Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo

Figure 2

In vivo and in vitro effect of MMP-12 inhibition in endotoxemia. (a) Survival in function of time of MMP-12^+/+ (black) and MMP-12^−/− (grey) mice following i.p. challenge with a lethal dose of LPS. (b) Survival in function of time of C57BL/6 mice injected with vehicle (black) or MMP-12i (grey) following i.p. challenge with a lethal dose of LPS. (c) Relative Mmp-12 expression in choroid plexus tissue isolated before and 1, 4, and 8 hours after LPS challenge (-4). (d) Relative permeability of the blood-CSF barrier determined by measuring leakage of fluorescently labeled dextran (4 kDa) from the blood into the CSF 8 hours after LPS challenge in vehicle (black) and MMP-12i (grey) treated wild type mice, compared to PBS injected wild type mice. (e) Normalized resistance measured at low frequency using the ECIS instrument of primary choroid plexus epithelial cells incubated with vehicle (black), 1000 ng/mL LPS (black dotted line), and 1000 ng/mL LPS pretreated with 1 μM MMP-12 inhibitor (grey) (). Data are presented as means ± standard error of mean (sem). Survival curves were compared using a log-rank test. Other data were analyzed by Student’s t-test. 0.01 ≤ ; 0.0001 ≤ ; .

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