Oxidative stress inhibits ionomycin‐mediated cell death in cortical neurons

Abstract

Thiol-proteases play important roles in many cellular processes, including maintenance of protein homeostasis and execution of cell death. Therefore, determining how this family of enzymes is regulated is critical for our understanding of both physiological and pathological conditions. Because these proteases require a reduced cysteine residue for activity, the cellular redox state plays a crucial role in regulating the activity of thiol proteases. Importantly, increased oxidative stress can result in the direct modification of the active site cysteine, leading to enzyme inactivation. This would suggest that oxidative stress that occurs during pathological insults could prolong cell survival by preventing the execution of thiol-protease-dependent cell death pathways. To test this hypothesis, cultured rat cortical neurons were treated with the oxidizing agent diamide or doxorubicin in the presence or absence of the calcium ionophore ionomycin. Under normoxic conditions, ionomycin treatment resulted in approximately 70% cell death, which was prevented by addition of the calpain-selective inhibitor benyzloxycarbonyl-Leu-Leu-Tyr fluoromethylketone. Similarly, pretreatment of neurons with either oxidant was also protective. Protection resulting from oxidative stress was not due to new protein synthesis, insofar as cycloheximide did not affect oxidant-mediated protection. Interestingly, treatment with the antioxidant Trolox to reverse or prevent oxidative stress blocked the protective effects of both oxidants against ionomycin-induced cell death. We interpret these findings to suggest that, in diseases or conditions in which oxidative stress is increased, the ability of thiol-proteases to execute cell death pathways fully is decreased and may prolong cell survival.

Adverse Neurodevelopmental Effects of Dexamethasone Modeled in PC12 Cells: Identifying the Critical Stages and Concentration Thresholds for the Targeting of Cell Acquisition, Differentiation and Viability

“…One possibility, then, is that DEX reduces oxidative stress in differentiating neural cells, an effect that could contribute to apparent protective actions of this treatment toward hypoxic-ischemic brain damage (Barks et al, 1991). On the other hand, a moderate degree of oxidative stress actually provides one of the normal ontogenetic signals that initiates differentiation and is also required to prevent apoptotic cell death (Ikeda et al, 2002;Katoh et al, 1997;McCollum et al, 2004). The key factor may then be both the dose and timing of DEX administration.…”

Photoreceptor Cell Death Mechanisms in Inherited Retinal Degeneration

“…Since antioxidants and calpain inhibitors have synergistic protective effects [186], it is even possible that oxidative stress and calpain activation go hand in hand. Paradoxically, oxidative stress may also prolong neuronal survival by inactivating calpains and caspases through oxidation of the cysteine residue that is essential for their activity [185,196]. Further experimental studies will be required to identify the relation between oxidative stress and calpains by investigating their interplay in the context of photoreceptor cell death.…”

Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

“…pattern emerged from reports on the antibacterial potential of carboxyl polyethers with respect to a strong selectivity towards Gram-positive bacteria [ 1 ,5,10,8,16,17-19 ,20,21]. Monensin (2), narasin (3), salinomycin (4), nigericin (5), lenoremycin (6), septamycin (7), carriomycin (8), X-14766A (9), noboritomycin A (10), alborixin (11), ionomycin (12), A23187 (13), X-14547A (14), lysocellin (15) and lasalocid (1) were all evaluated against eight Gram-positive bacteria (cocci, rods, filamentous) as well as against seven Gramnegative bacteria, and four fungal species. All but ionomycin (12) showed potent activity against Gram-positive bacteria (MIC varying in the range 0.006 -12.5 μg/ml).…”

“…There are some exceptions: several species of fungi such as Paecilomyces variotii, Candida albicans, Saccharomyces cerevisiae and Penicillium digitatum are reported as moderately sensitive to some carboxylic polyethers, for example, grisorixin (16) [ 11 ], monensin (2) [ 1 ], narasin (3) [ 1 ], salinomycin (4) [ 1 ], lenoremycin (6) [ 1 ], carriomycin (8) [ 1 ], alborixin (11) [ 1 ], A23187 (13) [ 1 ], dianemycin (20) [ 11 ], lysocellin (45) [ 1 ], X-14931A (48) [ 16 ] and leuseramycin (26) [ 23 ], with MIC values varying in the range of 20 -100 μg/ml. P. variotii, C. albicans, S. cerevisiae and P. digitatum were quite sensitive to several other carboxyl polyethers such as lysocellin (15) [ 1 ], A23187 (13) [ 1 ], lenoremycin (6) [ 1 ] and nigericin (5) [ 1 ]. The MIC values for these compounds were < 2 μg/ml.…”