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Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia.
J Cereb Blood Flow Metab. 2008 Oct; 28(10):1674-85.JC

Abstract

Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1(-/-) and TIMP-2(-/-) mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1(-/-) mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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Authors+Show Affiliations

Fujimoto M
Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takagi Y
No affiliation info available
Aoki T
No affiliation info available
Hayase M
No affiliation info available
Marumo T
No affiliation info available
Gomi M
No affiliation info available
Nishimura M
No affiliation info available
Kataoka H
No affiliation info available
Hashimoto N
No affiliation info available
Nozaki K
No affiliation info available

MeSH

AnimalsApoptosisBlood-Brain BarrierBrainBrain IschemiaCaspase 3MaleMatrix Metalloproteinase 2Matrix Metalloproteinase 9MiceMice, Inbred C57BLMice, KnockoutNeuronsRNA, MessengerTight JunctionsTissue Inhibitor of Metalloproteinase-1Tissue Inhibitor of Metalloproteinase-2

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18560439

Citation

Fujimoto, Motoaki, et al. "Tissue Inhibitor of Metalloproteinases Protect Blood-brain Barrier Disruption in Focal Cerebral Ischemia." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 28, no. 10, 2008, pp. 1674-85.
Fujimoto M, Takagi Y, Aoki T, et al. Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia. J Cereb Blood Flow Metab. 2008;28(10):1674-85.
Fujimoto, M., Takagi, Y., Aoki, T., Hayase, M., Marumo, T., Gomi, M., Nishimura, M., Kataoka, H., Hashimoto, N., & Nozaki, K. (2008). Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 28(10), 1674-85. https://doi.org/10.1038/jcbfm.2008.59
Fujimoto M, et al. Tissue Inhibitor of Metalloproteinases Protect Blood-brain Barrier Disruption in Focal Cerebral Ischemia. J Cereb Blood Flow Metab. 2008;28(10):1674-85. PubMed PMID: 18560439.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia. AU - Fujimoto,Motoaki, AU - Takagi,Yasushi, AU - Aoki,Tomohiro, AU - Hayase,Makoto, AU - Marumo,Takeshi, AU - Gomi,Masanori, AU - Nishimura,Masaki, AU - Kataoka,Hiroharu, AU - Hashimoto,Nobuo, AU - Nozaki,Kazuhiko, Y1 - 2008/06/18/ PY - 2008/6/19/pubmed PY - 2008/10/18/medline PY - 2008/6/19/entrez SP - 1674 EP - 85 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J Cereb Blood Flow Metab VL - 28 IS - 10 N2 - Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1(-/-) and TIMP-2(-/-) mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1(-/-) mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/18560439/Tissue_inhibitor_of_metalloproteinases_protect_blood_brain_barrier_disruption_in_focal_cerebral_ischemia_ L2 - https://journals.sagepub.com/doi/10.1038/jcbfm.2008.59?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -