The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus
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Recent studies demonstrate that matrix metalloproteinase-9 (MMP-9) is closely involved in the pathogenesis of epilepsy. This study investigated the role of MMP-9 in hippocampal cell death after pilocarpine-induced status epilepticus (SE). We showed that MMP-9 expression and activity significantly increased and beta1-integrin levels decreased on day 3 after SE. beta1-integrin degradation was also observed in hippocampal ex vivo extracts incubated with recombinant active MMP-9. Treatment with a selective MMP-9 inhibitor attenuated MMP-9 up-regulation, beta1-integrin degradation, the reduction of ILK activity and Akt phosphorylation, and subsequent hippocampal damage after SE. However, co-treatment with anti-beta1-integrin antibody almost completely blocked the protective effects of the MMP-9 inhibitor on both integrin-mediated survival signaling and hippocampal cell death. Our study demonstrates that MMP-9 induces apoptotic hippocampal cell death by interrupting integrin-mediated survival signaling after SE and suggests that MMP-9 may be a promising target for a neuroprotective approach to preventing seizure-induced hippocampal damage.
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Heightened MMP activity has been reported in other models of epilepsy, with elevated MMP level associated with epileptiform activity.
“While we suggest a pivotal role for the MMP activity in glioma-associated epilepsy, heightened MMP activity has also been reported in other models of epilepsy46 with elevated MMP level being associated with epileptiform activity47–50.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [48]
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“In experimentally-induced epilepsy, MMP-9 induces apoptosis of hypocampal cells by cleaving b1-integrin and thereby disrupting the integrin-mediated survival signals (Kim et al., 2009).”
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“, 2007; Huntley, 2012), acting via b1 integrins (Nagy et al., 2006; Kim et al., 2009; Michaluk et al., 2009; Michaluk et al., 2011), indicate that MMP-9 could play a crucial role in epileptogenesis through a similar mechanism.”
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“A role of MMP-9 in the development of epilepsy has also been supported by studies in pilocarpine and 4aminopyridine treated animal models (Kim et al., 2009; Takacs et al., 2010).”
ResultInfluence of matrix metalloproteinase MMP-9 on dendritic spine morphology
Michaluk, P., Wawrzyniak, M., Alot, P., Szczot, M., Wyrembek, P., Mercik, K., Medvedev, N., Wilczek, E., De Roo, M., Zuschratter, W., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.090852 · Cited by 214 · see citing works
“…al., 2006; Nagy et al., 2006; Okulski et al., 2007) and in pathological conditions implicating neuronal plasticity (e.g. epilepsy and drug addiction) (see Kim et al., 2009; Mash et al., 2007; Rivera et al., 2010; Samochowiec et al., 2010; Takacs et al., 2010; Wilczynski et al., 2008; Yamada, 2008).”
BackgroundTewari, B. P., Chaunsali, L., Campbell, S. L., Patel, D. C., Goode, A. E., & Sontheimer, H. (2018) · Nature Communications · doi:10.1038/s41467-018-07113-0 · Cited by 208 · see citing works
MMPs in learning and memory and neuropsychiatric disorders
Beroun, A., Mitra, S., Michaluk, P., Pijet, B., Stefaniuk, M., & Kaczmarek, L. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03180-8 · Cited by 207 · see citing works
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“…some evidence suggests that, in addition to its known extracellular role in macromolecule degradation, MMP may mediate apo- ptotic and/or necrotic cell death (Jourquin et al., 2003; Kim et al., 2009) and synaptic plasticity (Tian et al., 2007; Wilczynski et al., 2008; Takács et al., 2010).”
BackgroundVerslegers, M., Lemmens, K., Hove, I. V., & Moons, L. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.03.004 · Cited by 196 · see citing works
“Indeed, the MMP-9-mediated induction of synaptic strength is attenuated after addition of integrin function-blocking reagents (Kim et al., 2009; Kramar et al., 2006; Nagy et al., 2006).”
The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders
Wen, T. H., Binder, D. K., Ethell, I. M., & Razak, K. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00270 · Cited by 170 · see citing works
Advances in the Potential Biomarkers of Epilepsy
Kobylarek, D., Iwanowski, P. S., Lewandowska, Z., Limphaibool, N., Szafranek, S., Labrzycka, A., & Kozubski, W. P. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00685 · Cited by 153 · see citing works
Crosstalk between neuroinflammation and oxidative stress in epilepsy
Fabisiak, T., & Patel, M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.976953 · Cited by 142 · see citing works
“This can lead to the disruption of the blood brain barrier (BBB) and perineuronal nets (PNs) surrounding inhibitory parvalbumin interneurons (PVINs).”
