Apoptotic and Anti-Angiogenic Effects of Benzimidazole Compounds: Relationship with Oxidative Stress Mediated Ischemia/Reperfusion Injury in Rat Hind Limb

Abstract

Ischemia/reperfusion (I/R)-induced injury is a pathophysiological process consisting of a complex cascade characterized by an increase in reactive oxygen species production, pro-inflammatory cytokine release, and activated endothelial cells leading to cell damage and death. The aim of this study was to investigate effects of substituted 2-benzylbenzimidazole derivatives, 2-(3-methoxybenzyl)benzimidazole (BB3) and 2-(4-methoxybenzyl)benzimidazole (BB4), on I/R-induced changes in the markers of oxidative stress, apoptosis, and angiogenesis in rats. BB3 and BB4 were synthesized with microwave irradiation and conventional Phillips methods. I/R was performed by occlusion of femoral artery. Catalase activity and reduced glutathione (GSH) levels as well as caspase-3, -8, and -9 activities were measured in muscle tissues as an index for oxidative stress and apoptosis, respectively. Vascular endothelial growth factor (VEGF) levels as an index for angiogenesis were also measured in the muscle tissues and sera. I/R decreased GSH levels, increased catalase activity and VEGF levels, and did not change caspase-3, -8, and -9 activities compared to control groups. BB3 and BB4 caused a further decrease in GSH levels and increased caspase-3, -8, and -9 activities in I/R group. These compounds caused a further increase in catalase activity and prevented the increase in VEGF levels induced by I/R. These data suggest that BB3 and BB4 exhibit apoptotic and anti-angiogenic activity with pro-oxidative effects resulting in oxidative stress in pathophysiological process of I/R-induced hind limb injury in rats.

Role of Scutellarin in Ameliorating Lung Injury in a Rat Model of Bilateral Hind Limb Ischemia–Reperfusion

“…The concept that hind limb I/R could exert oxidative stress in rats (Algul et al, 2012;Zhu et al, 2017) was confirmed by the present study, as our data revealed a statistically significant upregulation of iNOS immunoexpression in the lung tissue cells of rats undergoing hind limb I-R as compared to control. During I-R injury, it has been shown that oxidants (especially iNOS), infiltrated leukocytes, and inflammatory molecules can work together to injure the pulmonary microvasculature leading to a loss of microvascular integrity and eventually gas exchange impairment and pulmonary dysfunction (Wang le et al, 2002).…”

Anti-GBM potential of Rosmarinic acid and its synthetic derivatives via targeting IL17A mediated angiogenesis pathway

“…The FDA has recently approved ROS generating monoclonal antibody based drugs for brain tumors. A similar kind of pro-oxidative, apoptotic and anti-angiogenic mechanism is also observed in RA derivatives (Oztekin et al, 2012).…”

Green Synthesis of Privileged Benzimidazole Scaffolds Using Active Deep Eutectic Solvent

“…More recently, the treatment potency of benzimidazoles in diseases such as ischemia-reperfusion injury or hypertension, have also been reported [5].…”