Abstract
Hypoxia (HYPX) induced-overload Ca2+ entry results in increase of mitochondrial oxidative stress, inflammation and apoptosis in several neurons. Ca2+ permeable TRPM2 channel was gated by ADP-ribose (ADPR) and reactive oxygen species (ROS), although its activity was modulated in HYPX-exposed neurons by resveratrol (RSV). The aim of this study was to evaluate if a therapy of RSV can modulate the effect of HYPX in the TRPM2 expressing SH-SY5Y neuronal and HEK293 (no expression of TRPM2) cell lines. The SH-SY5Y and HEK293 cells were divided into four groups as control, RSV (50 μM and 24 hours), and HYPX and RSV + HYPX. For induction of HYPX in the cells, CoCl2 (200 μM and 24 hours) incubation was used. HYPX-induced intracellular Ca2+ responses to TRPM2 activation were increased in the SH-SY5Y cells but not in the HEK293 cells from coming H2O2 and ADPR. RSV treatment improved intracellular Ca2+ responses, mitochondrial function, suppressed the generation of cytokine (IL-1β and TNF-α), cytosolic and mitochondrial ROS in the SH-SY5Y cells. Intracellular free Zn2+, apoptosis, cell death, PARP-1, TRPM2 expression, caspase −3 and −9 levels are increased through activating TRPM2 in the SH-SY5Y cells exposed to the HYPX. However, the values were decreased in the cells by RSV and TRPM2 blockers (ACA and 2-APB). In SH-SY5Y neuronal cells exposed to HYPX conditions, the neuroprotective effects of RSV were shown to be exerted via modulation of oxidative stress, inflammation, apoptosis and death through modulation of TRPM2 channel. RSV could be used as an effective agent in the treatment of neurodegeneration exposure to HYPX.
Highlights
Extensive death in neurons was induced by acute hypoxia, because disability and mortality of the neurons were increased by acute hypoxia[1]
As the first step in the current study whether activations of TRP melastatin 2 (TRPM2) are related to HYPX treatment, the influences of the channels on [Ca2+]i concentration was examined by measurement of [Ca2+]i concentration using the TRPM2 channel activator (H2O2) and inhibitors [2-aminoethyl diphenylborinate, 2APB and N-(p-amylcinnamoyl) anthranilic acid, ACA]
We found that RSV incubation ameliorated HYPX-induced deleterious effects via modulating the intracellular Ca2+ hemostasis, inflammation, cell death, cell viability and apoptosis pathways, as www.nature.com/scientificreports
Summary
Extensive death in neurons was induced by acute hypoxia, because disability and mortality of the neurons were increased by acute hypoxia[1]. Hypoxia-induced mitochondria ROS generation was inhibited through modulation of voltage gated calcium channel (VGCC) in the heart cells by resveratrol (RSV) treatment[7,8]. RSV can be useful for treatment of hypoxia in neuronal cells by modulation of mitochondrial ROS generation and the subject should be clarified in the hypoxia-induced SH-SY5Y neuronal cells. In SH-SY5Y cells, increase of [Ca2+]i concentration through activation of TRPM2 channel induces increase the rate of caspase activation and apoptosis[14]. TRPM2 channel might be activated in SH-SY5Y neuronal cells by hypoxia-induced mitochondria ROS generation, the subject still remains uninvestigated. We propose that modulation of TRPM2 in the RSV treatment might represent a mechanism controlling adverse neurotoxicity actions in the SH-SY5Y neuronal cells with hypoxia. We used CoCl2 incubation in the SH-SY5Y model for induction of HYPX
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