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Int J Mol Sci. 2018 Jul 25;19(8). pii: E2178. doi: 10.3390/ijms19082178.

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

Author information

1
Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. jonathan.vinet@unimore.it.
2
Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. annamaria.costa@unimore.it.
3
Laboratory of Neural Circuit Development and Regeneration, Department of Biology, KU Leuven, 3000 Leuven, Belgium. manuel.salinas@um.es.
4
Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. giuseppina.leo@unimore.it.
5
Laboratory of Neural Circuit Development and Regeneration, Department of Biology, KU Leuven, 3000 Leuven, Belgium. lieve.moons@kuleuven.be.
6
Laboratory of Neuroplasticity and Neuroproteomics, Department of Biology, KU Leuven, 3000 Leuven, Belgium. lut.arckens@kuleuven.be.
7
Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. giuseppe.biagini@unimore.it.
8
Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41125 Modena, Italy. giuseppe.biagini@unimore.it.

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.

KEYWORDS:

blood–brain barrier leakage; metalloproteinase-12; optical neuropathy; pilocarpine; retinal ganglion cells; status epilepticus

PMID:
30044455
PMCID:
PMC6121268
DOI:
10.3390/ijms19082178
[Indexed for MEDLINE]
Free PMC Article

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