Protein markers of cerebrovascular disruption of neurovascular unit: immunohistochemical and imaging approaches

Amtul, Zareen; Hepburn, Jeffrey D.

doi:10.1515/revneuro-2013-0041

Cited by 28 publications

(19 citation statements)

References 220 publications

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“…ET1 is a potent activator of microglia (25) and can cause prominent microglial staining in rats receiving only ET1. After the elimination of cell debris, in the remodeled adult brain, phagocytic microglial cells rapidly transform into a ramified microglial state (4,44). Large numbers of these ramified microglia are what we observe at the site of inflammation in the ET1and Aβ+ET1 rat brains in both the striatum and even more significantly in the neocortex, which could partly explain the formation of dementia observed clinically when these two conditions coexist.…”

Section: Discussionsupporting

confidence: 54%

Comorbid Rat Model of Ischemia and β‐Amyloid Toxicity: Striatal and Cortical Degeneration

et al. 2014

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Levels of cerebral amyloid, presumably β-amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin-1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in β-amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta-treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.

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Section: Discussionsupporting

confidence: 54%

Comorbid Rat Model of Ischemia and β‐Amyloid Toxicity: Striatal and Cortical Degeneration

et al. 2014

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“…The neurovascular unit and the associated BBB consists of endothelial cells, astrocytes, and pericytes that form a structural basement membrane [48]. The unit acts as a consortium that dictates vascular constriction and dilation in response to stimuli [49].…”

Section: Resultsmentioning

confidence: 99%

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

et al. 2014

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Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the ‘signature injury’ of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague–Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan’s blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan’s blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t=4.808, p<0.05), and a reduction back toward control levels when bryostatin-1 was administered (t=5.113, p<0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t=4.559, p<0.01) and increased the neuroprotective isozyme PKCε (t=6.102, p<0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.

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“…Sections were immunostained using a standard free-oating section protocol as described (45,46). Brie y, sections were blocked with PBS, methanol, and 30% hydrogen peroxide (Fisher Scienti c, Pittsburgh, PA) and incubated on a shaker for 15 min.…”

Section: Histological Con Rmation Of Dose Deposition and Absolute Posmentioning

confidence: 99%

Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Sprowls

Arsiwala

Kielkowski

et al. 2020

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Background Brain metastasis is a devastating stage of cancer progression, occurring in ~30% of metastatic breast cancer patients. Two-year survival rates for these patients is low, and most typically survive less than one year. Treatments for these women are limited by the blood-brain barrier, but include cytotoxic chemotherapy, surgical resection, and radiation therapy (whole-brain radiotherapy or stereotactic radiosurgery). Radiotherapy is considered to be capable of inducing disruption of the blood-brain barrier and eliciting an abscopal response to extracranial tumors. Methods A combination of ionization chamber and Gafchromic film dosimetry was used to commission and determine dose outputs for our experimental design. Dose deposition in-vivo was verified by immunohistochemistry. To evaluate the effects of ionizing radiation at the normal blood-brain barrier and the blood-tumor barrier, athymic nude and FVB mice were used. Athymic nude mice were injected with MDA-MB-231Br cells. Lesions were allowed to develop for ~28 days. Mice were then irradiated at the prescribed dose. Prior to tissue collection, mice were injected with Texas red, followed by a vascular washout with physiological buffer. Fluorescence in normal and diseased brain was quantified by fluorescent microscopy. Results Using a 10mmx10mm collimator, determined to have adequate field homogeneity as determined by Gafchromic film analysis, we were able to successfully treat a single hemisphere in mice. The blood-brain-barrier remained undisrupted in athymic nude mice at doses up to 12Gy compared to untreated brain and radiation naïve controls. Immune competent FVB mice treated with radiation showed significant blood-brain barrier disruption at a dose of 12Gy only. The blood-tumor barrier showed significant disruption at 24hrs following radiation treatment (6 or 12Gy). Conclusion Our study demonstrated that radiation therapy disrupts the blood-tumor barrier, but fails to disrupt the normal blood-brain barrier in athymic nude mice. However, in FVB immune competent mice, the blood-brain barrier was disrupted at a dose of 12Gy, suggesting an abscopal-like response impacts extent of barrier leakage.

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Protein markers of cerebrovascular disruption of neurovascular unit: immunohistochemical and imaging approaches

Cited by 28 publications

References 220 publications

Comorbid Rat Model of Ischemia and β‐Amyloid Toxicity: Striatal and Cortical Degeneration

Comorbid Rat Model of Ischemia and β‐Amyloid Toxicity: Striatal and Cortical Degeneration

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

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