title: The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo.
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.
authors.affiliation: Department of Health Sciences, University 'Magna Graecia', Catanzaro, Italy.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Janda
authors.forename: Maddalena
authors.initials: M
authors.lastname: Parafati
authors.forename: Serafina
authors.initials: S
authors.lastname: Aprigliano
authors.forename: Cristina
authors.initials: C
authors.lastname: Carresi
authors.forename: Valeria
authors.initials: V
authors.lastname: Visalli
authors.forename: Iolanda
authors.initials: I
authors.lastname: Sacco
authors.forename: Domenica
authors.initials: D
authors.lastname: Ventrice
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mega
authors.forename: Nuria
authors.initials: N
authors.lastname: Vadalá
authors.forename: Stefano
authors.initials: S
authors.lastname: Rinaldi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Musolino
authors.forename: Ernesto
authors.initials: E
authors.lastname: Palma
authors.forename: Santo
authors.initials: S
authors.lastname: Gratteri
authors.forename: Domenicantonio
authors.initials: D
authors.lastname: Rotiroti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mollace
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D010269:Paraquat / Q000633:toxicity*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
chemical_list: D000931:Antidotes; D006540:Herbicides; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D010269:Paraquat