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Int. J. Mol. Sci. 2018, 19(8), 2178; https://doi.org/10.3390/ijms19082178

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

1
Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
2
Laboratory of Neural Circuit Development and Regeneration, Department of Biology, KU Leuven, 3000 Leuven, Belgium
3
Laboratory of Neuroplasticity and Neuroproteomics, Department of Biology, KU Leuven, 3000 Leuven, Belgium
4
Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41125 Modena, Italy
*
Author to whom correspondence should be addressed.
Received: 28 June 2018 / Revised: 19 July 2018 / Accepted: 23 July 2018 / Published: 25 July 2018
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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Abstract

Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss. View Full-Text
Keywords: metalloproteinase-12; status epilepticus; optical neuropathy; blood–brain barrier leakage; pilocarpine; retinal ganglion cells metalloproteinase-12; status epilepticus; optical neuropathy; blood–brain barrier leakage; pilocarpine; retinal ganglion cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Vinet, J.; Costa, A.-M.; Salinas-Navarro, M.; Leo, G.; Moons, L.; Arckens, L.; Biagini, G. A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models. Int. J. Mol. Sci. 2018, 19, 2178.

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