nagai M, et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res 2011; 89: 718-28.
Tsuji K, Aoki T, Tejima E, et al. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke 2005; 36: 1954-9.
Vitlianova K, Georgieva J, Milanova M, Tzonev S. Blood pressure control predicts plasma matrix metalloproteinase-9 in diabetes mellitus type II. Arch Med Sci 2015; 11: 85-91.
Stein VM, Puff C, Genini S, Contioso VB, Baumgartner W, Tipold A. Variations on brain microglial gene expression of MMPs, RECK, and TIMPs in inflammatory and non-inflammatory diseases in dogs. Vet Immunol Immunopathol 2011; 144: 17-26.
Takata F, Dohgu S, Matsumoto J, et al. Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-alpha, releasing matrix metalloproteinase-9 and migrating in vitro. J Neuroinflammation 2011; 8: 106.
Hong S, Park KK, Magae J, et al. Ascochlorin inhibits matrix metalloproteinase-9 expression by suppressing activator protein-1-mediated gene expression through the ERK1/2 signaling pathway: inhibitory effects of ascochlorin on the invasion of renal carcinoma cells. J Biol Chem 2005; 280: 25202-9.
Seth R, Yang C, Kaushal V, Shah SV, Kaushal GP. p53-dependent caspase-2 activation in mitochondrial release of apoptosis-inducing factor and its role in renal tubular epithelial cell injury. J Biol Chem 2005; 280: 31230-9.
Gidday JM, Gasche YG, Copin JC, et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol 2005; 289: H558-68.
Franchi A, Santucci M, Masini E, Sardi I, Paglierani M, Gallo O. Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck. Cancer 2002; 95: 1902-10.
Ma C, Xu G. Expression of MMP-9 and p53 in meningiomas tissues. J Zhengzhou Univ 2004; 39: 616-9.
Huang CQ. X-ray signs of bone and joint among residents of endemic fluorosis area 40 years after improvement of water. Chin J Endemiol 2006; 25: 192-5.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe