کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6016953 | 1580153 | 2016 | 45 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
عصب شناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental Neurology - Volume 282, August 2016, Pages 99-118
Journal: Experimental Neurology - Volume 282, August 2016, Pages 99-118
نویسندگان
Vahri Beaumont, Ladislav Mrzljak, Ulrike Dijkman, Robert Freije, Mariette Heins, Arash Rassoulpour, Geoffrey Tombaugh, Simon Gelman, Amyaouch Bradaia, Esther Steidl, Melanie Gleyzes, Taneli Heikkinen, Kimmo Lehtimäki, Jukka Puoliväli, Outi Kontkanen,