Background The optimal management of posterior fossa arteriovenous malformations (pfAVMs) is a matter of debate. To advance this discussion, we present our clinical series and the results of a systematic literature review according to the... more
Background The optimal management of posterior fossa arteriovenous malformations (pfAVMs) is a matter of debate. To advance this discussion, we present our clinical series and the results of a systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Methods Fourteen consecutive patients with pfAVMs were admitted between 2007 and 2018. Preoperative status, radiologic parameters, and outcome were assessed. A systematic literature review was performed according to the PRISMA-P guidelines. Results Ten patients presented with rupture (71%), of whom three had associated aneurysms (AAs). The treatments were microsurgery (n = 4), endovascular (n = 3), radiosurgery (n = 2), a combination of two or three treatment modalities (n = 3), or conservative (n = 2). At discharge, all four patients (100%) with unruptured pfAVMs had a good outcome (modified Rankin Scale [mRS]: 0–2). In contrast, in ruptured pfAVM cases, mRS wa...
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OBJECTIVEAlthough several studies have suggested that the incidence of intracranial aneurysms (IAs) is higher in smokers, the higher prevalence of subarachnoid hemorrhage (SAH) in smokers remains uncertain. It is unclear whether smoking... more
OBJECTIVEAlthough several studies have suggested that the incidence of intracranial aneurysms (IAs) is higher in smokers, the higher prevalence of subarachnoid hemorrhage (SAH) in smokers remains uncertain. It is unclear whether smoking additionally contributes to the formation of multiple aneurysms and the risk of rupture. The aim of this study was to determine whether smoking is associated with IA formation, multiplicity, or rupture.METHODSPatients from the prospective multicenter @neurIST database (n = 1410; 985 females [69.9%]) were reviewed for the presence of SAH, multiple aneurysms, and smoking status. The prevalence of smokers in the population of patients diagnosed with at least one IA was compared with that of smokers in the general population.RESULTSThe proportion of smokers was higher in patients with IAs (56.2%) than in the reference population (51.4%; p < 0.001). A significant association of smoking with the presence of an IA was found throughout group comparisons (...
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The disease resulting in the formation, growth, and rupture of intracranial aneurysms is complex. Research is accumulating evidence that the disease is driven by many different factors, some constant and others variable over time.... more
The disease resulting in the formation, growth, and rupture of intracranial aneurysms is complex. Research is accumulating evidence that the disease is driven by many different factors, some constant and others variable over time. Combinations of factors may induce specific biophysical reactions at different stages of the disease. A better understanding of the biophysical mechanisms responsible for the disease initiation and progression is essential to predict the natural history of the disease. More accurate predictions are mandatory to adequately balance risks between observation and intervention at the individual level as expected in the age of personalized medicine. Multidisciplinary exploration of the disease also opens an avenue to the discovery of possible preventive actions or medical treatments. Modern information technologies and data processing methods offer tools to address such complex challenges requiring 1) the collection of a high volume of information provided globa...
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For a treatment decision of unruptured cerebral aneurysms, physicians and patients need to weigh the risk of treatment against the risk of hemorrhagic stroke caused by aneurysm rupture. The aim of this study was to externally evaluate a... more
For a treatment decision of unruptured cerebral aneurysms, physicians and patients need to weigh the risk of treatment against the risk of hemorrhagic stroke caused by aneurysm rupture. The aim of this study was to externally evaluate a recently developed statistical aneurysm rupture probability model, which could potentially support such treatment decisions. Segmented image data and patient information obtained from two patient cohorts including 203 patients with 249 aneurysms were used for patient-specific computational fluid dynamics simulations and subsequent evaluation of the statistical model in terms of accuracy, discrimination, and goodness of fit. The model's performance was further compared to a similarity-based approach for rupture assessment by identifying aneurysms in the training cohort that were similar in terms of hemodynamics and shape compared to a given aneurysm from the external cohorts. When applied to the external data, the model achieved a good discriminat...
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The exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm... more
The exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results. To evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2). Prospective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited. Part 1: Effec...