BackgroundInfluentialMatrix Metalloproteinase 9 in Epilepsy: The Role of Neuroinflammation in Seizure Development
Bronisz, E., & Kurkowska‐Jastrzębska, I. (2016) · Mediators of Inflammation · doi:10.1155/2016/7369020 · Cited by 105 · see citing works
“death of hippocampal cells in the mechanism of apoptosis [106].”
BackgroundRanaivo, H. R., Hodge, J. N., Choi, N., & Wainwright, M. S. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-68 · Cited by 104 · see citing works
Matrix metalloproteinase-9 involvement in the structural plasticity of dendritic spines
Stawarski, M., Stefaniuk, M., & Włodarczyk, J. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00068 · Cited by 83 · see citing works
“Metalloproteinases, enzymes that modulate the ECM, grow to be important players in these processes.”
BackgroundInfluentialAstrocyte-neuron circuits in epilepsy
Purnell, B. S., Alves, M., & Boison, D. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106058 · Cited by 83 · see citing works
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Metalloproteinase inhibition prevents inhibitory synapse reorganization and seizure genesis
Pollock, E., Everest, M., Brown, A., & Poulter, M. O. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.06.003 · Cited by 75 · see citing works
Annese, V., Herrero, M. T., Pentima, M. D., Gómez, A., Lombardi, L., Ros, C. M. B., de Pablos, V., Fernández‐Villalba, E., & Stefano, M. E. D. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0718-8 · Cited by 76 · see citing works
“We do not exclude that MMP-9, early released by affected DA neurons, may contribute to neuronal death by disrupting cell–cell and cell-ECM linkage (Kim et al. 2009).”
BackgroundThe emerging role of furin in neurodegenerative and neuropsychiatric diseases
Zhang, Y., Gao, X., Bai, X., Yao, S., Chang, Y., & Gao, G. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00313-1 · Cited by 79 · see citing works
Elevation of MMP-9 Levels Promotes Epileptogenesis After Traumatic Brain Injury
Pijet, B., Stefaniuk, M., Kostrzewska-Księżyk, A., Tsilibary, P.-E., Tzinia, A. K., & Kaczmarek, L. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1061-5 · Cited by 71 · see citing works
Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome
Carstens, K. E., Lustberg, D. J., Shaughnessy, E. K., McCann, K. E., Alexander, G. M., & Dudek, S. M. (2021) · Journal of Clinical Investigation · doi:10.1172/jci137221 · Cited by 57 · see citing works
Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia
Konopka, A., Grajkowska, W., Ziemiańska, K., Roszkowski, M., Daszkiewicz, P., Rysz, A., Marchel, A., Koperski, Ł., Wilczynski, G. M., & Dzwonek, J. (2012) · Epilepsy Research · doi:10.1016/j.eplepsyres.2012.09.018 · Cited by 68 · see citing works
Takács, E., Nyilas, R., Szepesi, Z., Baracskay, P., Karlsen, B., Røsvold, T., Bjørkum, A. A., Czurkó, A., Kovács, Z., Kékesi, A. K., et al. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.03.003 · Cited by 63 · see citing works
Perineuronal Net Dynamics in the Pathophysiology of Epilepsy
Chaunsali, L., Tewari, B. P., & Sontheimer, H. W. (2021) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597211018688 · Cited by 60 · see citing works
Mizoguchi, H., Yamada, K., & Nabeshima, T. (2011) · Biochemistry Research International · doi:10.1155/2011/681385 · Cited by 68 · see citing works
The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects
Broekaart, D. W. M., Bertran, A., Jia, S., Korotkov, A., Senkov, O., Bongaarts, A., Mills, J. D., Anink, J. J., Seco, J., Baayen, J. C., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138332 · Cited by 59 · see citing works
“Furthermore, Kim et al. showed, by Western blot and immunohistochemistry, an increase in MMP9 expression in mice 3 days after pilocarpine-induced SE (36).”
Guo, X., Cao, Y., Hao, F., Yan, Z., Wang, M., & Liu, X. (2017) · Advances in Medical Sciences · doi:10.1016/j.advms.2016.11.011 · Cited by 56 · see citing works
Pitkänen, A., Ndode‐Ekane, X. E., Łukasiuk, K., Wilczynski, G. M., Dityatev, A. E., Walker, M. C., Chabrol, E., Dedeurwaerdere, S., Vázquez, N., & Powell, E. M. (2014) · Progress in brain research · doi:10.1016/b978-0-444-63486-3.00011-6 · Cited by 49 · see citing works
Gualtieri, F., Curia, G., Marinelli, C., & Biagini, G. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.05.018 · Cited by 52 · see citing works
“metalloproteinase 9, but it is undetermined if this effect may affect blood vessels (Kim et al., 2009).”
