P2X7 Cell Death Receptor Activation and Mitochondrial Impairment in Oxaliplatin-Induced Apoptosis and Neuronal Injury: Cellular Mechanisms and In Vivo Approach

France Massicot, Guillaume Hache, Ludivine David, Dominique Chen, Charlotte Leuxe, Laure Garnier-Legrand, Patrice Rat, Olivier Laprévote, François Coudoré, France Massicot, Guillaume Hache, Ludivine David, Dominique Chen, Charlotte Leuxe, Laure Garnier-Legrand, Patrice Rat, Olivier Laprévote, François Coudoré

Abstract

Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Cell viability and membrane integrity…
Figure 1. Cell viability and membrane integrity in SH-SY5Y cells exposed to oxaliplatin.
Cells (2×105 cells/well) were exposed 24 h to oxaliplatin (OXA) (2–200 µM). Cell viability (redox potential) was evaluated with Alamar blue and membrane integrity was evaluated with neutral red tests (A). Cell viability which is indicative of mitochondrial metabolism was evaluated with MTT test (B). Values are the mean ± S.E.M. expressed as percentage of the control, five different assays per group. *: statistically different (p<0.05) from the mean values in control cells.
Figure 2. Oxidative stress and mitochondrial activity…
Figure 2. Oxidative stress and mitochondrial activity in SH-SY5Y cells exposed to oxaliplatin.
Cells (2×105 cells/well) were exposed 24 h to oxaliplatin (OXA) (2–200 µM). Oxidative stress was evaluated by Reactive Oxygen Species (ROS) production using dihydroethidium and DCF-DA tests (A) and Nitric Oxide (NO) production evaluated as nitrite content (B) by the Griess reaction. Mitochondrial activity was evaluated by determining mitochondrial membrane potential (Δφm) (C) using JC-1 test and mitochondrial levels of negatively charged phospholipids, mainly cardiolipin, using nonyl acridine orange test (D). Values are the mean ± S.E.M. expressed as percentage of the control, five different assays per group. *: statistically different (p<0.05) from the mean values in control cells.
Figure 3. P2X7 receptor activation, chromatin condensation…
Figure 3. P2X7 receptor activation, chromatin condensation and caspase-3 activity in SH-SY5Y cells exposed to oxaliplatin.
Cells were exposed 24 h to oxaliplatin (OXA) (2–200 µM). P2X7 receptor activation (A) was evaluated using YOPRO-1 test. The resulting fluorescence was viewed with a microscope (B). Chromatin condensation (C) was evaluated using Hoechst 33342 test. Caspase-3 proteolytic activity (D) in lysates of cells was evaluated using the apoTargetTM Caspase-3 Protease assay. In these tests, cells were exposed or not to a 30-min pre-treatment with the specific P2X7 receptor antagonist Brilliant Blue G (BBG; 10 µM) prior to OXA for an additional 24 h. Values are the mean ± S.E.M. expressed as percentage of the control, five different assays per group. *: statistically different (p<0.05) from the mean values in control cells.
Figure 4. Cell viability and oxidative stress…
Figure 4. Cell viability and oxidative stress in oxaliplatin-treated SH-SY5Y cells pre-treated by protective drugs.
Cells (2×105 cells/well) were exposed for 24 h to oxaliplatin (OXA) (50, 100 or 200 µM) after a 30-min pre-treatment either with acetaminophen (AAP, 50 µM), ibuprofen (IBU, 1 µM) or N-acetyl cysteine (NAC, 1 mM). Cell viability (redox potential) was evaluated with Alamar blue (A). Oxidative stress was evaluated by ROS production using dihydroethidium (B) and DCF-DA (C) tests and nitric oxide (NO) production evaluated as nitrite content (D) by the Griess reaction. Lipid peroxidation (E) was determined using the thiobarbituric acid (TBA) method at 200 µM OXA. Mitochondrial activity was evaluated by determining mitochondrial membrane potential (Δφm) (F) using JC-1 test and mitochondrial levels of negatively charged phospholipids, mainly cardiolipin, using nonyl acridine orange test (G). Values are the mean ± S.E.M. expressed as percentage of the control, five different assays per group. Significance of differences: OXA alone versus control, *p<0.05; AAP, or IBU, or NAC versus OXA alone: $ p<0.05.
Figure 5. Chromatin condensation, P2X7R activation and…
Figure 5. Chromatin condensation, P2X7R activation and caspase-3 activity in oxaliplatin-treated SH-SY5Y cells pre-treated by protective drugs.
Cells (2×105 cells/well) were exposed for 24 h to oxaliplatin (OXA) (50, 100 or 200 µM) after a 30-min pre-treatment either with acetaminophen (AAP, 50 µM), ibuprofen (IBU, 1 µM) or N-acetyl cysteine (NAC, 1 mM). Chromatin condensation (A) was evaluated using Hoechst 33342 test and P2X7 receptor (P2X7R) activation (B) using YOPRO-1 test. The apoTargetTM Caspase-3 Protease assay was used for the in vitro determination of caspase-3 proteolytic activity (C) in lysates of SH-SY5Y cells as described by the manufacturer's instructions. Values are the mean ± S.E.M. expressed as percentage of the control, five different assays per group. Significance of differences: OXA alone versus control, *p<0.05; AAP, or IBU, or NAC versus OXA alone: $ p<0.05.
Figure 6. Behavioral assessment of cold hyperalgesia…
Figure 6. Behavioral assessment of cold hyperalgesia in oxaliplatin-treated C57BL/6 mice using the cold plate test.
Mice were repeatedly injected i.p. with 7 mg/kg oxaliplatin (OXA) at days 1, 2, 5 and 6 (28 mg/kg cumulated dose). The latency of first jump was used to evaluate the painful response at 2°C (A), values represent mean ± SEM, * p

