کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3055654 1186522 2012 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Protection from cerebral ischemia by inhibition of TGFβ-activated kinase
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی عصب شناسی
پیش نمایش صفحه اول مقاله
Protection from cerebral ischemia by inhibition of TGFβ-activated kinase
چکیده انگلیسی

ObjectiveTransforming growth factor-β-activated kinase (TAK1) is a member of the mitogen-activated protein kinase family that plays important roles in apoptosis and inflammatory signaling, both of which are critical components of stroke pathology. TAK1 has recently been identified as a major upstream kinase that phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK), a major mediator of neuronal injury after experimental cerebral ischemia. We studied the functional role of TAK1 and its mechanistic link with AMPK after stroke.MethodsMale mice were subjected to transient middle cerebral artery occlusion (MCAO). The TAK1 inhibitor 5Z-7-oxozeaenol was injected either intracerebroventricularly or intraperitoneally at various doses and infarct size and functional outcome after long term survival was assessed. Mice with deletion of the AMPK α2 isoform were utilized to assess the contribution of downstream AMPK signaling to stroke outcomes. Levels of pTAK1, pAMPK, and other TAK1 targets including the pro-apoptotic molecule c-Jun-N-terminal kinase (JNK)/c-Jun and the pro-inflammatory protein cyclooxygenase-2 were also examined.ResultsTAK1 is critical in stroke pathology. Delayed treatment with a TAK1 inhibitor reduced infarct size and improved behavioral outcome even when given several hours after stroke onset. This protective effect may be independent of AMPK activation but was associated with a reduction in JNK and c-Jun signaling.ConclusionsEnhanced TAK1 signaling, via activation of JNK, contributes to cell death in ischemic stroke. TAK1 inhibition is a novel therapeutic approach for stroke as it is neuroprotective with systemic administration, has a delayed therapeutic window, and demonstrates sustained neuroprotective effects.


► Stroke injury propagation involves complex molecular processes.
► Inhibiting transforming growth factor-β-activated kinase 1 (TAK1) reduced injury.
► TAK1 is a critical molecule in deciding neuronal fate in stroke.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental Neurology - Volume 237, Issue 1, September 2012, Pages 238–245
نویسندگان
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