Structural alterations and breakdown of the blood brain barrier (BBB) is often a primary or secondary consequence of disease, resulting in brain oedema and the transport of unwanted substances into ...the brain. It is critical that effective
models are developed to model the
environment to aid in clinically relevant research, especially regarding drug screening and permeability studies. Our novel model uses only primary human cells and includes four of the key cells of the BBB: astrocytes, pericytes, brain microvascular endothelial cells (HBMEC) and neurons. We show that using a larger membrane pore size (3.0 μM) there is an improved connection between the endothelial cells, astrocytes and pericytes. Compared to a two and three cell model, we show that when neurons are added to HBMECs, astrocytes and pericytes, BBB integrity was more sensitive to oxygen-glucose deprivation evidenced by increased permeability and markers of cell damage. Our data also show that a four cell model responds faster to the barrier tightening effects of glucocorticoid dexamethasone, when compared to a two cell and three cell model. These data highlight the important role that neurons play in response to ischaemia, particularly how they contribute to BBB maintenance and breakdown. We consider that this model is more representative of the interactions at the neurovascular unit than other transwell models and is a useful method to study BBB physiology.
Background and Purpose In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models and against epithelial barrier damage in ...numerous disease models. We aimed to investigate whether CBD also affects blood-brain barrier (BBB) permeability following ischaemia. Experimental Approach Human brain microvascular endothelial cell (HBMEC) and human astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Key Results CBD (10 µM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered before the OGD, but protective effects were observed up to 2 h into reperfusion. This protective effect was inhibited by a PPARgamma antagonist and partly reduced by a 5-HT1A receptor antagonist, but was unaffected by antagonists of cannabinoid CB1 or CB2 receptors, TRPV1 channels or adenosine A2A receptors. CBD also reduced cell damage, as measured by LDH release and by markers of cellular adhesion, such as the adhesion molecule VCAM-1. In HBMEC monocultures, CBD decreased VCAM-1 and increased VEGF levels, effects which were inhibited by PPARgamma antagonism. Conclusions and Implications These data suggest that preventing permeability changes at the BBB could represent an as yet unrecognized mechanism of CBD-induced neuroprotection in ischaemic stroke, a mechanism mediated by activation of PPARgamma and 5-HT1A receptors.
Background and Purpose
In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models and against epithelial barrier damage in ...numerous disease models. We aimed to investigate whether CBD also affects blood–brain barrier (BBB) permeability following ischaemia.
Experimental Approach
Human brain microvascular endothelial cell (HBMEC) and human astrocyte co‐cultures modelled the BBB. Ischaemia was modelled by oxygen–glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance.
Key Results
CBD (10 μM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered before the OGD, but protective effects were observed up to 2 h into reperfusion. This protective effect was inhibited by a PPARγ antagonist and partly reduced by a 5‐HT1A receptor antagonist, but was unaffected by antagonists of cannabinoid CB1 or CB2 receptors, TRPV1 channels or adenosine A2A receptors. CBD also reduced cell damage, as measured by LDH release and by markers of cellular adhesion, such as the adhesion molecule VCAM‐1. In HBMEC monocultures, CBD decreased VCAM‐1 and increased VEGF levels, effects which were inhibited by PPARγ antagonism.
Conclusions and Implications
These data suggest that preventing permeability changes at the BBB could represent an as yet unrecognized mechanism of CBD‐induced neuroprotection in ischaemic stroke, a mechanism mediated by activation of PPARγ and 5‐HT1A receptors.
Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol and Δ9‐tetrahydrocannabinol, including ...Δ9‐tetrahydrocannabinolic acid, Δ9‐tetrahydrocannabivarin, cannabidiolic acid, cannabidivarin, cannabichromene, cannabichromenic acid, cannabichromevarin, cannabigerol, cannabigerolic acid, cannabigerivarin, cannabigerovarinic acid, cannabichromevarinic acid, cannabidivarinic acid, and cannabinol. Out of 2,341 studies, 31 articles met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg−1) and cannabidivarin (range 0.2 to 400 mg·kg−1) displayed efficacy in models of Huntington's disease and epilepsy. Cannabichromene (10–75 mg·kg−1), Δ9‐tetrahydrocannabinolic acid (20 mg·kg−1), and tetrahydrocannabivarin (range 0.025–2.5 mg·kg−1) showed promise in models of seizure and hypomobility, Huntington's and Parkinson's disease. Limited mechanistic data showed cannabigerol, its derivatives VCE.003 and VCE.003.2, and Δ9‐tetrahydrocannabinolic acid mediated some of their effects through PPAR‐γ, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.
Background
In vivo studies show that cannabidiol (CBD) acutely reduces blood pressure (BP) in men. The aim of this study was to assess the effects of repeated CBD dosing on haemodynamics.
Methods
...Twenty‐six healthy males were given CBD (600 mg) or placebo orally for seven days in a randomised, placebo‐controlled, double‐blind, parallel study (n = 13/group). Cardiovascular parameters were assessed at rest and in response to isometric exercise after acute and repeated dosing using Finometer®, Vicorder® and Duplex ultrasound.