Figure 7. Oxidative stress and mitochondrial activity…

Figure 7. Oxidative stress and mitochondrial activity in oxaliplatin-treated C57BL/6 mice.

Mice were repeatedly injected…

Figure 7. Oxidative stress and mitochondrial activity in oxaliplatin-treated C57BL/6 mice.
Mice were repeatedly injected i.p. with 7 mg/kg oxaliplatin (OXA) at days 1, 2, 5 and 6 (28 mg/kg cumulated dose; n = 10). Oxidative stress was evaluated by ROS production using dihydroethidium (A) and DCF-DA (B) tests and NO content (C) by the Griess reaction. Values are the mean ± S.E.M. expressed as percentage of the control (n = 8). *: statistically different (p

Figure 8. Chromatin condensation, P2X7 receptor activation…

Figure 8. Chromatin condensation, P2X7 receptor activation and caspase-3 activity in oxaliplatin-treated C57BL/6 mice.

Mice…

Figure 8. Chromatin condensation, P2X7 receptor activation and caspase-3 activity in oxaliplatin-treated C57BL/6 mice.
Mice were repeatedly injected i.p. with 7 mg/kg oxaliplatin (OXA) at days 1, 2, 5 and 6 (28 mg/kg cumulated dose; n = 10). Mitochondrial activity was evaluated by determining mitochondrial membrane potential (A) using JC-1 test and mitochondrial levels of negatively charged phospholipids (B) using nonyl acridine orange test. Chromatin condensation (C) was evaluated using Hoechst 33342 test and P2X7 receptor activation (D) using YOPRO-1 test. The apoTargetTM Caspase-3 Protease assay was used for the in vitro determination of caspase-3 proteolytic activity (E) in lysates of brain mitochondrial homogenates as described by the manufacturer's instructions. Values are the mean ± S.E.M. expressed as percentage of the control (n = 8). *: statistically different (p<0.05) from the mean values in control mice.

Figure 9. Hypothesis of pathophysiological mechanisms of…

Figure 9. Hypothesis of pathophysiological mechanisms of OXA-induced pain neuropathy.

