Systemic low‐molecular weight drug delivery to pre‐selected neuronal regions

Campbell, Matthew; Humphries, Marian M.; Kiang, Anna‐Sophia; Nguyen, Anh Thi Hong; Gobbo, Oliviero L.; Tam, Lawrence C. S.; Suzuki, Mayu; Hanrahan, Finnian; Ozaki, Ema; Farrar, G. Jane; Kenna, Paul F.; Humphries, Peter

doi:10.1002/emmm.201100126

Cited by 42 publications

(45 citation statements)

References 31 publications

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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.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Because selective and sufficient entry of drugs and their modification tools is important in CNS drug design, while still limiting the access of toxic compounds, knowledge about the BBB behaviour of drugs is highly researched (Chu et al 2006;Engelhardt 2006). Moreover, the addition of physical techniques to temporarily and spatial-selectively open the BBB, can even further extend the clinical possibilities (Campbell et al 2011;Liu et al 2010;Madsen and Hirschberg 2010;Rossi 2011).…”

Section: Introductionmentioning

confidence: 98%

Brainpeps: the blood–brain barrier peptide database

et al. 2011

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Peptides are able to cross the blood-brain barrier (BBB) through various mechanisms, opening new diagnostic and therapeutic avenues. However, their BBB transport data are scattered in the literature over different disciplines, using different methodologies reporting different influx or efflux aspects. Therefore, a comprehensive BBB peptide database (Brainpeps) was constructed to collect the BBB data available in the literature. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure-property (BBB behaviour) relationships of peptides. Because a multitude of methods have been used to assess the BBB behaviour of compounds, we classified these methods and their responses. Moreover, the relationships between the different BBB transport methods have been clarified and visualized.

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“…Using RNA interference targeting the tight junction component claudin-5, we show that the BBB can be modulated to enhance the exchange of very low molecular weight molecules of up to ~1 kDa for periods of between 24 apparent negative phenotypic or genotypic effects on experimental animals [15][16][17] . Claudin-5 has a key role in the formation of paracellular pores or channels that function in mediating selective ion permeability at the BBB 18,19 .…”

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confidence: 99%

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

et al. 2012

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Traumatic brain injury is the leading cause of death in children and young adults globally. malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RnA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology.

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Systemic low‐molecular weight drug delivery to pre‐selected neuronal regions

Cited by 42 publications

References 31 publications

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

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

Brainpeps: the blood–brain barrier peptide database

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

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