Abstract:
:Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1+/- and Ccm3+/- mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1+/- and Ccm3+/- transgenic mice were treated for 3 (Ccm3+/-) or 4 months (Ccm1+/-), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3+/-Trp53-/- lesions. Ccm1+/-Msh2-/- (n=68) and Ccm3+/-Trp53-/- (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.
journal_name
Transl Stroke Resjournal_title
Translational stroke researchauthors
McKerracher L,Shenkar R,Abbinanti M,Cao Y,Peiper A,Liao JK,Lightle R,Moore T,Hobson N,Gallione C,Ruschel J,Koskimäki J,Girard R,Rosen K,Marchuk DA,Awad IAdoi
10.1007/s12975-019-00725-8subject
Has Abstractpub_date
2020-06-01 00:00:00pages
365-376issue
3eissn
1868-4483issn
1868-601Xpii
10.1007/s12975-019-00725-8journal_volume
11pub_type
杂志文章abstract::Monocytes recruitment from the blood to inflamed tissues following ischemic stroke is an important immune response to wound healing and tissue repair. Mouse monocytes can be endogenously divided into two distinct populations: pro-inflammatory or classical monocytes that express CCR2highCX3CR1low and circulate in blood...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-020-00878-x
更新日期:2021-01-06 00:00:00
abstract::Stroke prevention efforts typically focus on either ischemic or hemorrhagic stroke. This approach is overly simplistic due to the frequent coexistence of ischemic and hemorrhagic cerebrovascular disease. This coexistence, termed "mixed cerebrovascular disease", offers a conceptual framework that appears useful for str...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-012-0185-6
更新日期:2012-07-01 00:00:00
abstract::Although used extensively in stroke research, there is limited knowledge of how 2, 3, 5-triphenyltetrazolium chloride (TTC)-treated rat brain sections are altered and if they can be used for immunohistochemical quantification after staining with TTC. In the present study, we hypothesized that TTC treatment (TTC+) woul...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-017-0604-9
更新日期:2018-10-01 00:00:00
abstract::Approximately, 16 million strokes occur worldwide each year, causing 6 million deaths and considerable disability, implying an enormous social, individual health, and economic burden. Due to this high incidence, strategies to promote stroke recovery are urgently needed. Research into new therapeutic approaches for str...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-018-0654-7
更新日期:2019-06-01 00:00:00
abstract::Magnetic resonance imaging (MRI) has dramatically changed our ability to diagnose and treat stroke as well as follow its evolution and response to treatment. Early stroke and ischemia can be visualized using diffusion-weighted imaging that utilizes water diffusion within tissues as a reporter for evolving neuropatholo...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-011-0139-4
更新日期:2012-03-01 00:00:00
abstract::Impaired cerebral autoregulation and neurovascular coupling (NVC) contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Retinal vessel analysis (RVA) allows non-invasive assessment of vessel dimension and NVC hereby demonstrating a predictive value in the context of various neurovascular disease...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-017-0585-8
更新日期:2018-06-01 00:00:00
abstract::In the original publication of the article, there was a switched order of author names. ...
journal_title:Translational stroke research
pub_type: 杂志文章,已发布勘误
doi:10.1007/s12975-018-0618-y
更新日期:2018-12-01 00:00:00
abstract::Intracerebral hemorrhage is a devastating disease. Despite its clinical importance, the pathophysiology of intracerebral hemorrhage is not well understood. Hematoma expansion occurs in a large subset of patients and is a predictor of poor outcomes. Since hematoma growth provides a potential opportunity for therapeutic...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-015-0410-1
更新日期:2015-08-01 00:00:00
abstract::Pathophysiological findings of early brain injury in humans have not permitted conclusive determinations. We explored the essence of this phenomenon by taking intraoperative cortical specimens of Hunt-Kosnik grades IV~V (poor-grade) subarachnoid hemorrhages (SAH). From 2013 to 2017, we treated 39 consecutive poor-grad...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-020-00875-0
更新日期:2020-11-27 00:00:00
abstract::Activation and repression of gene expression are key features of ischemic tolerance. Converging lines of inquiry from several groups suggests that epigenetic proteins may transduce sublethal stresses, including bioenergetic or oxidative stress into durable (2-3 days) changes in gene expression that mediate ischemic to...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-012-0235-0
更新日期:2013-02-01 00:00:00
abstract::Despite being a conveniently portable technology for stroke assessment, Transcranial Doppler ultrasound (TCD) remains widely underutilized due to complex training requirements necessary to reliably obtain and interpret cerebral blood flow velocity (CBFV) waveforms. The validation of objective TCD metrics for large ves...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-018-0667-2
更新日期:2019-10-01 00:00:00
abstract::Despite ischemic stroke being the fifth leading cause of death in the USA, there are few therapeutic options available. We recently showed that the neuroprotective compound P7C3-A20 reduced brain atrophy, increased neurogenesis, and improved functional recovery when treatment was initiated immediately post-reperfusion...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-017-0565-z
更新日期:2018-04-01 00:00:00
abstract::The presence of active developmental angiogenesis and vascular outgrowth in the postnatal brain may differentially affect vascular responses to stroke in newborns and adults, but very little is known about the dynamics of vascular injury and re-growth after stroke during the neonatal period. In this study we used a cl...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-012-0214-5
更新日期:2013-04-01 00:00:00
abstract::Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-018-0622-2
更新日期:2019-02-01 00:00:00
abstract::Positron emission tomography (PET) is widely used in clinical and animal studies, along with the development of diverse tracers. The biochemical characteristics of PET tracers may help uncover the pathophysiological consequences of cardiac arrest (CA) and ischemic stroke, which include cerebral ischemia and reperfusio...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-019-00765-0
更新日期:2020-08-01 00:00:00
abstract::Subarachnoid haemorrhage (SAH) is a devastating disease and a major burden on society. Despite this, pharmacological treatment options are limited. Appropriate animal modelling of SAH is essential for the development of neuroprotective drugs, but experimental SAH often fails to produce widespread neuronal loss, as fre...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-011-0124-y
更新日期:2012-03-01 00:00:00
abstract::Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death of neurons. Injury-mediated inc...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-013-0297-7
更新日期:2014-02-01 00:00:00
abstract::Neonatal hypoxia-ischemia (HI) is a devastating condition resulting in neuronal cell death and often culminates in neurological deficits. Granulocyte-colony stimulating factor (G-CSF) has been shown to have neuroprotective activity via inhibition of apoptosis and inflammation in various stroke models. Stem cell factor...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-012-0225-2
更新日期:2013-04-01 00:00:00
abstract::For years, strategies have been proposed to improve translational success in stroke research by improving the quality of animal studies. However, articles that report preclinical intracerebral hemorrhage (ICH) studies continue to lack adequate qualitative and quantitative descriptions of fresh brain tissue collection....
