Activation of Nuclear Factor κB in Cerebral Arteriovenous Malformations

Aziz, Mohamed Mostafa; Takagi, Yasushi; Hashimoto, Nobuo; Miyamoto, Susumu

doi:10.1227/neu.0b013e3181fa00f1

Cited by 20 publications

(19 citation statements)

References 33 publications

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“…The IMIDs do not inhibit endothelial cell proliferation, but rather, migration [148, 149]. There is a remarkable overlap in the pathways targeted by IMIDs in neoplastic disorders [144] with those dysregulated in bAVM, e.g., NFκB activation [94], VEGF overexpression [66], HIF-1α [150], αvβ3 [67, 151], and cytokine elaboration [105], including TNF-α [152] and IL-1β [153]. Both thalidomide and lenalidomide improved outcomes and reduced TNF-α and IL-1β expression in an amyotrophic lateral sclerosis mouse model [154, 155], suggesting that the drug can cross the blood-brain barrier in a setting with some impairment of barrier integrity like our bAVM model [65].…”

Section: New Therapeutic Targetsmentioning

confidence: 99%

Brain Arteriovenous Malformation Modeling, Pathogenesis, and Novel Therapeutic Targets

Chen

Choi

McDougall

et al. 2014

Transl. Stroke Res.

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Patients harboring brain arteriovenous malformation (bAVM) are at life-threatening risk of rupture and intracranial hemorrhage (ICH). The pathogenesis of bAVM has not been completely understood. Current treatment options are invasive and ≈ 20% of patients are not offered interventional therapy because of excessive treatment risk. There are no specific medical therapies to treat bAVMs. The lack of validated animal models has been an obstacle for testing hypotheses of bAVM pathogenesis and testing new therapies. In this review, we summarize bAVM model development; and bAVM pathogenesis and potential therapeutic targets that have been identified during model development.

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Section: New Therapeutic Targetsmentioning

confidence: 99%

Brain Arteriovenous Malformation Modeling, Pathogenesis, and Novel Therapeutic Targets

Chen

Choi

McDougall

et al. 2014

Transl. Stroke Res.

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“…Moreover, we reported that the death receptor pathway and the NF-kappaB pathway were upregulated in AVMs. 9 , 11) These results indicate that dynamic vascular remodeling and neuronal death occur in and around the nidus of AVMs. 16 – 20) The majority of these studies, however, have focused on only one or a few genes or protein products.…”

Section: Discussionmentioning

confidence: 74%

“… 5 – 8) Moreover, we have reported that AVM lesions display DNA fragmentation and increased expression of apoptosis-related factors. 9 – 11) In this study, we examined differential gene expression in AVMs and analyzed this expression in relation to clinical manifestations in Japanese patients.…”

Section: Introductionmentioning

confidence: 99%

Differential Gene Expression in Relation to the Clinical Characteristics of Human Brain Arteriovenous Malformations

Takagi

Aoki

Takahashi

et al. 2014

Neurol. Med. Chir.(Tokyo)

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Arteriovenous malformations (AVMs) of the central nervous system are considered as congenital disorders. They are composed of abnormally developed dilated arteries and veins and are characterized microscopically by the absence of a capillary network. We previously reported DNA fragmentation and increased expression of apoptosis-related factors in AVM lesions. In this article, we used microarray analysis to examine differential gene expression in relation to clinical manifestations in 11 AVM samples from Japanese patients. We categorized the genes with altered expression into four groups: deathrelated, neuron-related, inflammation-related, and other. The death-related differentially expressed genes were MMP9, LIF, SOD2, BCL2A1, MMP12, and HSPA6. The neuron-related genes were NPY, S100A9, NeuroD2, S100Abeta, CAMK2A, SYNPR, CHRM2, and CAMKV. The inflammation-related genes were PTX3, IL8, IL6, CXCL10, GBP1, CHRM3, CXCL1, IL1R2, CCL18, and CCL13. In addition, we compared gene expression in those with or without clinical characteristics including deep drainer, embolization, and high-flow nidus. We identified a small number of genes. Using these microarray data we are able to generate and test new hypotheses to explore AVM pathophysiology. Microarray analysis is a useful technique to study clinical specimens from patients with brain vascular malformations.

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“…Previously, immune cells were mostly analyzed in ruptured [24] and irradiated [25] bAVMs. Our previous study showed that adaptive immune cells were rarely observed in unruptured bAVM.…”

Section: Discussionmentioning

confidence: 99%

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

Guo¹,

Tihan²,

Kim³

et al. 2014

Neuroimmunol Neuroinflammation

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Aim To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation (bAVM) is not associated with iron deposition (indicator of microhemorrhage). Methods Sections of unruptured, previously untreated bAVM specimens (n=19) were stained immunohistochemically for T-lymphocytes (CD3+), B-lymphocytes (CD20+), plasma cells (CD138+) and macrophages (CD68+). Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains. Superficial temporal arteries (STA) were used as control. Results Both T lymphocytes and macrophages were present in unruptured, previously untreated bAVM specimens, whereas few B cells and plasma cells were detected. Iron deposition was detected in 8 specimens (42%; 95% confidence interval =20–67%). The samples with iron deposition tended to have more macrophages than those without (666±313 vs 478±174 cells/mm2; P=0.11). T-cells were clustered on the luminal side of the endothelial surface, on the vessel-wall, and in the perivascular regions. There was no correlation between T lymphocyte load and iron deposition (P=0.88). No macrophages and lymphocytes were detected in STA controls. Conclusions T-lymphocytes were present in bAVM specimens. Unlike macrophages, the load and location of T-lymphocytes were not associated with iron deposition, suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.

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Activation of Nuclear Factor κB in Cerebral Arteriovenous Malformations

Abstract: We detected activation of NF-κB in the endothelium and perivascular infiltrating inflammatory cells within the cerebral AVM nidus, suggesting a role in the pathophysiology of cerebral AVM.

Cited by 20 publications

References 33 publications

Brain Arteriovenous Malformation Modeling, Pathogenesis, and Novel Therapeutic Targets

Brain Arteriovenous Malformation Modeling, Pathogenesis, and Novel Therapeutic Targets

Differential Gene Expression in Relation to the Clinical Characteristics of Human Brain Arteriovenous Malformations

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

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