A hydroxypyrone-based inhibitor of metalloproteinase-12 displays neuroprotective properties in both status epilepticus and optic nerve crush animal models

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.