Assessment of the role of multidrug resistance-associated proteins in MPTP neurotoxicity in mice.

Ideggyogyaszati szemle (2014-02-22)
Imola Plangár, Dénes Zádori, Levente Szalárdy, László Vécsei, Péter Klivényi
RESUMO

The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-b nding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1 ,2, 4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and allopurinol (with MRP4 stimulatory effect in doses of 100 mg/kg, 100 mg/kg, 100 mg/kg and 60 mg/kg, respectively, for one week before and after the administration of MPTP in C57B/6 mice in acute dosing regimen the striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid has been measured using high-performance liquid chromatography. Although the results of these experiments showed that neither of these substances exerted significant influence on MPTP-induced striatal depletion of dopamine and its metabolites, naringenin exerted a slight prevention of dopamine decrease, while allopurinol considerably enhanced the MPTP-induced lethality in mice. The explanation of these findings would be that the stimulation of MRP1- and MRP2-mediated transport of glutathione conjugates of toxic substances may have slight beneficial effects, while stimulation of MRP4-mediated efflux of brain urate, which has an important antioxidant potency, may worsen the effects of oxidative stress.

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Dopamine hydrochloride
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Phosphoric acid, 85 wt. % in H2O, 99.99% trace metals basis
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Perchloric acid, ACS reagent, 70%
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Ethylenediaminetetraacetic acid solution, BioUltra, for molecular biology, pH 8.0, ~0.5 M in H2O
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Sodium phosphate, 96%
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Acetonitrile, for HPLC, for UV, ≥99.9% (GC)
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Phosphoric acid, ACS reagent, ≥85 wt. % in H2O
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Ethylenediaminetetraacetic acid, anhydrous, BioUltra, ≥99% (titration)
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Acetonitrile, ACS reagent, ≥99.5%
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Phosphoric acid, ACS reagent, ≥85 wt. % in H2O
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Ethylenediaminetetraacetic acid, purified grade, ≥98.5%, powder
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Phosphoric acid, crystalline, ≥99.999% trace metals basis
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(±)-Naringenin, ≥95%
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Sodium metabisulfite, reagent grade, 97%
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