N‐acetyl‐L‐cysteine protects against cadmium‐induced neuronal apoptosis by inhibiting ROS‐dependent activation of Akt/mTOR pathway in mouse brain

Abstract

Aims This study explores the neuroprotective effects and mechanisms of N-acetyl-L-cysteine (NAC) in mice exposed to cadmium (Cd). Methods NAC (150 mg/kg) was intraperitoneally administered to mice exposed to Cd (10-50 mg/L) in drinking water for 6 weeks. The changes of cell damage and death, reactive oxygen species (ROS), antioxidant enzymes, as well as Akt/mammalian target of rapamycin (mTOR) signaling pathway in brain neurons were assessed. To verify the role of mTOR activation in Cd-induced neurotoxicity, mice also received a subacute regimen of intraperitoneally administered Cd (1 mg/kg) with/without rapamycin (7.5 mg/kg) for 11 days. Results Chronic exposure of mice to Cd induced brain damage or neuronal cell death, due to ROS induction. Co-administration of NAC significantly reduced Cd levels in the plasma and brain of the animals. NAC prevented Cd-induced ROS and significantly attenuated Cd-induced brain damage or neuronal cell death. The protective effect of NAC was mediated, at least partially, by elevating the activities of Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, as well as the level of glutathione in the brain. Furthermore, Cd-induced activation of Akt/mTOR pathway in the brain was also inhibited by NAC. Rapamycin in vitro and in vivo protected against Cd-induced neurotoxicity. Conclusions NAC protects against Cd-induced neuronal apoptosis in mouse brain partially by inhibiting ROS-dependent activation of Akt/mTOR pathway. The findings highlight that NAC may be exploited for prevention and treatment of Cd-induced neurodegenerative diseases.

Effect Comparison of Both Iron Chelators on Outcomes, Iron Deposit, and Iron Transporters After Intracerebral Hemorrhage in Rats

“…Fluorescent intensity for the conversion of DCFH-DA to fluorescent product DCF was analyzed at 485 nm excitation and 535 nm emission using a fluorescence spectrophotometer. ROS was quantified from a DCF standard curve and data are expressed as picomole per minute per milligram protein [19].…”

The environmental pollutant cadmium induces homeostasis alteration in muscle cells in vitro

“…Interestingly, ER, both alpha and beta, has been described in skeletal muscle cells [43], strongly indicating that the protective effects of estrogen replacement therapy on both muscle mass and strength might be mediated by a specific receptor-mediated mechanism [44]. Since our group, as well as others, has demonstrated a potential interfering role of Cd on ER pathways [11][12][13], the exposure to this environmental pollutant could interfere with muscle homeostasis maintained by ER. Indeed estrogens are known to modulate energy metabolism and mitochondrial function in muscle cells by an ERmediated mechanism [45].…”

“…Cd is a multitarget toxicant responsible for kidney, liver, reproductive organs and bone damages as recently well reviewed by Bernhoft [3]. This pollutant increases DNA synthesis, stimulates proto-oncogene and transcription factors expression, as well as stress proteins synthesis, and up-regulates proinflammatory cytokines levels and several kinases activity [4][5][6][7] in different cell types such as kidney cells, thymocites, pancreatic beta cells, osteoblasts and breast cancer cells [7][8][9][10][11][12][13]. All these previously published data suggest an interaction between Cd and intracellular proteins leading to activation of downstream signaling events which can significantly alter the physiological cellular homeostasis.…”

Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner

“…Despite many studies showing that ROS generation can inhibit Akt/mTOR pathway, there is, however, mounting evidence demonstrating that mTOR pathway can be activated by ROS and that the addition of antioxidants can prevent its stimulation [44][45][46][47][48]. Since mTOR pathway, in addition to promoting protein synthesis, activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease [49], our results can represent a first step in the elucidation of the metabolic reprogramming of cancer cells treated with RNases.…”