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
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
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
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
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
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
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
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
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
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
Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6:931–944. https://doi.org/10.1038/nrn1807
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
Dubois-Dalcq M, Murray K (2000) Why are growth factors important in oligodendrocyte physiology? Pathol Biol (Paris) 48:80–86
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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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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.
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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