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-015-0399-5
更新日期:2015-10-01 00:00:00
abstract::Clinical studies on subarachnoid hemorrhage (SAH) have shown discrepancies between large vessel vasospasm, cerebral perfusion, and clinical outcome. We set out to analyze the contribution of large vessel vasospasm to impaired cerebral perfusion and neurological impairment in a murine model of SAH. SAH was induced in C...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-018-0647-6
更新日期:2018-07-12 00:00:00
abstract::Quantitative susceptibility mapping (QSM) has been recently introduced as a novel MRI post-processing technique of gradient recalled echo (GRE) data. QSM is useful in depicting both brain anatomy and for detecting abnormalities. Its utility in the context of ischemic stroke has, however, not been extensively character...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-017-0591-x
更新日期:2018-08-01 00:00:00
abstract::Intracerebral hemorrhage is by far the most destructive form of stroke. Apart from the management in a specialized stroke or neurological intensive care unit (NICU), no specific therapies have been shown to consistently improve outcomes after ICH. Current guidelines endorse early aggressive optimization of physiologic...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-012-0175-8
更新日期:2012-07-01 00:00:00
abstract::Ischemic stroke contributes to the majority of brain injuries and remains to be a leading cause of death and long-term disability. Despite the devastating pathology and high incidence of disease, there remain only few treatment options (TPA and endovascular procedures), which may be hampered by time-dependent administ...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-013-0319-5
更新日期:2014-02-01 00:00:00
abstract::Global ischemia following cardiac arrest is characterized by high mortality and significant neurological deficits in long-term survivors. Its mechanisms of neuronal cell death have only partially been elucidated. 12/15-lipoxygenase (12/15-LOX) is a major contributor to delayed neuronal cell death and vascular injury i...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-016-0509-z
更新日期:2017-04-01 00:00:00
abstract::Noninvasive magnetic resonance (MR) methods have been explored to provide quantitative measurements of cerebral blood flow (CBF), oxygen extraction fraction (OEF), and oxygen metabolic index (OMI = CBF × OEF). In this study, we sought to evaluate whether MR measured OEF, CBF, and OMI can consistently detect the expect...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-011-0142-9
更新日期:2012-06-01 00:00:00
abstract::Anticoagulation increases the risk of intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA), so the management of stroke-risk in patients with both atrial fibrillation (AF) and CAA is controversial. Advances in left atrial appendage closure (LAAC) techniques provide a stroke-risk-reduction ...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-020-00838-5
更新日期:2020-08-07 00:00:00
abstract::Infection is a leading cause of death in patients with stroke; however, the impact of cerebral infarct size or location on infectious outcome is unclear. To examine the effect of infarct size on post-stroke infection, we utilised the intraluminal middle-cerebral artery occlusion (MCAO) mouse model of ischemic stroke a...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-019-00738-3
更新日期:2020-06-01 00:00:00
abstract::Preconditioning is a paradigm in which sublethal stress-prior to a more injurious insult-induces protection against injury. In the central nervous system (CNS), preconditioning against ischemic stroke is induced by short durations of ischemia, brief seizures, exposure to anesthetics, and other stresses. Increasing evi...
journal_title:Translational stroke research
pub_type: 杂志文章,评审
doi:10.1007/s12975-017-0547-1
更新日期:2017-12-01 00:00:00
abstract::Pulmonary complications associated with persistent respiratory muscle weakness, paralysis, and spasticity are among the most important problems faced by patients with spinal cord injury when lack of muscle strength and disorganization of reciprocal respiratory muscle control lead to breathing insufficiency. This revie...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-011-0114-0
更新日期:2011-12-01 00:00:00
abstract::This review focuses on assessment of behavioral outcomes following traumatic brain injury in juvenile animal models. In the 15 years since the first publication in this field, the majority of studies have used rats roughly equivalent to human toddlers in terms of brain development. Few studies have tested ages closer ...
journal_title:Translational stroke research
pub_type: 杂志文章
doi:10.1007/s12975-011-0132-y
更新日期:2011-12-01 00:00:00