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The Barrow Neurological Institute (BNI) scale is a novel quantitative scale measuring maximal subarachnoid hemorrhage (SAH) thickness to predict delayed cerebral ischemia (DCI). This scale could replace the Fisher score, which was... more
The Barrow Neurological Institute (BNI) scale is a novel quantitative scale measuring maximal subarachnoid hemorrhage (SAH) thickness to predict delayed cerebral ischemia (DCI). This scale could replace the Fisher score, which was traditionally used for DCI prediction. To validate the BNI scale. All patient data were obtained from the prospective aneurysmal SAH multicenter registry. In 1321 patients, demographic data, BNI scale, DCI, and modified Rankin Scale (mRS) score up to the 1-yr follow-up (1FU) were available for descriptive and univariate statistics. Outcome was dichotomized in favorable (mRS 0-2) and unfavorable (mRS 3-6). Odds ratios (OR) for DCI of Fisher 3 patients (n = 1115, 84%) compared to a control cohort of Fisher grade 1, 2, and 4 patients (n = 206, 16%) were calculated for each BNI grade separately. Overall, 409 patients (31%) developed DCI with a high DCI rate in the Fisher 3 cohort (34%). With regard to the BNI scale, DCI rates went up progressively from 26% (BN...
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Grading scales yield objective measure of the severity of aneurysmal subarachnoid hemorrhage and serve as to guide treatment decisions and for prognostication. The purpose of this cohort study was to determine what factors govern a... more
Grading scales yield objective measure of the severity of aneurysmal subarachnoid hemorrhage and serve as to guide treatment decisions and for prognostication. The purpose of this cohort study was to determine what factors govern a patient's disease-specific admission scores in a representative Central European cohort. The Swiss Study of Subarachnoid Hemorrhage includes anonymized data from all tertiary referral centers serving subarachnoid hemorrhage patients in Switzerland. The 2009-2014 dataset was used to evaluate the impact of patient and aneurysm characteristics on the patients' status at admission using descriptive and multivariate regression analysis. The primary/co-primary endpoints were the GCS and the WFNS grade. The secondary endpoints were the Fisher grade, the presence of a thick cisternal or ventricular clot, the presence of a new focal neurological deficit or cranial nerve palsy, and the patient's intubation status. In our cohort of 1787 consecutive patie...
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Treatment of ruptured deep-seated arteriovenous malformations is challenging and associated with elevated risks. This is due to the proximity or involvement of critical brain structures and the specifically fine and delicate... more
Treatment of ruptured deep-seated arteriovenous malformations is challenging and associated with elevated risks. This is due to the proximity or involvement of critical brain structures and the specifically fine and delicate angioarchitecture of these lesions, making both endovascular and surgical access technically complicated. We present the advantages of a true combined, open surgical and endovascular transvenous approach in a hybrid operating room. The technique may overcome in part the difficulties and may improve safety and risk related concerns.
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To identify predictors of in-hospital mortality in patients with aneurysmal subarachnoid hemorrhage and to estimate their impact. Retrospective analysis of prospective data from a nationwide multicenter registry on all aneurysmal... more
To identify predictors of in-hospital mortality in patients with aneurysmal subarachnoid hemorrhage and to estimate their impact. Retrospective analysis of prospective data from a nationwide multicenter registry on all aneurysmal subarachnoid hemorrhage cases admitted to a tertiary neurosurgical department in Switzerland (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]; 2009-2015). Both clinical and radiological independent predictors of in-hospital mortality were identified, and their effect size was determined by calculating adjusted odds ratios (aORs) using multivariate logistic regression. Survival was displayed using Kaplan-Meier curves. Data of n=1866 aneurysmal subarachnoid hemorrhage patients in the Swiss SOS database were available. In-hospital mortality was 20% (n=373). In n=197 patients (10.6%), active treatment was discontinued after hospital admission (no aneurysm occlusion attempted), and this cohort was excluded from analysis of the main statistical mode...
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The literature on multiple intracranial aneurysms (MIA) in patients with aneurysmal subarachnoid hemorrhage (aSAH) focuses largely on risk factor analysis and consists essentially of retrospective cohort studies of limited sample size, or... more
The literature on multiple intracranial aneurysms (MIA) in patients with aneurysmal subarachnoid hemorrhage (aSAH) focuses largely on risk factor analysis and consists essentially of retrospective cohort studies of limited sample size, or studies in populations outside Europe and North America. The purpose of this cohort study was to identify predictors for aneurysm multiplicity and to investigate the anatomic distribution of MIA in a representative Western cohort of patients with aSAH. The Swiss Study of Subarachnoid Hemorrhage (SOS) database includes anonymized data from all tertiary neurovascular facilities in Switzerland. The dataset for 2009-2014 was used to compare characteristics of patients with aSAH and MIA and those with a single intracranial aneurysm (SIA) by means of descriptive and multivariate regression analysis. Among 1689 unselected patients with aSAH, 467 had MIA (prevalence, 27.6%). The location of the ruptured index aneurysm was correlated with the probability of...
