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Necrostatin: A potentially novel cardioprotective agent?

Smith, CCT; Davidson, SM; Lim, SY; Simpkin, JC; Hothersall, JS; Yellon, DM; (2007) Necrostatin: A potentially novel cardioprotective agent? Cardiovascular Drugs and Therapy , 21 (4) pp. 227-233. 10.1007/s10557-007-6035-1.

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Abstract

Background: 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. Materials and methods: 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. Results: Nec-1 at 30 μM and 100 μM (but not 100 μM 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 μM Nec-1, p<0.05) and 45.4±3.3% (100 μM Nec-1, p<0.01). In the isolated perfused heart Nec-1 (30 μM) 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 μM) 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 μM but increased at 100 μM i.e. 91% (p<0.05 vs control) and 152% (p<0.001) for Nec-1 and Nec-1i, respectively. Conclusion: 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. © 2007 Springer Science+Business Media, LLC.

Type: Article
Title: Necrostatin: A potentially novel cardioprotective agent?
DOI: 10.1007/s10557-007-6035-1
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: http://discovery.ucl.ac.uk/id/eprint/10029775
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