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Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the hippocampus of lithium-pilocarpine-induced acute epileptic rats

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Abstract

Background

Epilepsy is characterised by abnormal neuronal discharges, including aberrant expression of extracellular matrix (ECM) components and synaptic plasticity stabilisation. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) interact to remodel the ECM in the central nervous system (CNS), to modulate synaptic plasticity in epileptogenesis.

Methods and Results

In the present study, the expression of MMP activators (tPA and uPA), 10 MMPs, and 3 TIMPs was detected by western blot analysis and quantitative polymerase chain reaction (RT-qPCR) to assess their potential pathogenetic role in the epileptogenesis in the hippocampus of lithium-pilocarpine hydrochloride-induced epileptic rats. Our results showed that The expression of MMP7 and MMP14 was impeded in the hippocampus of lithium-pilocarpine-induced acute epileptic rats compared with that in controls. The transcriptional level of tPA was enhanced on day 1 post-seizure in the hippocampus, while the levels of several MMPs and TIMPs did not change on days 1 and 3 post-seizure compared with that in controls.

Conclusions

The expression of MMPs and TIMPs reflects a novel feature of epileptogenesis and may offer new perspectives for future therapeutic interventions.

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Data availability statement

All data generated or analysed during this study are included in this published article.

References

  1. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472. https://doi.org/10.1111/j.0013-9580.2005.66104.x

    Article  PubMed  Google Scholar 

  2. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshé SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51:676–685. https://doi.org/10.1111/j.1528-1167.2010.02522.x

    Article  PubMed  Google Scholar 

  3. Pitkänen A, Lukasiuk K (2009) Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav 14:16–25. https://doi.org/10.1016/j.yebeh.2008.09.023

    Article  PubMed  Google Scholar 

  4. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233. https://doi.org/10.1038/nrm2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3:a005058. https://doi.org/10.1101/cshperspect.a005058

    Article  PubMed  PubMed Central  Google Scholar 

  6. Agrawal SM, Lau L, Yong VW (2008) MMPs in the central nervous system: where the good guys go bad. Semin Cell Dev Biol 19:42–51. https://doi.org/10.1016/j.semcdb.2007.06.003

    Article  CAS  PubMed  Google Scholar 

  7. Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13:743–757. https://doi.org/10.1038/nrn3320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ben-Ari Y (2001) Cell death and synaptic reorganizations produced by seizures. Epilepsia 42:5–7. https://doi.org/10.1046/j.1528-1157.2001.042suppl.3005.x

    Article  PubMed  Google Scholar 

  9. Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2:502–511. https://doi.org/10.1038/35081571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6:931–944. https://doi.org/10.1038/nrn1807

    Article  CAS  PubMed  Google Scholar 

  11. Javaid MA, Abdallah MN, Ahmed AS, Sheikh Z (2013) Matrix metalloproteinases and their pathological upregulation in multiple sclerosis: an overview. Acta Neurol Belg 113:381–390. https://doi.org/10.1007/s13760-013-0239-x

    Article  PubMed  Google Scholar 

  12. Dubois-Dalcq M, Murray K (2000) Why are growth factors important in oligodendrocyte physiology? Pathol Biol (Paris) 48:80–86

    CAS  Google Scholar 

  13. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  14. Stein VM, Puff C, Genini S, Contioso VB, Baumgärtner W, Tipold A (2011) Variations on brain microglial gene expression of MMPs, RECK, and TIMPs in inflammatory and non-inflammatory diseases in dogs. Vet Immunol Immunopathol 144:17–26. https://doi.org/10.1016/j.vetimm.2011.06.029

    Article  CAS  PubMed  Google Scholar 

  15. Wang P, Ma K, Yang L, Zhang G, Ye M, Wang S, Wei S, Chen Z, Gu J, Zhang L, Niu J, Tao S (2021) Predicting signaling pathways regulating demyelination in a rat model of lithium-pilocarpine-induced acute epilepsy: A proteomics study. Int J Biol Macromol. 2021 Dec 15;193(Pt B):1457–1470 https://doi.org/10.1016/j.ijbiomac.2021.10.209

  16. Buhler LA, Samara R, Guzman E, Wilson CL, Krizanac-Bengez L, Janigro D, Ethell DW (2009) Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis. BMC Neurosci 10:17. https://doi.org/10.1186/1471-2202-10-17

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ethell DW, Kinloch R, Green DR (2002) Metalloproteinase shedding of Fas ligand regulates beta-amyloid neurotoxicity. Curr Biol 12:1595–1600. https://doi.org/10.1016/s0960-9822(02)01140-5