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Hemodynamics play a driving role in the life cycle of brain aneurysms from initiation through growth until eventual rupture. The specific factors behind aneurysm growth, especially in small aneurysms, are not well elucidated. The goal of... more
Hemodynamics play a driving role in the life cycle of brain aneurysms from initiation through growth until eventual rupture. The specific factors behind aneurysm growth, especially in small aneurysms, are not well elucidated. The goal of this study was to differentiate focal versus general growth and to analyze the hemodynamic microenvironment at the sites of enlargement in small cerebral aneurysms. Small aneurysms showing growth during follow-up were identified from our prospective aneurysm database. Three dimensional rotational angiography (3DRA) studies before and after morphology changes were available for all aneurysms included in the study, allowing for detailed shape and computational fluid dynamic (CFD) based hemodynamic analysis. Six patients fulfilled the inclusion criteria. Two different types of change were observed: focal growth, with bleb or blister formation in three, and global aneurysm enlargement accompanied by neck broadening in other three patients. Areas of foca...
To determine the neurosurgeon's agreement in aneurysmal subarachnoid haemorrhage (aSAH) management with special emphasis on the rater's level of experience. A secondary aim was to analyse potential aneurysm variables associated... more
To determine the neurosurgeon's agreement in aneurysmal subarachnoid haemorrhage (aSAH) management with special emphasis on the rater's level of experience. A secondary aim was to analyse potential aneurysm variables associated with the therapeutic recommendation. Basic clinical information and admission computed tomography angiography (CTA) images of 30 consecutive aSAH patients were provided. Twelve neurosurgeons independently evaluated aneurysm characteristics and gave recommendations regarding the emergency management and aneurysm occlusion therapy. Inter-rater variability and predictors of treatment recommendation were evaluated. There was an overall moderate agreement in treatment decision [κ = 0.43; 95% confidence interval ((CI), 0.387-0.474] with moderate agreement for surgical (κ = 0.43; 95% CI, 0.386-0.479) and endovascular treatment recommendation (κ = 0.45; 95% CI, 0.398-0.49). Agreement on detailed treatment recommendations including clip, coil, bypass, stent, f...
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Hybrid room treatment (HRT) provides the surgeon immediate intraoperative angiography control of aneurysm occlusion and vessel patency. Since it is relatively resource demanding, in clinical routine HRT is reserved for elective cases.... more
Hybrid room treatment (HRT) provides the surgeon immediate intraoperative angiography control of aneurysm occlusion and vessel patency. Since it is relatively resource demanding, in clinical routine HRT is reserved for elective cases. However, since its introduction in our department in 2008, several random cases of ruptured intracranial aneurysms (IAs) have been treated in the HR. This study aims to compare the clinical and radiological outcomes of these cases with cases treated conventionally using a matched pair analysis. Twenty (20%) consecutive patients with ruptured IA treated by microsurgical clipping in the HR between 2009 and 2015 were retrospectively matched with &amp;amp;quot;conventionally&amp;amp;quot; (C) treated patients (overall n = 101). Clinical and radiological outcome variables were assessed and compared. Despite a trend in favor of the HR group, no significant difference between both matched groups (HR vs. C) could be demonstrated regarding the functional outcome (upper/lower good recovery 16/20 vs. 17/20, p &amp;amp;gt; 0.05), frequency of clipping-related vascular insults on CT scans (0/20 vs. 3/20, p &amp;amp;gt; 0.05), aneurysm remnant rate on postoperative angiography (1/20 vs. 4/20, p &amp;amp;gt; 0.05) and retreatment rate (0/20 vs. 1/20, p &amp;amp;gt; 0.05). When cumulating all outcome events by a scoring system, however, the HR cohort showed a significantly lower occurrence of events (p &amp;amp;lt; 0.05). In three cases co-treatment by an endovascular approach was performed in the HR cohort. In this relatively small cohort, a matched pair analysis revealed a discrete but not significant tendency toward a lower frequency of aneurysm remnants and clipping-related vascular insults in the HR cohort. However, HR cohort patients benefited from direct endovascular co-treatment in selected cases.
