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The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse

Toldo, Stefano, PhD1,2; Mauro, Adolfo Gabriele, PhD1,2; Cutter, Zachary, MS1,2; Van Tassell, Benjamin W., PharmD1,2,3; Mezzaroma, Eleonora, PhD3; Del Buono, Marco Giuseppe, MD1; Prestamburgo, Andrea, MD1; Potere, Nicola, MD1; Abbate, Antonio, MD, PhD1,2

doi: 10.1097/FJC.0000000000000658
Original Article: PDF Only
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PAP

Background: Activation of the NLRP3 inflammasome is a primary driver of sterile inflammation in response to myocardial ischemia reperfusion. Pharmacologic inhibitors of the NLRP3 inflammasome are being developed. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could preserve myocardial function after ischemia reperfusion injury in the mouse.

Methods: We used an experimental murine model of myocardial ischemia reperfusion injury through transient ligation of the left coronary artery, and measured the effects of OLT1177 (6, 60 or 600 mg/kg intraperitoneal dose) on infarct size at pathology and on systolic cardiac function at echocardiography. To simulate a clinical scenario, we investigated the time window of therapeutic intervention with OLT1177 (60 mg/kg) administered 60, 120, or 180 minutes after reperfusion.

Results: OLT1177 was rapidly detectable in the plasma following intraperitoneal injection and had no effect on cardiac function in healthy mice. OLT1177 treatment at reperfusion showed significant dose-dependent reduction in infarct size (-36%, -67% and -62% for 6, 60 and 600 mg/kg, respectively; P<0.001 for linear trend, P=0.010 vs vehicle for 6 mg/kg and P<0.001 vs vehicle for 60 and 600 mg/kg) and preserved cardiac systolic function measured as LV fractional shortening (LVFS) at 24 hour and 7 days after injury (P=0.015 for 6 mg/kg and P<0.01 for 60 and 600 mg/kg). OLT1177 reduced infarct size also when given after 60 minutes of reperfusion (-71%, P<0.001 versus vehicle).

Conclusion: OLT1177 (dapansutrile), a NLRP3 inflammasome inhibitor, limits infarct size and prevents LV systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse.

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1VCU Pauley Heart Center,

2Victoria Johnson Research laboratories,

3Department of Pharmacotherapy and Outcome Studies - Virginia Commonwealth University, Richmond, VA, USA.

Address for correspondence: Stefano Toldo, PhD Assistant Professor of Medicine Virginia Commonwealth University, VCU Pauley Heart Center, Box 980281, 1200 E. road St., Richmond, VA, 23298 - USA Stefano.toldo@vcuhealth.org

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