Thioridazine interacts with the membrane of mitochondria acquiring antioxidant activity toward apoptosis – potentially implicated mechanisms

Abstract

1 We evaluated the eects of the phenothiazine derivative thioridazine on mechanisms of mitochondria potentially implicated in apoptosis, such as those involving reactive oxygen species (ROS) and cytochrome c release, as well as the involvement of drug interaction with mitochondrial membrane in these eects. 2 Within the 0 ± 100 mM range thioridazine did not reduce the free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) nor did it chelate iron. 3 However, at 10 mM thioridazine showed important antioxidant activity on mitochondria, characterized by inhibition of accumulation of mitochondria-generated O 2 .7, assayed as lucigeninderived chemiluminescence, inhibition of Fe 2+ /citrate-mediated lipid peroxidation of the mitochondrial membrane (LPO), assayed as malondialdehyde generation, and inhibition of Ca 2+ /t-butyl hydroperoxide (t-BOOH)-induced mitochondrial permeability transition (MPT)/protein-thiol oxidation, assayed as mitochondrial swelling. 4 Thioridazine respectively increased and decreased the¯uorescence responses of mitochondria labelled with 1-aniline-8-naphthalene sulfonate (ANS) and 1-(4-trimethylammonium phenyl)-6 phenyl 1,3,5-hexatriene (TMA-DPH). 5 The inhibition of LPO and MPT onset correlated well with the inhibition of cytochrome c release from mitochondria. 6 We conclude that thioridazine interacts with the inner membrane of mitochondria, more likely close to its surface, acquiring antioxidant activity toward processes with potential implications in apoptosis such as O 2 .7 accumulation, as well as LPO, MPT and associated release of cytochrome c.

Evaluation of functional stability of quercetin as a raw material and in different topical formulations by its antilipoperoxidative activity

“…32 There is consistent evidence that quercetin presents high antilipoperoxidative activity by scavenging free radicals and chelating metals. 23 Reinforcing these concepts, it was detected that quercetin interferes with the formation of the Fe 2 (BPS) 3 complex, and additionally, the Fe-flavonoid complex maintains the free-radical scavenging activity. 8,10,33 Due to these properties of quercetin, the method used in this study was shown to be appropriate.…”

“…21 This is a widely used method to evaluate antilipoperoxidative activity. 7,22,23 To 1.0 mL of medium 1, were added, respectively, 10 μL of each sample of the above prepared solutions and mitochondria to produce a final concentration of 1 mg of protein, plus 50 μmol/L of (NH 4 ) 2 Fe(SO 4 ) 2 and 2 mmol/L of sodium citrate. The solution was kept for 30 minutes at 37°C.…”

Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning

“…Released cytochrome C and apoptotic protease activating factor-1 (Apaf-1) and Caspase-9 were combined, and then Cytc-Apaf-1-Caspase-9 compound was formed, which would lead to the activation of pro-Caspase-9, and subsequently, downstream Caspase-3 was activated, and apoptic cascade reaction was promoted. At the same time, part of the unreleased cytochrome C was steadily combined with cytochrome b-c1 and C oxidase, and adequate ATP was produced to provide energy for apoptosis [20][21][22][23] . The other was through necrotic process.…”

Mitochondrial involvement in psychiatric disorders

“…Research suggests antipsychotic treatment may be related to increased antiapoptotic effects mediated by mitochondrial signals (43). Expression of antiapoptosis genes Bcl-2 and Bcl-x L is increased by haloperidol treatment (44)(45)(46), and both prevent the release of proapoptotic substances such as cytochrome c (44).…”