    Article  CAS  PubMed  Google Scholar 

  18. Wang P, Gorter RP, de Jonge JC, Nazmuddin M, Zhao C, Amor S, Hoekstra D, Baron W (2018) MMP7 cleaves remyelination-impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions. Glia 66:1625–1643. https://doi.org/10.1002/glia.23328

    Article  PubMed  PubMed Central  Google Scholar 

  19. Le AP, Friedman WJ (2012) Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J Neurosci 32:703–712. https://doi.org/10.1523/JNEUROSCI.4128-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chandler S, Cossins J, Lury J, Wells G (1996) Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem Biophys Res Commun 228:421–429. https://doi.org/10.1006/bbrc.1996.1677

    Article  CAS  PubMed  Google Scholar 

  21. Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, Lipton SA (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25:6401–6408. https://doi.org/10.1523/JNEUROSCI.1563-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vinet J, Vainchtein ID, Spano C, Giordano C, Bordini D, Curia G, Dominici M, Boddeke HW, Eggen BJ, Biagini G (2016) Microglia are less pro-inflammatory than myeloid infiltrates in the hippocampus of mice exposed to status epilepticus. Glia 64:1350–1362. https://doi.org/10.1002/glia.23008., DOI: 10.1002/glia.23008

    Article  PubMed  Google Scholar 

  23. Mohan H, Krumbholz M, Sharma R, Eisele S, Junker A, Sixt M, Newcombe J, Wekerle H, Hohlfeld R, Lassmann H, Meinl E (2010) Extracellular matrix in multiple sclerosis lesions: fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells. Brain Pathol 20:966–975. https://doi.org/10.1111/j.1750-3639.2010.00399.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rodríguez-Cruces R, Concha L (2015) White matter in temporal lobe epilepsy: clinico-pathological correlates of water diffusion abnormalities. Quant Imaging Med Surg 5:264–278. https://doi.org/10.3978/j.issn.2223-4292.2015.02.06

    Article  PubMed  PubMed Central  Google Scholar 

  25. You Y, Bai H, Wang C, Chen LW, Liu B, Zhang H, Gao GD (2011) Myelin damage of hippocampus and cerebral cortex in rat pentylenetetrazol model. Brain Res 1381:208–216. https://doi.org/10.1016/j.brainres.2011.01.011

    Article  CAS  PubMed  Google Scholar 

  26. Langenfurth A, Rinnenthal JL, Vinnakota K, Prinz V, Carlo AS, Stadelmann C, Siffrin V, Peaschke S, Endres M, Heppner F, Glass R, Wolf SA, Kettenmann H (2014) Membrane-type 1 metalloproteinase is upregulated in microglia/brain macrophages in neurodegenerative and neuroinflammatory diseases. J Neurosci Res 92:275–286. https://doi.org/10.1002/jnr.23288

    Article  CAS  PubMed  Google Scholar 

  27. Liao MC, Van Nostrand WE (2010) Degradation of soluble and fibrillar amyloid beta-protein by matrix metalloproteinase (MT1-MMP) in vitro. Biochemistry 49:1127–1136. https://doi.org/10.1021/bi901994d

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was funded by grants from the Key R&D Plan Project of Ningxia (2019BEB04041), National Natural Science Foundation of China (81960232 and 82001282), Youth Talents Supporting Program of Ningxia Medical University and Ningxia (XT2019018 and TJGC2019081), Natural Science Foundation of Ningxia (2018A0597).

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Authors and Affiliations

Authors

Contributions

DW, and PW conceived and designed the experiments. DW, LY, CZ, LC, and XYS, performed experiments. JR, HYH, and QH, analysed the data and collected the references. DW and PW wrote the first draft; JGN, TS and PW checked and revised the draft. All authors approved the submission of this manuscript to be published.

Corresponding authors

Correspondence to Tao Sun or Peng Wang.

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Conflict of interest

The authors declare no conflict of interest related to this work.

Research involving animals and all protocols and procedures were approved by the National Institutes of Health and the animal welfare committee of Ningxia Medical University (Ethics Approval Number: 2019 − 151, Ningxia, China).

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Ding Wan and Lu Yang contributed equally to this article.

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Wan, D., Yang, L., Ren, J. et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the hippocampus of lithium-pilocarpine-induced acute epileptic rats. Mol Biol Rep 49, 5805–5810 (2022). https://doi.org/10.1007/s11033-022-07277-5

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  • DOI: https://doi.org/10.1007/s11033-022-07277-5

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