Background and purpose: Mechanisms of paraquat (PQ)-induced toxicity are not well understood and methods to counteract it with an antidote efficacy are unknown. NRH:Quinone Oxidoreductase 2 (NQO2/QR2) catalyses quinone reductions and nitroreductions and may act as a mediator of antioxidant effects of melatonin. Experimental approach: NMDPEF, a melatonin-related QR2 inhibitor was tested as a protective agent against PQ in different cells, including primary pneumocytes and astroglial U373 cells. Cell death and reactive oxygen species (ROS) were analyzed by flow cytometry and fluorescent probes (Mitosox, APF). QR2 silencing was achieved by lentiviral shRNAs. PQ (30 mg/kg) and NMDPEF were administered i.p. in Wistar rats and animals were monitored for 28 days and longer. PQ toxicity in the Substantia Nigra (SN) was tested by a localized microinfusion and electrocorticography. QR2 activity was measured by fluorometry of BNAH oxidation. Key results: NMDPEF potently antagonized non-apoptotic PQ-induced cell death and ROS generation and inhibited QR2 activity in cells at cell-protective concentrations. The protective effect of melatonin and apocynin appeared poor and transient compared to NMDPEF . Silencing of QR2 attenuated PQinduced cell death and reduced the response to QR2 inhibitor. Importantly, NMDPEF (4,5 mg/kg) strongly antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of NMDPEF into SN counteracted severe behavioural and electrocortical effects of PQ. This correlated with inhibition of malondialdehyde accumulation in cells and tissues. Conclusions and implications: These data document an antidote-like effect of NMDPEF against PQinduced toxicity in vitro and in vivo and suggest a key role for QR2 in the regulation of oxidative stress.

The antidote effect of Quinone Oxidoreductase 2 (QR2) inhibitor on paraquat-induced toxicity in vitro and in vivo

Carresi C;Musolino V;Palma E;Mollace V.;Gratteri S
2013-01-01

Abstract

Background and purpose: Mechanisms of paraquat (PQ)-induced toxicity are not well understood and methods to counteract it with an antidote efficacy are unknown. NRH:Quinone Oxidoreductase 2 (NQO2/QR2) catalyses quinone reductions and nitroreductions and may act as a mediator of antioxidant effects of melatonin. Experimental approach: NMDPEF, a melatonin-related QR2 inhibitor was tested as a protective agent against PQ in different cells, including primary pneumocytes and astroglial U373 cells. Cell death and reactive oxygen species (ROS) were analyzed by flow cytometry and fluorescent probes (Mitosox, APF). QR2 silencing was achieved by lentiviral shRNAs. PQ (30 mg/kg) and NMDPEF were administered i.p. in Wistar rats and animals were monitored for 28 days and longer. PQ toxicity in the Substantia Nigra (SN) was tested by a localized microinfusion and electrocorticography. QR2 activity was measured by fluorometry of BNAH oxidation. Key results: NMDPEF potently antagonized non-apoptotic PQ-induced cell death and ROS generation and inhibited QR2 activity in cells at cell-protective concentrations. The protective effect of melatonin and apocynin appeared poor and transient compared to NMDPEF . Silencing of QR2 attenuated PQinduced cell death and reduced the response to QR2 inhibitor. Importantly, NMDPEF (4,5 mg/kg) strongly antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of NMDPEF into SN counteracted severe behavioural and electrocortical effects of PQ. This correlated with inhibition of malondialdehyde accumulation in cells and tissues. Conclusions and implications: These data document an antidote-like effect of NMDPEF against PQinduced toxicity in vitro and in vivo and suggest a key role for QR2 in the regulation of oxidative stress.
2013
NQO2, ; oxidative stress, ; ROS, paraquat, pesticides, astrocytes, mammary epithelial cells, Substantia Nigra, electrocorticogram
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/12732
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