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The objective of this study was to determine interrater agreement in the initial radiological characterization of ruptured intracranial aneurysms based on CTA with special emphasis on the rater's level of experience. One junior and... more
The objective of this study was to determine interrater agreement in the initial radiological characterization of ruptured intracranial aneurysms based on CTA with special emphasis on the rater's level of experience. One junior and one senior rater of five high volume neurovascular tertiary centers evaluated anonymized CTA images of 30 consecutive aneurysmal SAH patients. Each rater described location, side, size and morphology in a standardized manner. Interrater variability was analyzed using intraclass correlation and Fleiss´kappa analysis. There was a high level of agreement for location (κ = 0,76, 95% confidence interval (CI) 0.74 - 0.79), side (κ = 0.95, CI 0.91 - 0.99), maximum diameter (Intraclass Correlation Coefficient (ICC) = 0.81, CI 0.70 - 0.90) and dome (ICC = 0.78, CI 0.66 - 0.88) of IA. In contrast a lower level of agreement was observed for aneurysms neck diameter (ICC = 0.39, CI 0.28 - 0.58), presence of multiple aneurysms (κ = 0.35, CI 0.30 - 0.40) and aneurys...
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To compare the assessment of cerebrovascular reserve (CVR) using CO2BOLD magnetic resonance imaging (MRI) vs positron emission tomography (PET) and single photon emission computed tomography (SPECT) as reference standard. Ten consecutive... more
To compare the assessment of cerebrovascular reserve (CVR) using CO2BOLD magnetic resonance imaging (MRI) vs positron emission tomography (PET) and single photon emission computed tomography (SPECT) as reference standard. Ten consecutive patients (8 women, mean age of 41 ± 26 years) with moyamoya syndrome underwent 14 pre-surgical evaluations for external-internal carotid artery bypass surgery. CVR was assessed using CO2BOLD and PET (4)/SPECT (11) with a maximum interval of 36 d, and evaluated by two experienced neuroradiologists. The inter-rater agreement was 0.81 for SPECT (excellent), 0.43 for PET (fair) and 0.7 for CO2BOLD (good). In 9/14 cases, there was a correspondence between CO2BOLD and PET/SPECT. In 4/14 cases, CVR was over-estimated in CO2BOLD, while in 1/14 case, CVR was underestimated in CO2BOLD. The sensitivity of CO2BOLD was 86% and a specificity of 43%. CO2BOLD can be used for pre-surgical assessment of CVR in patients with moyamoya syndrome and combines the advantag...
The management of small unruptured incidentally discovered intracranial aneurysms (SUIAs) is still controversial. The aim of this study is to assess the safety of a management protocol of SUIAs, where selected cases with SUIAs are... more
The management of small unruptured incidentally discovered intracranial aneurysms (SUIAs) is still controversial. The aim of this study is to assess the safety of a management protocol of SUIAs, where selected cases with SUIAs are observed and secured only if signs of instability (growth) are documented. A prospective consecutive cohort of 292 patients (2006-2014) and 368 SUIAs (anterior circulation aneurysms (ACs) smaller than 7 mm and posterior circulation aneurysms smaller than 4 mm without previous subarachnoid haemorrhage) was observed (mean follow-up time of 3.2 years and 1177.6 aneurysm years). Factors associated with aneurysm growth were systematically reviewed from the literature. The aneurysm growth probability was 2.6±0.1% per year. The rate of unexpected aneurysm rupture before treatment was 0.24% per year (95% CI 0.17% to 2.40%). The calculated rate of aneurysm rupture after growth was 6.3% per aneurysm-year (95% CI 1% to 22%). Aneurysms located in the posterior circula...
Research Interests: Patient Safety, Risk assessment, Humans, Female, Male, and 13 moreIncidental Findings, Aged, Middle Aged, Longitudinal Studies, Adult, Risk Assessment, Cohort Studies, Magnetic resonance angiography, Psychology and Cognitive Sciences, Patient selection, Intracranial aneurysm, Medical and Health Sciences, and Watchful waiting
Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic... more
Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show sign...
