Role of Peripheral Benzodiazepine Receptors in Mitochondrial, Cellular, and Cardiac Damage Induced by Oxidative Stress and Ischemia-Reperfusion

Abstract

Mitochondrial dysfunction has been identified as a possible early event in ischemia-reperfusion damage. The peripheral benzodiazepine receptor, a mitochondrial inner membrane protein, has already been proposed to play a role in mitochondrial regulation, although its exact function remains unclear. The aim of this work was to determine the role of peripheral benzodiazepine receptor in ischemia-reperfusion injury and to test the potential beneficial effect of a novel potent peripheral benzodiazepine receptor ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b]indole-1-acetamide (SSR180575). To characterize and link the mitochondrial, cellular, and cardiac consequences of ischemia-reperfusion, we examined the effects of SSR180575 in several in vitro and in vivo models of oxidative stress. Hydrogen peroxide decreased mitochondrial membrane potential, reduced oxidative phosphorylation capacities, and caused cytochrome c release, caspase 3 activation, and DNA fragmentation. SSR180575 (100 nM-1 M) prevented all these effects. In perfused rat hearts, SSR180575 administered in vitro (100 nM-1 M) or by oral pretreatment (3-30 mg/kg) greatly reduced the contractile dysfunction associated with ischemia-reperfusion. Furthermore, in anesthetized rats, SSR180575 (3-30 mg/kg p.o.) produced significant reductions in infarct size after coronary artery occlusion/reperfusion. In conclusion, we have demonstrated that peripheral benzodiazepine receptor play a major role in the regulation of cardiac ischemia-reperfusion injury and that SSR180575, a novel peripheral benzodiazepine receptor ligand, is of potential interest in these indications.

Peripheral Benzodiazepine Receptor-Induced Myocardial Protection is Mediated by Inhibition of Mitochondrial Membrane Permeabilization

“…Several reports suggest that PBR ligands might modulate apoptotic responses (Bono et al, 1999) and play an antiapoptotic role in oxidative stress conditions such as ischemia-reperfusion (Carayon et al, 1996). In agreement with this role, Leducq et al (2003) showed that the irreversible PBR ligand SSR180575 prevented the cellular damages against oxidative stress and cardiac injuries induced by ischemia-reperfusion in rodents, but the mechanism involved in these effects remains unclear.…”

TRO40303, a New Cardioprotective Compound, Inhibits Mitochondrial Permeability Transition

“…Additional proteins such as the translocator protein 18 kDa (TSPO), formerly known as the peripheral benzodiazepine receptor, have been shown to interact with proteins implicated in mPTP formation and potentially regulate the pore (Veenman et al, 2007). Selective TSPO ligands, such as chlorodiazepam (Ro5-4864) (Obame et al, 2007) or 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575) (Leducq et al, 2003), were reported to provide cardioprotection in preclinical models of I/R. The pro-and antiapoptotic Bcl-2 family proteins regulate mitochondrial permeability transition either by directly and independently forming a membrane channel or by interaction with mitochondrial membrane proteins such as VDAC (Shimizu et al, 1999) or adenine nucleotide translocase (Marzo et al, 1998).…”

The Effect of Diazepam on the Function of Hypertrophied Rats’ Hearts in Ischemia-Reperfusion Conditions

“…This showed the relative reduction of CMI% in the presence of diazepam. Consistently, several studies have shown that the presence of PBR ligands, including Ro5-4864 and SSR180575, could reduce oxidative stress, thereby preventing cardiac hypertrophy (3,23,24). Oxidative stress is implicated in development and progression of cardiac hypertrophy (25).…”

“…Similarly, our results showed for the first time that diazepam, as a common clinical drug, could prevent isoproterenol-induced cardiac hypertrophy, which could probably be explained by the above-mentioned modulatory effect of this drug as a PBR ligand. On the other hand, several studies have shown that diazepam was able to affect cells by mechanisms related or unrelated to PBRs (24,26). For example, diazepam decreased the Ca 2+ transient and the L-type Ca 2+ channel, which are both important in the negative inotropism and chronotropism caused by this drug (27)(28)(29).…”