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.
['Vinet|Jonathan|J|', 'Costa|Anna-Maria|AM|0000-0003-3152-9890', 'Salinas-Navarro|Manuel|M|', 'Leo|Giuseppina|G|', 'Moons|Lieve|L|', 'Arckens|Lutgarde|L|', 'Biagini|Giuseppe|G|']
D000818:Animals D056654:CA3 Region, Hippocampal D018891:Dentate Gyrus D004195:Disease Models, Animal D004791:Enzyme Inhibitors D006801:Humans D008297:Male D053508:Matrix Metalloproteinase 12 D008810:Mice, Inbred C57BL D009409:Nerve Crush D018696:Neuroprotective Agents D009900:Optic Nerve D020221:Optic Nerve Injuries D010862:Pilocarpine D011753:Pyrones D051381:Rats D012640:Seizures D013226:Status Epilepticus
metalloproteinase-12 status epilepticus pilocarpine blood–brain barrier leakage optical neuropathy retinal ganglion cells