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The @neurIST ontology is currently under development within the scope of the European project @neurIST intended to serve as a module in a complex architecture aiming at providing a better understanding and management of intracranial... more
The @neurIST ontology is currently under development within the scope of the European project @neurIST intended to serve as a module in a complex architecture aiming at providing a better understanding and management of intracranial aneurysms and subarachnoid hemorrhages. Due to the integrative structure of the project the ontology needs to represent entities from various disciplines on a large spatial and temporal scale. Initial term acquisition was performed by exploiting a database scaffold, literature analysis and communications with domain experts. The ontology design is based on the DOLCE upper ontology and other existing domain ontologies were linked or partly included whenever appropriate (e.g., the FMA for anatomical entities and the UMLS for definitions and lexical information). About 2300 predominantly medical entities were represented but also a multitude of biomolecular, epidemiological, and hemodynamic entities. The usage of the ontology in the project comprises terminological control, text mining, annotation, and data mediation.
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Despite progress in the understanding of risk factors for aneurysm rupture, the decision whether or not to treat an unruptured intracranial aneurysm (UIA) should be treated remains a challenge. A multidisciplinary team of neurovascular... more
Despite progress in the understanding of risk factors for aneurysm rupture, the decision whether or not to treat an unruptured intracranial aneurysm (UIA) should be treated remains a challenge. A multidisciplinary team of neurovascular surgeons and interventional radiologists with broad experience in the field should make this decision under critical consideration of their own skills, complication rates and treatment outcomes. Preventive aneurysm occlusion should be proposed whenever the risk of the natural course is estimated higher than the risk associated with the treatment. While the treatment risks have been well documented, a growing body of literature nowadays guides the physician to estimate the risk of aneurysmal subarachnoid hemorrhage from an UIA. Scores like the PHASES score somewhat facilitate the estimation of the rupture risk and prove helpful for the discussion with the patient – whether to treat or whether to follow the aneurysm.
Subarachnoid hemorrhage (SAH) still carries a high morbidity and mortality, despite improvement in surgical and medical management. Seizures and delayed cerebral ischemia (DCI) secondary to vasospasm or cortical spreading depression are... more
Subarachnoid hemorrhage (SAH) still carries a high morbidity and mortality, despite improvement in surgical and medical management. Seizures and delayed cerebral ischemia (DCI) secondary to vasospasm or cortical spreading depression are frequent after SAH. Continuous EEG allows early detection of non-convulsive seizures or delayed cerebral ischemia and may become a promissing tool in the monitoring of SAH patients. However, its use in clinical practice is still limited because many resources are required for recording and analyzing continuous EEG. Moreover, we require more data to confirm the relationship between aggressive treatment of non-convulsive seizure or delayed cerebral ischemia triggered by continuous EEG and outcome.
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This paper presents an overview of computerised decision support for clinical practice. The concept of computer-interpretable guidelines is introduced in the context of the @neurIST project, which aims at supporting the research and... more
This paper presents an overview of computerised decision support for clinical practice. The concept of computer-interpretable guidelines is introduced in the context of the @neurIST project, which aims at supporting the research and treatment of asymptomatic unruptured cerebral aneurysms by bringing together heterogeneous data, computing and complex processing services. The architecture is generic enough to adapt it to the treatment of other diseases beyond cerebral aneurysms. The paper reviews the generic requirements of the @neurIST system and presents the innovative work in distributing executable clinical guidelines.
