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

Neural Regeneration Research 2018年第2期13卷 252-256页

作者： Shelly A.Cruz Zhaohong Qin Alexandre E R.Stewart Hsiao-Huei Chen Ottawa Hospital Research Institute OttawaCanada University of Ottawa Brain and Mind InstituteOttawaCanada University of Ottawa Heart Institute OttawaCanada canadian partnership for storke recovery OttawaCanada

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-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate 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 con- centrations. 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-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.

关键词： ischemic brain injury inflammation macrophage Dabrafenib tumor necrosis factor-alpha photothrombosis receptor-interacting protein kinases necroptosis microgIia stroke neural regeneration

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Biomarker-guided drug therapy: personalized medicine for treating Alzheimer’s disease

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Neural Regeneration Research 2021年第10期16卷 2010-2011页

作者： Charvi Syal Jing Wang Regenerative Medicine Program Ottawa Hospital Research InstituteOttawaONCanada Department of Cellular and Molecular Medicine Faculty of MedicineBrain and Mind Research InstituteUniversity of OttawaOttawaONCanada canadian partnership for Stroke recovery OttawaONCanada

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive *** is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril ***,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).

关键词： Alzheimer drugs Aβ

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Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes:current and emerging concepts

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Translational Neurodegeneration 2017年第1期6卷 67-91页

作者： Usman Saeed Jordana Compagnone Richard I.Aviv Antonio P.Strafella Sandra E.Black Anthony E.Lang Mario Masellis Institute of Medical Science Faculty of MedicineUniversity of TorontoTorontoCanada LC Campbell Cognitive Neurology Research Unit Sunnybrook Research InstituteTorontoCanada Department of Medical Imaging University of Toronto and Division of NeuroradiologySunnybrook Health Sciences CentreTorontoCanada Research Imaging Centre Centre for Addiction and Mental HealthTorontoCanada Division of Brain Imaging&Behaviour-Systems NeuroscienceToronto Western HospitalTorontoCanada Division of Neurology Department of MedicineUniversity of TorontoTorontoCanada Heart&Stroke Foundation canadian partnership for Stroke recovery Sunnybrook Health Sciences CentreTorontoCanada Movement Disorders Centre Toronto Western HospitalTorontoCanada Edmond J.Safra Program in Parkinson’s Disease University Health NetworkTorontoCanada Cognitive&Movement Disorders Clinic Sunnybrook Health Sciences Centre2075 Bayview Ave.Room A4-55TorontoOntario M4N 3 M5Canada

Two centuries ago in 1817,James Parkinson provided the first medical description of Parkinson’s disease,later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants(also termed,Parkinson-plus syndromes).Today,Parkinson’s disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 ***,atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson’s disease,but are uncommon distinct clinicopathological *** of scientific advancements have vastly improved our understanding of these disorders,including improvements in in vivo imaging for biomarker *** imaging for the visualization of structural and functional brain changes is especially important,as it allows a‘window’into the underlying pathophysiological *** this article,we first present an overview of the cardinal clinical and neuropathological features of,1)synucleinopathies:Parkinson’s disease and other Lewy body spectrum disorders,as well as multiple system atrophy,and 2)tauopathies:progressive supranuclear palsy,and corticobasal degeneration.A comprehensive presentation of wellestablished and emerging imaging biomarkers for each disorder are then *** for the following imaging modalities are reviewed:1)structural magnetic resonance imaging(MRI)using T1,T2,and susceptibilityweighted sequences for volumetric and voxel-based morphometric analyses,as well as MRI derived visual signatures,2)diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity,3)proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites,4)single photon emission computed tomography for the evaluation of nigrostriatal integrity(as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors),a

关键词： Biomarkers Parkinson’s disease Atypical parkinsonian syndrome MRI PET SPECT Diffusion tensor imaging Molecular imaging Myocardial scintigraphy Transcranial sonography

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