Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

Campbell, Matthew; Hanrahan, Finnian; Gobbo, Oliviero L.; Kelly, Michael; Kiang, Anna‐Sophia; Humphries, Marian M.; Nguyen, Anh Thi Hong; Ozaki, Ema; Keaney, James; Blau, Christoph W.; Kerskens, Christian; Cahalan, Stephen D.; Callanan, John J.; Wallace, Eugene; Grant, Gerald A.; Doherty, Colin P.; Humphries, Peter

doi:10.1038/ncomms1852

Cited by 102 publications

(75 citation statements)

References 41 publications

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“…Vascular permeability in lungs, brain, and eyes was assessed in vivo via MRI (Campbell et al., 2012) using a dedicated small rodent 7 T MRI system (http://www.tcd.ie/neuroscience/infrastructure/neuroimaging/index.php#7tesla). …”

Section: Methodsmentioning

confidence: 99%

Differential Apicobasal VEGF Signaling at Vascular Blood-Neural Barriers

et al. 2014

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SummaryThe vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly polarized receptor distribution contributed to distinct signaling patterns: VEGFR2, which was found to be predominantly abluminal, mediated increased permeability via p38; in contrast, luminal VEGFR1 led to Akt activation and facilitated cytoprotection. Importantly, such differential apicobasal signaling and VEGFR distribution were found in the microvasculature of brain and retina but not lung, indicating that endothelial cells at blood-neural barriers possess specialized signaling compartments that assign different functions depending on whether an agonist is tissue or blood borne.

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Section: Methodsmentioning

confidence: 99%

Differential Apicobasal VEGF Signaling at Vascular Blood-Neural Barriers

et al. 2014

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“…I, Myc and p21 protein levels determined by immunohistochemistry in subcutaneous tumor xenografts generated by PC3 cells transfected in vitro with GL3 and Myc13 siRNA. ÃÃ , P < 0.05. polymer preparation successfully used in previous studies (45). In cell culture experiments, this reagent was as effective as Lipofectamine in transfecting siRNA and inducing Myc silencing ($80% gene knockdown).…”

Section: Targeting Myc Reduces Cscs and Prevents Tumor Development Inmentioning

confidence: 99%

RNAi-Mediated Silencing of Myc Transcription Inhibits Stem-like Cell Maintenance and Tumorigenicity in Prostate Cancer

et al. 2013

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Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promotertargeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications. Cancer Res; 73(22);

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“…Cerebral endothelial tight junction proteins, such as claudin-5, play a critical role in maintenance of the BBB. Campbell et al 26,27 used claudin-5 siRNA to demonstrate that claudin-5 has a major role in BBB in mice. In the present study, the BBB was disrupted by decreased claudin-5 in the corpus callosum of WM via the ASK1-p38 signaling pathway during the early stages after cerebral hypoperfusion.…”

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confidence: 99%

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

Toyama

Koibuchi

Uekawa

et al. 2014

ATVB

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of VaD and the development of a clinical therapeutic strategy for VaD are urgent topics for research.Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein (MAP) kinase kinase kinase family, activates MAP kinase kinases, which in turn activate p38 and C-Jun N-terminal (JNK) MAP kinase. Objective-There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions. Approach and Results-A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCASinduced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1 −/− ) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1 −/− mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1 −/− mice. Cerebral nitrotyrosine was increased in wild-type and ASK1 −/− BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1 −/− mice. Conclusions-Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through bloodbrain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment. Figure I in the online-only Data Supplement). Our previous reports showed that ASK1 is involved in angiotensin II-induced vascular endothelial dysfunction and apoptosis, 10 balloon injury-induced vascular neointima formation, 11 and ischemia-induced angiogenesis. 12The potential role of ASK1 in cerebral vasculature/small vessels should be further investigated in relation to VaD. Cerebral ischemia increases cerebral oxidative stress levels 13 and vascular cognitive impairment induced by chronic cerebral ischemia is associated with BBB disruption.14-16 The BBB consists of endothelial cells, basal lamina matrix, astrocyte end-feet, and pericytes. Therefore, in the present study, we hypothesized that ASK1 might be involved in oxidative stress-induced BBB disruption because ...

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Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

Cited by 102 publications

References 41 publications

Differential Apicobasal VEGF Signaling at Vascular Blood-Neural Barriers

Differential Apicobasal VEGF Signaling at Vascular Blood-Neural Barriers

RNAi-Mediated Silencing of Myc Transcription Inhibits Stem-like Cell Maintenance and Tumorigenicity in Prostate Cancer

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

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