Research Interests: Chronic disease management, Clinical Practice, Library and Information Studies, Humans, Europe, and 9 moreComputer Systems, Chronic Disease, Decision Support, Heterogeneous Data, Public health systems and services research, Computer communication networks, Clinical Decision Support Systems, Disease Management, and Cerebral Aneurysm
1. Two early signs of human myoblast commitment to fusion are membrane potential hyperpolarization and concomitant expression of a non-inactivating delayed rectifier K+ current, IK(NI). This current closely resembles the outward K+... more
1. Two early signs of human myoblast commitment to fusion are membrane potential hyperpolarization and concomitant expression of a non-inactivating delayed rectifier K+ current, IK(NI). This current closely resembles the outward K+ current elicited by rat ether-à-go-go (r-eag) channels in its range of potential for activation and unitary conductance. 2. It is shown that activation kinetics of IK(NI), like those of r-eag, depend on holding potential and on [Mg2+]o, and that IK(NI), like r-eag, is reversibly inhibited by a rise in [Ca2+]i. 3. Forced expression of an isolated human ether-à-go-go K+ channel (h-eag) cDNA in undifferentiated myoblasts generates single-channel and whole-cell currents with remarkable similarity to IK(NI). 4. h-eag current (Ih-eag) is reversibly inhibited by a rise in [Ca2+]i, and the activation kinetics depend on holding potential and [Mg2+]o. 5. Forced expression of h-eag hyperpolarizes undifferentiated myoblasts from -9 to -50 mV, the threshold for the activation of both Ih-eag and IK(NI). Similarly, the higher the density of IK(NI), the more hyperpolarized the resting potential of fusion-competent myoblasts. 6. It is concluded that h-eag constitutes the channel underlying IK(NI) and that it contributes to the hyperpolarization of fusion-competent myoblasts. To our knowledge, this is the first demonstration of a physiological role for a mammalian eag K+ channel.
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Intracellular calcium increase is an early key event triggering ischemic neuronal cell damage. The role of T-type voltage-gated calcium channels in the neuronal response to ischemia, however, has never been studied. Using an in vitro... more
Intracellular calcium increase is an early key event triggering ischemic neuronal cell damage. The role of T-type voltage-gated calcium channels in the neuronal response to ischemia, however, has never been studied. Using an in vitro model of ischemia-induced delayed cell death in rat organotypic hippocampal slice cultures, we show that T-type calcium channels inhibitors drastically reduce ischemic cell damage. Immunostaining studies reveal the existence of Ca(V)3.1 and Ca(V)3.2 types of low-voltage-activated calcium channels in rat organotypic hippocampal cultures. Low extracellular calcium (100 nM) or increase of intracellular calcium buffering ability by BAPTA-acetoxymethyl ester significantly reduced ischemia-induced neuronal damage. Pharmacological inhibition of the T-type calcium current by mibefradil, kurtoxin, nickel, zinc, and pimozide during the oxygen-glucose deprivation episode provided a significant protection against delayed neuronal death. Mibefradil and nickel exerted neuroprotective effects, not only if administrated during the oxygen-glucose deprivation episode but also in conditions of postischemic treatment. These data point to a role of T-type calcium currents in ischemia-induced, calcium-mediated neuronal cell damage and suggest a possible new pharmacological approach to stroke treatment.
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Research Interests: Skeletal muscle biology, Food, Biological Chemistry, Ion Channels, Biological Sciences, and 16 moreCell line, Mice, Female, Animals, Male, Biological, Temperature, Food intake, CHEMICAL SCIENCES, Skeletal Muscle, Rats, Environmental Temperature, Calorimetry, Uncoupling Protein, Gene Expression Regulation, and Mitochondrial Proteins
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1. The effect of mibefradil (Ro 40-5967), an inhibitor of T-type Ca2+ current (I(Ca)(T)), on myoblast fusion and on several voltage-gated currents expressed by fusion-competent myoblasts was examined. 2. At a concentration of 5 microM,... more
1. The effect of mibefradil (Ro 40-5967), an inhibitor of T-type Ca2+ current (I(Ca)(T)), on myoblast fusion and on several voltage-gated currents expressed by fusion-competent myoblasts was examined. 2. At a concentration of 5 microM, mibefradil decreases myoblast fusion by 57%. At this concentration, the peak amplitudes of I(Ca)(T) and L-type Ca2+ current (I(Ca)(L)) measured in fusion-competent myoblasts are reduced by 95 and 80%, respectively. The IC50 of mibefradil for I(Ca)(T) and I(Ca)(L) are 0.7 and 2 microM, respectively. 3. At low concentrations, mibefradil increased the amplitude of I(Ca)(L) with respect to control. 4. Mibefradil blocked three voltage-gated K+ currents expressed by human fusion-competent myoblasts: a delayed rectifier K+ current, an ether-à-go-go K+ current, and an inward rectifier K+ current, with a respective IC50 of 0.3, 0.7 and 5.6 microM. 5. It is concluded that mibefradil can interfere with myoblast fusion, a mechanism fundamental to muscle growth and repair, and that the interpretation of the effect of mibefradil in a given system should take into account the action of this drug on ionic currents other than Ca2+ currents.