Propranolol stops progressive multiple cerebral cavernoma in an adult patient

Reinhard, Matthias; Schuchardt, Florian; Meckel, Stephan; Heinz, Jürgen; Felbor, Ute; Sure, Ulrich; Geisen, Ulrich

doi:10.1016/j.jns.2016.04.053

Cited by 45 publications

(29 citation statements)

References 7 publications

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“…The identification of these misregulated signaling pathways has suggested potential routes for pharmacological interventions, and molecules that modulate these pathways have been tested in preclinical studies of murine endothelial‐specific inducible CCM models and even in clinical studies. These studies investigated the potential of the Rho/Rock signaling inhibitors fasudil or simvastatin (Zhou et al , ; Shenkar et al , ), the blood pressure lowering drug propranolol (Reinhard et al , ), the Wnt signaling inhibitor sulindac sulfone (Bravi et al , ), the TGFβ and pSMAD inhibitors LY‐364947 and SB‐431542 (Maddaluno et al , ), the TLR4 antagonist TAK‐242 (resatorvid; Tang et al , ), or treatment with antibiotics (Tang et al , ). However, since many of these candidate drugs may cause severe side effects in patients and because a comprehensive overview of CCM‐relevant molecular pathways is still lacking, the scientific community has recognized the need of performing more systematic small‐molecule screens.…”

Section: Introductionmentioning

confidence: 99%

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

et al. 2018

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Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non‐invasive pharmacological therapies. Here, we present the results of several unbiased small‐molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology‐based target prediction tool to integrate the results with the whole‐transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small‐molecule‐based therapies. We found indirubin‐3‐monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss‐of‐CCM phenotypes in human endothelial cells. Our multi‐organism‐based approach reveals new components of the CCM regulatory network and foreshadows novel small‐molecule‐based therapeutic applications for suppressing this devastating disease in patients.

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Section: Introductionmentioning

confidence: 99%

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

et al. 2018

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“…In these patients, the histological nature of the lesions was not clear, but the success of the treatment encouraged using it in dramatic adult cases who could not be operated (cf. Table 1) [10,33].…”

Section: Two Inaccessible Ccmmentioning

confidence: 99%

Could propranolol be beneficial in adult cerebral cavernous malformations?

et al. 2019

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Surgery is the only therapeutic option for cerebral cavernous malformations (CCM) and is proposed, whenever possible, after haemorrhagic events, neurological symptoms, or epilepsy, radiosurgery being a controversial alternative in some cases. However, there is no treatment for non-accessible lesions, such as brainstem CCM, multiple CCM, or those located in functional areas. Propranolol, a non-selective beta-blocker used as first-line treatment for infantile haemangiomas, has proved spectacularly effective in a few cases of adult patients with CCM. We herein review the histological, in vitro data and clinical findings that support the idea of propranolol as a potential treatment for CCM. Since one retrospective study has not been conclusive, we support the idea that prospective trials are necessary.

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“…43 In humans, there are recent case reports of reduction of recurrent hemorrhage rates and regression of lesion size with low-dose propranolol in patients with a progressive, aggressive course from multiple CCMs. 47,53 The therapeutic mechanism of propranolol is unknown, but has been posited to include the induction of vasoconstriction, the decreased expression of vascular endothelial growth factor and angiogenic factors, and the suppression of proliferation, migration, and differentiation of endothelial cells.…”

Section: Monogenic Causes Of Hemorrhagic Stroke Cerebral Cavernous Mamentioning

confidence: 99%

Single Gene Causes of Stroke

Majersik

2017

Semin Neurol

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Though rare, monogenic causes of stroke are recognizable by key clinical and radiographic features. A lack of epidemiological data leaves their true incidence unknown, but the most common monogenetic causes of stroke are sickle cell disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Fabry's disease, and cerebral cavernous malformations. In this article, the author covers the epidemiology, clinical features, and treatment of those diseases as well as other well-described monogenic causes of ischemic and hemorrhagic stroke. A “shotgun” approach to genetic testing should be avoided in favor of targeted testing that can provide a higher yield. Neurologists caring for stroke patients should be familiar with these monogenic causes of stroke, as heightened awareness and an armamentarium of additional diagnostic techniques will allow neurologists to diagnose correctly, implement individual distinct treatment paradigms, and provide future risk assessment.

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Propranolol stops progressive multiple cerebral cavernoma in an adult patient

Cited by 45 publications

References 7 publications

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

Could propranolol be beneficial in adult cerebral cavernous malformations?

Single Gene Causes of Stroke

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