OXA-induced pain neuropathy seems mediated…

Figure 9. Hypothesis of pathophysiological mechanisms of OXA-induced pain neuropathy.
OXA-induced pain neuropathy seems mediated by cell death P2X7 receptor activation and mitotoxicity which induce apoptosis. Symbols: inhibiting pathway; LPO: lipoperoxydation; AAP: acetaminophen; IBU: ibuprofen; NAC: N-acetyl cysteine.
All figures (9)
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References
    1. Saris CP, van de Vaart PJ, Rietbroek RC, Blommaert FA (1996) In vitro formation of DNA adducts by cisplatin, lobaplatin and oxaliplatin in calf thymus DNA in solution and in cultured human cells. Carcinogenesis 17: 2763–2769. - PubMed
    1. Woynarowski JM, Faivre S, Herzig MC, Arnett B, Chapman WG, et al. (2000) Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol 58: 920–927. - PubMed
    1. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK (2004) Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 29: 387–392. - PubMed
    1. Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, et al. (2011) Utilizing natural activity to dissect the pathophysiology of acute oxaliplatin-induced neuropathy. Exp Neurol 227: 120–127. - PubMed
    1. Sittl R, Lampert A, Huth T, Schuy ET, Link AS, et al. (2012) Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc Natl Acad Sci USA 109: 6704–6709. - PMC - PubMed
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This work was supported by Adebiopharm ER67. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Figure 7. Oxidative stress and mitochondrial activity…
Figure 7. Oxidative stress and mitochondrial activity in oxaliplatin-treated C57BL/6 mice.
Mice were repeatedly injected i.p. with 7 mg/kg oxaliplatin (OXA) at days 1, 2, 5 and 6 (28 mg/kg cumulated dose; n = 10). Oxidative stress was evaluated by ROS production using dihydroethidium (A) and DCF-DA (B) tests and NO content (C) by the Griess reaction. Values are the mean ± S.E.M. expressed as percentage of the control (n = 8). *: statistically different (p

Figure 8. Chromatin condensation, P2X7 receptor activation…

Figure 8. Chromatin condensation, P2X7 receptor activation and caspase-3 activity in oxaliplatin-treated C57BL/6 mice.

Mice…

Figure 8. Chromatin condensation, P2X7 receptor activation and caspase-3 activity in oxaliplatin-treated C57BL/6 mice.
Mice were repeatedly injected i.p. with 7 mg/kg oxaliplatin (OXA) at days 1, 2, 5 and 6 (28 mg/kg cumulated dose; n = 10). Mitochondrial activity was evaluated by determining mitochondrial membrane potential (A) using JC-1 test and mitochondrial levels of negatively charged phospholipids (B) using nonyl acridine orange test. Chromatin condensation (C) was evaluated using Hoechst 33342 test and P2X7 receptor activation (D) using YOPRO-1 test. The apoTargetTM Caspase-3 Protease assay was used for the in vitro determination of caspase-3 proteolytic activity (E) in lysates of brain mitochondrial homogenates as described by the manufacturer's instructions. Values are the mean ± S.E.M. expressed as percentage of the control (n = 8). *: statistically different (p<0.05) from the mean values in control mice.

Figure 9. Hypothesis of pathophysiological mechanisms of…

Figure 9. Hypothesis of pathophysiological mechanisms of OXA-induced pain neuropathy.

OXA-induced pain neuropathy seems mediated…

Figure 9. Hypothesis of pathophysiological mechanisms of OXA-induced pain neuropathy.
OXA-induced pain neuropathy seems mediated by cell death P2X7 receptor activation and mitotoxicity which induce apoptosis. Symbols: inhibiting pathway; LPO: lipoperoxydation; AAP: acetaminophen; IBU: ibuprofen; NAC: N-acetyl cysteine.
All figures (9)
Figure 8. Chromatin condensation, P2X7 receptor activation…
Figure 8. Chromatin condensation, P2X7 receptor activation and caspase-3 activity in oxaliplatin-treated C57BL/6 mice.
Mice were repeatedly injected i.p. with 7 mg/kg oxaliplatin (OXA) at days 1, 2, 5 and 6 (28 mg/kg cumulated dose; n = 10). Mitochondrial activity was evaluated by determining mitochondrial membrane potential (A) using JC-1 test and mitochondrial levels of negatively charged phospholipids (B) using nonyl acridine orange test. Chromatin condensation (C) was evaluated using Hoechst 33342 test and P2X7 receptor activation (D) using YOPRO-1 test. The apoTargetTM Caspase-3 Protease assay was used for the in vitro determination of caspase-3 proteolytic activity (E) in lysates of brain mitochondrial homogenates as described by the manufacturer's instructions. Values are the mean ± S.E.M. expressed as percentage of the control (n = 8). *: statistically different (p<0.05) from the mean values in control mice.
Figure 9. Hypothesis of pathophysiological mechanisms of…
Figure 9. Hypothesis of pathophysiological mechanisms of OXA-induced pain neuropathy.
OXA-induced pain neuropathy seems mediated by cell death P2X7 receptor activation and mitotoxicity which induce apoptosis. Symbols: inhibiting pathway; LPO: lipoperoxydation; AAP: acetaminophen; IBU: ibuprofen; NAC: N-acetyl cysteine.

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Source: PubMed

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