Send to

Choose Destination
Neural Regen Res. 2018 Feb;13(2):252-256. doi: 10.4103/1673-5374.226394.

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

Author information

Ottawa Hospital Research Institute; University of Ottawa, Brain and Mind Institute; Canadian Partnership for Storke Recovery, Ottawa, Canada.
Ottawa Hospital Research Institute; Canadian Partnership for Storke Recovery, Ottawa, Canada.
University of Ottawa Heart Institute, Ottawa, Canada.


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.


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

Supplemental Content

Full text links

Icon for Medknow Publications and Media Pvt Ltd Icon for PubMed Central
Loading ...
Support Center