Sun, Z., Meng, F., Tu, L., & Sun, L. (2019) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2019.7282 · Cited by 50 · see citing works
Extracellular proteases in epilepsy
Łukasiuk, K., Wilczynski, G. M., & Kaczmarek, L. (2011) · Epilepsy Research · doi:10.1016/j.eplepsyres.2011.08.002 · Cited by 48 · see citing works
A potential role for glia‐derived extracellular matrix remodeling in postinjury epilepsy
Kim, S. Y., Porter, B. E., Friedman, A., & Kaufer, D. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23758 · Cited by 47 · see citing works
“ADAMTS-4 Reactive astrocytes (Satoh et al., 2000; Hamel et al., 2005; Cross et al., 2006) Increase (Cross et al., 2006) Increase (Yuan et al., 2002) Journal of Neuroscience Research findings highlight the pivotal role of ECM in the regulation of synaptic microenvironment as well as during epileptogenesis.”
InfluentialMatrix metalloproteinase-9 may be a potential therapeutic target in epilepsy
Yin, P., Yang, L., Zhou, H. Y., & Sun, R. P. (2010) · Medical Hypotheses · doi:10.1016/j.mehy.2010.09.013 · Cited by 41 · see citing works
“Firstly, neuronal death is presumed to alter the balance between excitatory and inhibitory neurons, which may lead to epileptogenesis by generating a new hyperexcitable circuit [2,4,5].”
BackgroundStefano, M. E. D., & Herrero, M. T. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.08.002 · Cited by 42 · see citing works
“…in the brain have been reported in several studies conducted on rodent models of epilepsy, treated with either pilocarpine (Ben-Ari et al., 1981; Kim et al., 2009), pentylenetetrazol (Rylski et al., 2009; Mizoguchi and Yamada, 2013), or kainic acid (Zhang et al., 1998; Konopacki et al., 2007).”
Excitotoxicity Triggered by Neonatal Monosodium Glutamate Treatment and Blood–Brain Barrier Function
Gudiño‐Cabrera, G., Ureña‐Guerrero, M. E., Rivera-Cervantes, M. C., Feria‐Velasco, A., & Beas‐Zárate, C. (2014) · Archives of Medical Research · doi:10.1016/j.arcmed.2014.11.014 · Cited by 38 · see citing works
Matrix metalloproteinase-9 regulates neuronal circuit development and excitability
Murase, S., Lantz, C. L., Kim, E., Gupta, N., Higgins, R., Stopfer, M., Hoffman, D. A., & Quinlan, E. M. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9295-y · Cited by 35 · see citing works
“Interestingly, seizure-induced neuronal death is mediated by the MMP-9-dependent disruption of integrin β1-PI3K/Akt signaling [66], the same survival pathway that is disrupted by MMP-9 early in neonatal natural cell death, which coincides with high MMP-9 expression levels [7].”
Roles of Matrix Metalloproteinases and Their Targets in Epileptogenesis and Seizures
Mizoguchi, H., & Yamada, K. (2013) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2013.11.2.45 · Cited by 35 · see citing works
Pathophysiology of Trans-Synaptic Adhesion Molecules: Implications for Epilepsy
Gorlewicz, A., & Kaczmarek, L. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00119 · Cited by 27 · see citing works
Hoehna, Y., Uckermann, O., Luksch, H., Stefovska, V. G., Marzahn, J., Theil, M., Górkiewicz, T., Gawlak, M., Wilczynski, G. M., Kaczmarek, L., et al. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.06.023 · Cited by 27 · see citing works
Ganguly, K., Adhikary, K., Acharjee, A., Acharjee, P., Trigun, S. K., Mutlaq, A. S., Ashique, S., Yasmin, S., Alshahrani, A. M., & Ansari, M. Y. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.135967 · Cited by 23 · see citing works
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“According to recent studies, MMP-9 is thought to be strongly associated with the pathogenesis of many neurological disorders, such as Alzheimer’s disease, stroke, seizures and epilepsy [16, 17, 19].”
