Protective effects of l-carnitine and piracetam against mitochondrial permeability transition and PC3 cell necrosis induced by simvastatin

Abstract

Mitochondrial oxidative stress followed by membrane permeability transition (MPT) has been considered as a possible mechanism for statins cytotoxicity. Statins use has been associated with reduced risk of cancer incidence, especially prostate cancer. Here we investigated the pathways leading to simvastatin-induced prostate cancer cell death as well as the mechanisms of cell death protection by l-carnitine or piracetam. These compounds are known to prevent and/or protect against cell death mediated by oxidative mitochondrial damage induced by a variety of conditions, either in vivo or in vitro. The results provide evidence that simvastatin induced MPT and cell necrosis were sensitive to either l-carnitine or piracetam in a dose-dependent fashion and mediated by additive mechanisms. When combined, l-carnitine and piracetam acted at concentrations significantly lower than they act individually. These results shed new light into both the cytotoxic mechanisms of statins and the mechanisms underlying the protection against MPT and cell death by the compounds l-carnitine and piracetam.

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis

“…The nootropic compound piracetam is used for the treatment of age-related cognitive impairment and dementia (Waegemans et al, 2002) and was found to enhance— among other mitochondrial parameters—mitochondrial respiration, ETC activity, and ATP production in particular in cells with compromised mitochondrial function (Costa et al, 2013; Keil et al, 2006; Kurz et al, 2010; Leuner et al, 2010; Stockburger et al, 2013; Zhang et al, 2010). Piracetam treatment of NSPCs derived from 1-year-old mice resulted in a trend toward increased proliferation, which was paralleled by a significant increase in ATP production in the absence of changes in mitochondrial membrane potential (Figures 5A–5C).…”

High-content screening of drug-induced mitochondrial impairment in hepatic cells: effects of statins

“…moreover, when cells were coincubated with cyclosporin A, a well-known mPT pore inhibitor, the different statins mPT was blocked. In fact, mPT has been implicated in simvastatin's toxicity (Costa et al 2013), which indicates that mitochondrial oxidative stress followed by membrane permeability transition could be considered as a possible mechanism for statins cytotoxicity (Costa et al 2013). However, pravastatin did not show mPT formation, although a significant increase in the amount of calcium was observed.…”

Creatine, L-Carnitine, andω3 Polyunsaturated Fatty Acid Supplementation from Healthy to Diseased Skeletal Muscle

“…Gramignano et al [139], studying the efficacy of L-carnitine supplementation (6 g/day for 4 weeks) in a population of advanced cancer patients, found a decreased ROS and increased glutathione peroxidase levels. Promising antioxidant activities have been also found following supplementation in patients with nonalcoholic steatohepatitis [140], renal disease [141], and phenylketonuria [142], as well as in several experimental models of oxidative stress [143–146]. Interestingly, recent evidence suggests that carnitine supplementation may also directly act as radical scavenger, thus contributing to protection against statin-induced oxidative muscle damage [146, 147].…”