Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury

Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprote...
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Gespeichert in:

Autor*in:	Shelly A Cruz [verfasserIn] Zhaohong Qin [verfasserIn] Alexandre F. R. Stewart [verfasserIn] Hsiao-Huei Chen [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration

Übergeordnetes Werk:	In: Neural Regeneration Research - Wolters Kluwer Medknow Publications, 2014, 13(2018), 2, Seite 252-256
Übergeordnetes Werk:	volume:13 ; year:2018 ; number:2 ; pages:252-256

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.4103/1673-5374.226394

Katalog-ID:	DOAJ04470254X

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spelling	10.4103/1673-5374.226394 doi (DE-627)DOAJ04470254X (DE-599)DOAJ0da94da1294a410a957354af85c4305a DE-627 ger DE-627 rakwb eng RC346-429 Shelly A Cruz verfasserin aut Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy. ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration Neurology. Diseases of the nervous system Zhaohong Qin verfasserin aut Alexandre F. R. Stewart verfasserin aut Hsiao-Huei Chen verfasserin aut In Neural Regeneration Research Wolters Kluwer Medknow Publications, 2014 13(2018), 2, Seite 252-256 (DE-627)545785499 (DE-600)2388460-5 18767958 nnns volume:13 year:2018 number:2 pages:252-256 https://doi.org/10.4103/1673-5374.226394 kostenfrei https://doaj.org/article/0da94da1294a410a957354af85c4305a kostenfrei http://www.nrronline.org/article.asp?issn=1673-5374;year=2018;volume=13;issue=2;spage=252;epage=256;aulast=Cruz kostenfrei https://doaj.org/toc/1673-5374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_2700 GBV_ILN_2817 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2018 2 252-256
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allfieldsSound	10.4103/1673-5374.226394 doi (DE-627)DOAJ04470254X (DE-599)DOAJ0da94da1294a410a957354af85c4305a DE-627 ger DE-627 rakwb eng RC346-429 Shelly A Cruz verfasserin aut Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy. ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration Neurology. Diseases of the nervous system Zhaohong Qin verfasserin aut Alexandre F. R. Stewart verfasserin aut Hsiao-Huei Chen verfasserin aut In Neural Regeneration Research Wolters Kluwer Medknow Publications, 2014 13(2018), 2, Seite 252-256 (DE-627)545785499 (DE-600)2388460-5 18767958 nnns volume:13 year:2018 number:2 pages:252-256 https://doi.org/10.4103/1673-5374.226394 kostenfrei https://doaj.org/article/0da94da1294a410a957354af85c4305a kostenfrei http://www.nrronline.org/article.asp?issn=1673-5374;year=2018;volume=13;issue=2;spage=252;epage=256;aulast=Cruz kostenfrei https://doaj.org/toc/1673-5374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_374 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_2700 GBV_ILN_2817 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2018 2 252-256
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author	Shelly A Cruz
spellingShingle	Shelly A Cruz misc RC346-429 misc ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration misc Neurology. Diseases of the nervous system Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury
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topic_title	RC346-429 Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration
topic	misc RC346-429 misc ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration misc Neurology. Diseases of the nervous system
topic_unstemmed	misc RC346-429 misc ischemic brain injury; inflammation; macrophage; Dabrafenib; tumor necrosis factor-alpha; photothrombosis; receptor-interacting protein kinases; necroptosis; microglia; stroke; neural regeneration misc Neurology. Diseases of the nervous system
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title	Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury
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title_full	Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury
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title_sort	dabrafenib, an inhibitor of rip3 kinase-dependent necroptosis, reduces ischemic brain injury
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title_auth	Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury
abstract	Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
abstractGer	Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
abstract_unstemmed	Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
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title_short	Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury
url	https://doi.org/10.4103/1673-5374.226394 https://doaj.org/article/0da94da1294a410a957354af85c4305a http://www.nrronline.org/article.asp?issn=1673-5374;year=2018;volume=13;issue=2;spage=252;epage=256;aulast=Cruz https://doaj.org/toc/1673-5374
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Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury

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