کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2590599 1131753 2006 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Potentiating effect of the ATP-sensitive potassium channel blocker glibenclamide on complex I inhibitor neurotoxicity in vitro and in vivo
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Potentiating effect of the ATP-sensitive potassium channel blocker glibenclamide on complex I inhibitor neurotoxicity in vitro and in vivo
چکیده انگلیسی

Previous studies have demonstrated a deficiency in mitochondrial function in Parkinson's disease. We measured the ability of mitochondrial inhibitors of complexes I (rotenone, MPP+, and HPP+), II (amdro), IV (Na cyanide), and an uncoupler (dinoseb) to release preloaded dopamine from murine striatal synaptosomes. These compounds were potent dopamine releasers, and the effect was calcium-dependent. The striatum also contains a significant density of KATP+ channels, which play a protective role during ATP decline. Blockage of these channels with glibenclamide only potentiated the dopamine release by complex I inhibitors, and a selective potentiating effect of glibenclamide on the toxicity of MPTP was also observed, in vivo, using C57BL/6 mice. Western blots of striatal dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins demonstrated that 30 mg/kg of glibenclamide alone did not affect the expression of DAT and TH after two weeks of daily treatments, but it significantly enhanced the reduction of DAT and TH by a single dose of 20 mg/kg of MPTP. Amdro or dinoseb alone, or in conjunction with glibenclamide did not alter the expression of DAT and TH. The possible mechanisms underlying dopamine release and the selectivity of glibenclamide were further evaluated, in vitro. 86Rb efflux assay showed that glibenclamide inhibited rotenone-induced K+ efflux, but not dinoseb-induced K+ efflux. Analysis of ATP titers in treated synaptosomes did not support a correlation between mitochondrial inhibition and KATP+ channel activation. However, assay of reactive oxygen species (ROS) showed that greater amounts of ROS generated by complex I inhibitors was a contributory factor to KATP+ channel activation and glibenclamide potentiation. Overall, these findings suggest that co-exposure to mitochondrial complex I inhibitors and glibenclamide or a genetic defect in KATP+ channel function, may increase neurotoxicity in the striatal dopaminergic system.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: NeuroToxicology - Volume 27, Issue 5, September 2006, Pages 826–834
نویسندگان
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