Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression

Abstract

Reperfusion after a period of ischemia is associated with the formation of reactive oxygen species (ROS) and Ca2+ overload resulting in the opening of a nonspecific pore in the inner membrane of the mitochondria, called the mitochondrial permeability transition pore (PTP), leading to cell damage. Although endogenous antioxidants are activated because of oxidative stress following ischemia, their levels are not high enough to prevent reperfusion injury. Hence there is always a need for exogenous supplement of antioxidants, especially after acute ischemia. Here we demonstrated the effects of the antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) in preventing reperfusion injury of the heart by inhibition of PTP opening. Ischemia (30 min) by left coronary artery (LCA) occlusion and reperfusion (120 min) in Wistar rats after pretreatment with MCI-186 (10 mg/kg iv) infusion starting from 30 min before LCA occlusion resulted in 1) less area of myocardial infarction (19.2% vs. 61.6%), 2) well-maintained myocardial ATP content (P < 0.03 vs. control), 3) decreased mitochondrial swelling and reduced cytochrome c release, 4) increased expression of BCl-2, 5) lower prevalence of apoptotic cells (14.3% vs. 2.9%), and 6) reduced DNA fragmentation in the MCI-186-treated group. These cytoprotective effects of MCI-186 were inhibited on opening PTP before MCI-186 treatment with the PTP activators lonidamine (10 mg/kg iv) or atractyloside (5 mg/kg iv) but failed to inhibit the protective effects exerted by another antioxidant, allopurinol, suggesting that the PTP inhibiting property is specific for MCI-186. These results demonstrate that the radical scavenger MCI-186, by inhibiting the opening of the PTP, prevents necrosis and cytochrome c release and hence pathological apoptosis.

Edaravone protects PC12 cells from ischemic-like injury via attenuating the damage to mitochondria

“…Recently, to prove edaravone prevents apoptosis, most researches were performed on animal model (Amemiya et al, 2005;Dong et al, 2004;Rajesh et al, 2003), and edaravone delaying apoptosis has been confirmed. But few experiments on cellular level were reported on the removal an obstacle from blood vessels and circulatory system.…”

Beyond neurological disease: New targets for edaravone (Review)

“…Edaravone also prevented lethal ventricular tachyarrhythmias upon reperfusion and deteriorations in cardiac function following ischemia and I/R in rats, by inhibiting lipid peroxidation (23). In an experimental rat model of coronary occlusion, edaravone reduced the MI area, maintained adequate myocardial ATP content, decreased mitochondrial swelling, reduced cytochrome-c release, increased the expression of Bcl2, and reduced the number of apoptotic cells and DNA fragmentation (24). Edaravone also protected cardiac function in rats and reduced infarct size by decreasing the production of tumor necrosis factor α (TNF-α) in the myocardium exposed to I/R injury, and by reducing the release of adhesion molecules, such as P-selectin, from vascular endothelial cells (25).…”

Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle

“…Elevated levels of oxidative and nitrosative stress have been shown to promote mPTP opening (Rajesh, Sasaguri, Suzuki, and Maeda 2003;Marriott, Ali, Read, Mitchell, Whyte, and Dockrell 2004;Zhang, Li, Prabhakaran, Borowitz, and Isom 2006) and to induce a pro-apoptotic shift of the mitochondrial Bcl-2 family pattern (Savory, Rao, Huang, Letada, and Herman 1999;Mishra, Randis, Ashraf, and ivoria-Papadopoulos 2006;Qin, Yan, Patel, Liu, and Dong 2006). Therefore, we determined tissue levels of lipid peroxidation and nitrosative stress by assaying for HNE-modified proteins and 3-nitrotyrosine, respectively.…”

“…In fact, Bid and Bax have been shown to promote mPTP opening Zamzami et al 2000), whereas anti-apoptotic members of the Bcl-2 family (e.g., Bcl-2 and Bcl-x L ) exert an inhibitory effect . Opening of the mPTP is provoked by several factors, including elevated levels of oxidative (Rajesh et al 2003) and nitrosative stress (Marriott et al 2004;Zhang et al 2006). Furthermore, it has been shown that enhanced production of reactive oxygen (ROS) and nitrogen species (RNS) may induce a proapoptotic shift of the pattern of expression of Bcl-2 proteins (e.g., increased Bax to Bcl-2 ratio) (Savory et al 1999;Mishra et al 2006;Qin et al 2006).…”