کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10757345 | 1050394 | 2014 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Small molecule glutaminase inhibitors block glutamate release from stimulated microglia
ترجمه فارسی عنوان
مهار کننده های مولکول مولکولی گلوتاماتای آزاد را از گلبول های تحریک شده جدا می کنند
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کلمات کلیدی
HRPGLSNF-κBTLRphorbol 12-myristate 13-acetateCpG oligodeoxynucleotideBPTESLPS6-Diazo-5-oxo-l-norleucine - 6-دیازو-5-اکسو-ال-نللیسینPMA - LDC هاinflammation - التهاب( توروم) tumor necrosis factor-α - تومور نکروز عامل αToll-like receptor - تیالآرHAD - داشته استCNS - دستگاه عصبی مرکزیHIV-associated dementia - دمانس مرتبط با HIVDON - دونcentral nervous system - سیستم عصبی مرکزیTNF-α - فاکتور نکروز توموری آلفاnuclear factor-κB - فاکتور هسته ای κBlipopolysaccharide - لیپوپلی ساکاریدMicroglia - میکروگلیاهاhuman immunodeficiency virus - ویروس نقص ایمنی انسانیHIV - ویروس نقص ایمنی انسانی horse radish peroxidase - پراکسیداز تربچه اسبPoly I:C - پلی I: Cglutamate - گلوتاماتglutamine - گلوتامینGlutaminase - گلوتامیناز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
چکیده انگلیسی
Glutaminase plays a critical role in the generation of glutamate, a key excitatory neurotransmitter in the CNS. Excess glutamate release from activated macrophages and microglia correlates with upregulated glutaminase suggesting a pathogenic role for glutaminase. Both glutaminase siRNA and small molecule inhibitors have been shown to decrease excess glutamate and provide neuroprotection in multiple models of disease, including HIV-associated dementia (HAD), multiple sclerosis and ischemia. Consequently, inhibition of glutaminase could be of interest for treatment of these diseases. Bis-2-(5-phenylacetimido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and 6-diazo-5-oxo-l-norleucine (DON), two most commonly used glutaminase inhibitors, are either poorly soluble or non-specific. Recently, several new BPTES analogs with improved physicochemical properties were reported. To evaluate these new inhibitors, we established a cell-based microglial activation assay measuring glutamate release. Microglia-mediated glutamate levels were significantly augmented by tumor necrosis factor (TNF)-α, phorbol 12-myristate 13-acetate (PMA) and Toll-like receptor (TLR) ligands coincident with increased glutaminase activity. While several potent glutaminase inhibitors abrogated the increase in glutamate, a structurally related analog devoid of glutaminase activity was unable to block the increase. In the absence of glutamine, glutamate levels were significantly attenuated. These data suggest that the in vitro microglia assay may be a useful tool in developing glutaminase inhibitors of therapeutic interest.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 443, Issue 1, 3 January 2014, Pages 32-36
Journal: Biochemical and Biophysical Research Communications - Volume 443, Issue 1, 3 January 2014, Pages 32-36
نویسندگان
Ajit G. Thomas, Cliona M. O'Driscoll, Joseph Bressler, Walter E. Kaufmann, Camilo J. Rojas, Barbara S. Slusher,