Protective effect of simvastatin on impaired intestine tight junction protein ZO-1 in a mouse model of Parkinson’s disease

Abstract

Recently, several studies showed that gastrointestinal tract may be associated with pathophysiology of Parkinson’s disease (PD). Intestine tight junction protein zonula occluden-1 (ZO-1) is an important component of intestinal barrier which can be degraded by matrix metallopeptidase 9 (MMP-9). In our previous study, a significant decline in ZO-1 was observed along with enhanced MMP-9 activity in the duodenum and distal colon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In this study, the protective effect of simvastatin on ZO-1 was investigated using an MPTP mouse model of PD. Seven days after the end of MPTP application, the expression level of ZO-1 was evaluated by immunohistochemistry. The protein expression levels of ZO-1 and MMP9 were detected by Western blotting. Meanwhile, MMP-9 activity was analyzed by gelatin zymography. MPTP treatment led to a decrease in the expression of ZO-1, which was accompanied by elevated MMP-9 activity. Treatment with simvastatin could partly reverse the MPTP-induced changes in ZO-1 expression and reduce MMP-9 protein and activity. Taken together, these findings suggest that simvastatin administration may partially reverse the impairment of ZO-1 induced by MPTP via inhibiting the activity of MMP9, fortify the impaired intestinal barrier and limit gut-derived toxins that pass across the intestinal barrier.

Keywords

duodenum / colon / simvastatin / tight junction protein / matrix metallopeptidase 9

References

[1] TufekciKU, GencS, GencK. The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinsons Dis, 2011, 2011: 487450 PMCID: 3034925 PMID: 21331154

[2] ForsythCB, ShannonKM, KordowerJH, et al. . Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One, 2011, 6(12): 28032

[3] ShannonKM, KeshavarzianA, MutluE, et al. . Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord, 2012, 27(6): 709-715 PMID: 21766334

[4] KellyLP, CarveyPM, KeshavarzianA, et al. . Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov Disord, 2014, 29(8): 999-1009 PMCID: 4050039 PMID: 24898698

[5] Sanchez-FerroA, RabanoA, CatalanMJ, et al. . In vivo gastric detection of alpha-synuclein inclusions in Parkinson’s disease. Mov Disord, 2015, 30(4): 517-524 PMID: 25113060

[6] RuanZ, LiuS, ZhouY, et al. . Chlorogenic acid decreases intestinal permeability and increases expression of intestinal tight junction proteins in weaned rats challenged with LPS. PLoS One, 2014, 9(6): 97815

[7] GuoS, Al-SadiR, SaidHM, et al. . Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol, 2013, 182(2): 375-387 PMCID: 3562736 PMID: 23201091

[8] ChenX, LanX, RocheI, et al. . Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum. J Neurochem, 2008, 107(4): 1147-1157 PMCID: 3692355 PMID: 18808450

[9] GaoX, SimonKC, SchwarzschildMA, et al. . Prospective study of statin use and risk of Parkinson disease. Arch Neurol, 2012, 69(3): 380-384 PMCID: 3398841 PMID: 22410446

[10] LeeYC, LinCH, WuRM, et al. . Discontinuation of statin therapy associates with Parkinson disease: a population-based study. Neurology, 2013, 81(5): 410-416 PMID: 23884037

[11] WolozinB, WangSW, LiNC, et al. . Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med, 2007, 5: 20 PMCID: 1955446 PMID: 17640385

[12] RoyA, PahanK. Prospects of statins in Parkinson disease. Neuroscientist, 2011, 17(3): 244-255 PMCID: 3132406 PMID: 21252380

[13] GhoshA, RoyA, MatrasJ, et al. . Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurosci, 2009, 29(43): 13543-13556 PMCID: 2862566 PMID: 19864567

[14] YanJ, SunJ, HuangL, et al. . Simvastatin prevents neuroinflammation by inhibiting N-methyl-D-aspartic acid receptor 1 in 6-hydroxydopamine-treated PC12 cells. J Neurosci Res, 2014, 92(5): 634-640 PMID: 24482148

[15] YanJ, XuY, ZhuC, et al. . Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses. PLoS One, 2011, 6(6): 20945

[16] ChengG, ChunleiW, PeiW, et al. . Simvastatin activates Akt/glycogen synthase kinase-3beta signal and inhibits caspase-3 activation after experimental subarachnoid hemorrhage. Vascul Pharmacol, 2010, 52(1-2): 77-83 PMID: 20004738

[17] IferganI, WosikK, CayrolR, et al. . Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann Neurol, 2006, 60(1): 45-55 PMID: 16729291

[18] MirzaH, WuZ, TeoJD, et al. . Statin pleiotropy prevents rho kinase-mediated intestinal epithelial barrier compromise induced by Blastocystis cysteine proteases. Cell Microbiol, 2012, 14(9): 1474-1484 PMID: 22587300

[19] LinY, ChangG, WangJ, et al. . NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP. Exp Cell Res, 2011, 317(14): 2031-2040 PMID: 21669197

[20] SantosCM. New agents promote neuroprotection in Parkinson’s disease models. CNS Neurol Disord Drug Targets, 2012, 11(4): 410-418 PMID: 22483311

[21] HossainZ, HirataT. Molecular mechanism of intestinal permeability: interaction at tight junctions. Mol Biosyst, 2008, 4(12): 1181-1185 PMID: 19396381

[22] AraiH, FuruyaT, YasudaT, et al. . Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and expression of caspase-11 in mice. J Biol Chem, 2004, 279(49): 51647-51653 PMID: 15383538

[23] LiG, SunS, CaoX, et al. . LPS-induced degeneration of dopaminergic neurons of substantia nigra in rats. J Huazhong Univ Sci Technolog Med Sci, 2004, 24(1): 83-86 PMID: 15165124

[24] QinL, LiuY, HongJS, et al. . NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia, 2013, 61(6): 855-868 PMCID: 3631289 PMID: 23536230

[25] GuoS, Al-SadiR, SaidHM, et al. . Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol, 2013, 182(2): 375-387 PMCID: 3562736 PMID: 23201091

[26] SchaedlerRW, DubosR, CostelloR. The development of the bacterial flora in the gastrointestinal tract of mice. J Exp Med, 1965, 122: 59-66 PMCID: 2138024 PMID: 14325473

[27] OkadaY, TsuzukiY, MiyazakiJ, et al. . Propionibacterium freudenreichii component 1.4-dihydroxy-2-naphthoic acid (DHNA) attenuates dextran sodium sulphate induced colitis by modulation of bacterial flora and lymphocyte homing. Gut, 2006, 55(5): 681-688 PMCID: 1856113 PMID: 16299037

[28] NusratA, TurnerJR, MadaraJL. Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells. Am J Physiol Gastrointest Liver Physiol, 2000, 279(5): 851-7

[29] GoldmanSM, KamelF, RossGW, et al. . Peptidoglycan recognition protein genes and risk of Parkinson’s disease. Mov Disord, 2014, 29(9): 1171-1180 PMID: 24838182

[30] GuS, ChenD, ZhangJN, et al. . Bacterial community mapping of the mouse gastrointestinal tract. PLoS One, 2013, 8(10): 74957

[31] DanielH, MoghaddasGA, BerryD, et al. . High-fat diet alters gut microbiota physiology in mice. ISME J, 2014, 8(2): 295-308 PMCID: 3906816 PMID: 24030595

[32] WangT, CaoX, ZhangT, et al. . Effect of simvastatin on L-DOPA-induced abnormal involuntary movements of hemiparkinsonian rats. Neurol Sci, 2015, 36(8): 1397-1402 PMID: 25787808