Backgroundde Araújo, M. A., Marques, T. E. B. S., Octacílio-Silva, S., Silva, C. L. D. A., Pereira, M. G. A. G., Peixoto-Santos, J. E., Kandratavicius, L., Leite, J. P., Garcia‐Cairasco, N., de Castro, O. W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163855 · Cited by 15 · see citing works
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Kaczmarek, L. (2018) · Postępy Biochemii · doi:10.18388/pb.2018_119 · Cited by 11 · see citing works
Talin 2 concentrations in cerebrospinal fluid in patients with epilepsy
Xiao, Z., Shen, L., Chen, D., Wang, L., Xi, Z., Xiao, F., & Wang, X. (2010) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2010.06.015 · Cited by 11 · see citing works
Ehlers, K., Brand, T., Bangert, A., Hauner, H., & Laumen, H. (2014) · British Journal Of Nutrition · doi:10.1017/s0007114514000208 · Cited by 10 · see citing works
“Furthermore, it is well established that Akt is activated by several other stimuli besides insulin or growth factors((35)) such as T- and B-cell receptor activation((36,37)) and integrins((38)).”
BackgroundChmielewska, N., Maciejak, P., Turzyńska, D., Sobolewska, A., Wisłowska-Stanek, A., Kołosowska, K., Płaźnik, A., & Szyndler, J. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.03.018 · Cited by 9 · see citing works
Effect of Androsterone after Pilocarpine-induced Status Epilepticus in Mice
Cho, I., Cho, Y., Kim, H., Heo, K. H., Lee, B.-I., & Won-Joo, K. (2014) · Journal of Epilepsy Research · doi:10.14581/jer.14002 · Cited by 7 · see citing works
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“Previous studies on animal models of epilepsy have indicated that MMPs are involved in epileptogenesis, apoptosis, and synaptic plasticity [39].”
BackgroundIshii, T., Kaya, M., & Muroi, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179259 · Cited by 7 · see citing works
“Moreover, a selective MMP-9 inhibitor and the polymethoxylated flavonoid tangeretin, which has an antiepileptic effect via MMP-9 downregulation, have been reported to prevent seizure-induced hippocampal damage via the activation of ILK and PI3K-Akt signaling [21,36].”
BackgroundInfluentialHippocampal YKL-40 expression in rats after status epilepticus.
Long, X., Hu, H., Li, S., Chen, M., Cai, J.-Z., & Song, B.-X. (2016) · Epilepsy Research · doi:10.1016/j.eplepsyres.2016.05.014 · Cited by 5 · see citing works
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“The role of Mmp9 in dendritic spine morphology, long-term potentiation, and seizure-induced cytotoxicity has previously been linked to the mechanisms of epileptogenesis 41–43 .”
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Expression of the Integrin-Linked Kinase in a Rat Kidney Model of Chronic Allograft Nephropathy
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Dolu, N., Artýþ, S., & Elalmýþ, D. (2011)
Extracellular matrix and perineuronal nets in neural plasticity, memory, and epileptogenesis
Zhu, H., Li, Q., Li, Y., & Wang, W. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1945520
“…pro-BDNF to mature BDNF (Mizoguchi et al., 2011); and Kim et al. demonstrated that after pilocarpine-induced status epilepticus, MMP-9 expression and activity increased while β 1-integrin levels decreased, supporting a role for MMP-9 in integrin-mediated hippocampal cell death (Kim et al., 2009).”
- Authors
- Kim, G. W., Kim, H.-J., Cho, K.-J., Kim, H.-W., Cho, Y.-J., & Lee, B. I.
- Affiliations
- Yonsei University (KR)
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 36
- Issue
- 1
- Pages
- 169-180
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2043899734
- Cited by
- 63
- References
- 68
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 1 · 2016: 6 · 2015: 2 · 2014: 8 · 2013: 6 · 2012: 5
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Yonsei University (6-2007-0118)
- Korea Science and Engineering Foundation (KOSEF-2-0709-0008)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- MMP-9, beta1 integrin, status epilepticus, pilocarpine, hippocampal cell death, apoptosis, integrin-linked kinase, Akt phosphorylation, MMP-9 inhibitors, neuroprotection, epilepsy
- MeSH terms
- Analysis of Variance, Animals, Antibodies, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Hippocampus, Male, Mice, Inbred C57BL, Phosphopyruvate Hydratase, Propidium, Statistics as Topic, Status Epilepticus, Time Factors, Signal Transduction, Up-Regulation, Cell Death, Integrin beta1, In Situ Nick-End Labeling, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Mice, Caspase 3, Matrix Metalloproteinase Inhibitors
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