Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function

Abstract

Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.

Indole Alkaloid Derivative B, a Novel Bifunctional Agent That Mitigates 5-Fluorouracil-Induced Cardiotoxicity

“…Initially, we evaluated the antioxidant effects of IADB , alone or in combination with 5-FU, in the control H9C2 rat cardiomyoblasts and the colon cancer cell line HT-29. We employed MitoProbe, − a sensitive fluorogenic reporter, for real-time monitoring of mitochondrial ROS (mtROS) generation. The MFI of MitoProbe was quantified as a gauge of mtROS production.…”

A Novel Mitophagy Enhancer Protects Cardiomyocytes against Hypoxia/Reoxygenation

“…b-carbolines are biologically active alkaloids, and these compounds have been reported to possess a wide range of biological effects, such as anti-inflammatory, antithrombotic activities, antivirus, anticancer and free radical scavenging activities [46]. Previous studies demonstrated the potential application of b-carboline derivatives in the treatment of cardiovascular diseases like hypertension [47], myocardial infarction [25], [48], cancer [49][50][51][52], and ischemia/reperfusion injury [53][54][55][56][57][58][59]. In addition, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (Tempol) has gained attention.…”

“…To monitor mitochondrial ROS production during H/R, H9C2 cells were labeled with MitoProbe (a fluorogenic dye that is highly sensitive for monitoring mtROS [33][34][35][36][37][38][39]). Through measurement of the MFI of MitoProbe at different time points of H/R, the total amount of mtROS could be estimated.…”

“…Cardiomyocytes H9C2 were counter-stained with MitoProbe and Hoechst 33342, respectively. MitoProbe is a group of novel fluorogenic probes specifically localized in mitochondria and can be employed both in vivo and in vitro for the detection of mitochondrial ROS generation [33][34][35][36][37][38][39]. Mitochondrial ROS (mtROS) generation and the mitochondrial morphology changes can be directly visualized under confocal fluorescence microscopy (Figure 3A) using cell samples subjected to the same H/R protocol.…”

Pharmacological Modulation of Autophagy Prevents Mutant SOD1G93AInduced Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)

“…34 The indole derivatives have been reported to possess anti-inflammatory, free radical scavenging activity, mitochondrial protection, and autophagy-modulating activity. [50][51][52][53][54][55] For example, IADB, a novel indole alkaloid-nitroxide conjugate, has been reported to exert mitochondrial protection and cardio-protection through its autophagy-modulating potential. 52 In our present study, we attempted to further examine the role of IADB in the SOD1 G93A -associated experimental models of ALS.…”