Necrostatin : A potentially novel cardioprotective agent?

• Published in: Cardiovascular drugs and therapy 2007-08, Vol.21 (4), p.227-233
• Main Authors: SMITH, Christopher C. T, DAVIDSON, Sean M, LIM, Shiang Y, SIMPKIN, James C, HOTHERSALL, John S, YELLON, Derek M
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardiotonic Agents - administration & dosage; Cardiotonic Agents - pharmacology; Cardiovascular system; Cell Death - drug effects; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles - administration & dosage; Imidazoles - pharmacology; Indoles - administration & dosage; Indoles - pharmacology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mitochondrial Membrane Transport Proteins - drug effects; Myocardial Infarction - drug therapy; Myocardial Reperfusion Injury - drug therapy; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; tert-Butylhydroperoxide
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-007-6035-1

Necrostatin-1 (Nec-1), a small tryptophan-based molecule, was recently reported to protect the cerebral cortex against ischemia-reperfusion (I/R) injury. We investigated the actions of Nec-1 and its so-called inactive analog, Nec-1i, in the setting of myocardial I/R injury. The actions of Nec-1 and Nec-1i were examined in cultured C2C12 and H9c2 myocytes, cardiomyocytes isolated from male Sprague-Dawley rats, Langendorff isolated perfused C57Bl/6J mouse hearts and an in vivo open-chest C57Bl/6J mouse heart model. Nec-1 at 30 microM and 100 microM (but not 100 microM Nec-1i) reduced peroxide-induced cell death in C2C12 cells from 51.2 +/- 1.1% (control) to 26.3 +/- 2.9% (p < 0.01 vs control) and 17.8 +/- 0.9% (p < 0.001), respectively. With H9c2 cells cell death was also reduced from 73.0 +/- 0.4% (control) to 56.7 +/- 0% (30 microM Nec-1, p < 0.05) and 45.4 +/- 3.3% (100 microM Nec-1, p < 0.01). In the isolated perfused heart Nec-1 (30 microM) reduced infarct size (calculated as a percentage of the risk area) from 48.0 +/- 2.0% (control) to 32.1 +/- 5.4% (p < 0.05). Nec-1i (30 microM) also reduced infarct size (32.9 +/- 5.1%, p < 0.05). In anesthetized C57Bl/6J mice Nec-1 (1.65 mg/kg), given intraperitoneally to coincide with reperfusion following left anterior descending artery ligation (30 min), also reduced infarct size from 45.3 +/- 5.1% (control) to 26.6 +/- 4.0% (p < 0.05), whilst Nec-1i (1.74 mg/kg) was ineffective (37.8 +/- 6.0%). Stimulus-induced opening of the mitochondrial permeability transition pore (MPTP) in rat cardiomyocytes, as reflected by the time until mitochondrial depolarisation, was unaffected by Nec-1 or Nec-1i at 30 muM but increased at 100 muM i.e. 91% (p < 0.05 vs control) and 152% (p < 0.001) for Nec-1 and Nec-1i, respectively. This is the first study to demonstrate that necrostatins inhibit myocardial cell death and reduce infarct size, possibly via a mechanism independent of the MPTP.