The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo

Elzbieta Janda, Maddalena Parafati, Serafina Aprigliano, Cristina Carresi, Valeria Visalli, Iolanda Sacco, Domenica Ventrice, Tiziana Mega, Nuria Vadalá, Stefano Rinaldi, Vincenzo Musolino, Ernesto Palma, Santo Gratteri, Domenicantonio Rotiroti, Vincenzo Mollace

Research output: Contribution to journalArticle

Abstract

Background and Purpose: The mechanisms of paraquat (PQ)-induced toxicity are poorly understood and PQ poisoning is often fatal due to a lack of effective antidotes. In this study we report the effects of N-[2-(2-methoxy-6H- dipyrido{2,3-a:3,2-e}pyrrolizin-11-yl)ethyl]-2-furamide (NMDPEF), a melatonin-related inhibitor of quinone oxidoreductase2 (QR2) on the toxicity of PQ in vitro & in vivo. Experimental Approach: Prevention of PQ-induced toxicity was tested in different cells, including primary pneumocytes and astroglial U373 cells. Cell death and reactive oxygen species (ROS) were analysed by flow cytometry and fluorescent probes. QR2 silencing was achieved by lentiviral shRNAs. PQ (30 mg·kg-1) and NMDPEF were administered i.p. to Wistar rats and animals were monitored for 28 days. PQ toxicity in the substantia nigra (SN) was tested by a localized microinfusion and electrocorticography. QR2 activity was measured by fluorimetry of N-benzyldihydronicotinamide oxidation. Key Results: NMDPEF potently antagonized non-apoptotic PQ-induced cell death, ROS generation and inhibited cellular QR2 activity. In contrast, the cytoprotective effect of melatonin and apocynin was limited and transient compared with NMDPEF. Silencing of QR2 attenuated PQ-induced cell death and reduced the efficacy of NMDPEF. Significantly, NMDPEF (4.5 mg·kg-1) potently antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of NMDPEF into SN prevented severe behavioural and electrocortical effects of PQ which correlated with inhibition of malondialdehyde accumulation in cells and tissues. Conclusions and Implications: NMDPEF protected against PQ-induced toxicity in vitro and in vivo, suggesting a key role for QR2 in the regulation of oxidative stress.

Original languageEnglish
Pages (from-to)46-59
Number of pages14
JournalBritish Journal of Pharmacology
Volume168
Issue number1
DOIs
Publication statusPublished - Jan 2013

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Keywords

  • astrocytes
  • electrocorticogram
  • mammary epithelial cells
  • NQO2
  • oxidative stress
  • paraquat
  • pesticides
  • ROS
  • substantia nigra

ASJC Scopus subject areas

  • Pharmacology

Cite this

Janda, E., Parafati, M., Aprigliano, S., Carresi, C., Visalli, V., Sacco, I., Ventrice, D., Mega, T., Vadalá, N., Rinaldi, S., Musolino, V., Palma, E., Gratteri, S., Rotiroti, D., & Mollace, V. (2013). The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo. British Journal of Pharmacology, 168(1), 46-59. https://doi.org/10.1111/j.1476-5381.2012.01870.x