Results
Compared to placebo, CBD significantly reduced resting mean arterial pressure (P = .04, two‐way ANOVA, mean difference (MD) –2 mmHg, 95% CI ‐3.6 to −0.3) after acute dosing, but not after repeated dosing. In response to stress, volunteers who had taken CBD had lower systolic BP after acute (P = .001, two‐way ANOVA, MD −6 mmHg, 95% CI –10 to −1) and repeated (P = .02, two‐way ANOVA, MD −5.7 mmHg, 95% CI –10 to −1) dosing. Seven days of CBD increased internal carotid artery diameter (MD +0.55 mm, P = .01). Within the CBD group, repeated dosing reduced arterial stiffness by day 7 (pulse wave velocity; MD −0.44 m/s, P = .05) and improved endothelial function (flow mediation dilatation, MD +3.5%, P = .02, n = 6 per group), compared to day 1.
Conclusion
CBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists. The reduction in arterial stiffness and improvements in endothelial function after repeated CBD dosing are findings that warrant further investigation in populations with vascular diseases.
Background
Direct mechanical thrombectomy may result in similar outcomes compared to a bridging approach with intravenous thrombolysis (IVT + MT) in acute ischemic stroke. Recent randomized ...controlled trials have varied in their design and noninferiority margin.
Aim
We sought to meta-analyze accumulated trial data to assess the difference and non-inferiority in clinical and procedural outcomes between direct mechanical thrombectomy and bridging therapy.
Summary of review
We conducted a systematic review of electronic databases following the preferred reporting items for systematic reviews and meta-analyses guidelines. Random effects meta-analyses were conducted for the pooled data. The primary outcome was good functional outcome at 90 days (modified Rankin scale (mRS) ≤ 2). Secondary outcomes included excellent functional outcome (mRS ≤ 1), mortality, any intracranial hemorrhage, symptomatic intracranial hemorrhage, successful reperfusion (thrombolysis in cerebral infarction ≥ 2 b), and procedure-related complications. Four randomized controlled trials comprising 1633 patients (817 direct mechanical thrombectomy, 816 bridging therapy) were included. There were no statistical differences for the 90-day good functional outcome (OR = 1.02, 95% CI 0.84–1.25, p = 0.54, I2 = 0%), and the absolute risk difference was 1% (95% CI: −4% to 5%). The lower 95% CI falls within the strictest noninferiority margin of −10% among included randomized control trials. Direct mechanical thrombectomy reduced the odds of successful reperfusion (OR = 0.76, 95% CI: 0.60–0.97, p = 0.03, I2 = 0%) and any intracranial hemorrhage (OR = 0.65, 95% CI: 0.49–0.86, p = 0.003, I2 = 38%). There was no difference in the remaining secondary outcomes. The risk of bias for all studies was low.
Conclusion
The combined trial data assessing direct mechanical thrombectomy versus bridging therapy showed no difference in improving good functional outcome. The wide noninferiority thresholds set by individual trials are in contrast with the clinical consensus on minimally important differences. However, our pooled analysis indicates noninferiority of direct mechanical thrombectomy with a 4% margin of confidence. The application of these findings is limited to patients presenting directly to mechanical thrombectomy-capable centers and real-world workflow times may differ against those achieved in a trial setting.
Remote ischemic conditioning (RIC) is the application of brief periods of ischemia to an organ or tissue with the aim of inducing protection from ischemia in a distant organ. It was first developed ...as a cardioprotective strategy but has been increasingly investigated as a neuroprotective intervention. The mechanisms by which RIC achieves neuroprotection are incompletely understood. Preclinical studies focus on the hypothesis that RIC can protect the brain from ischemia reperfusion (IR) injury following the restoration of blood flow after occlusion of a large cerebral artery. However, increasingly, a role of chronic RIC (CRIC) is being investigated as a means of promoting recovery following an ischemic insult to the brain. The recent publication of two large, randomized control trials has provided promise that RIC could improve functional outcomes after acute ischemic stroke, and that there may be a role for CRIC in the prevention of recurrent stroke. Although less developed, there is also proof-of-concept to suggest that RIC may be used to reduce vasospasm after subarachnoid hemorrhage or improve cognitive outcomes in vascular dementia. As a cheap, well-tolerated and almost universally applicable intervention, the motivation for investigating possible benefit of RIC in patients with cerebrovascular disease is great. In this review, we shall review the current evidence for RIC as applied to cerebrovascular disease.
To describe and systematically review the current evidence on the effects of swallow therapy augmented by biofeedback in adults with dysphagia (PROSPERO 2016:CRD42016052942).
Two independent ...reviewers conducted searches that included MEDLINE, EMBASE, trial registries, and gray literature up to December 2016.
Randomized controlled trials (RCTs) and non-RCTs were assessed, including for risk of bias and quality.
Data were extracted by 1 reviewer and verified by another on biofeedback type, measures of swallow function, physiology and clinical outcome, and analysed using Cochrane Review Manager (random effects models). Results are expressed as weighted mean difference (WMD) and odds ratio (OR).
Of 675 articles, we included 23 studies (N=448 participants). Three main types of biofeedback were used: accelerometry, surface electromyography (sEMG), and tongue manometry. Exercises included saliva swallows, maneuvers, and strength exercises. Dose varied between 6 and 72 sessions for 20-60 minutes. Five controlled studies (stroke n=95; head and neck cancer n=33; mixed etiology n=10) were included in meta-analyses. Compared to control, biofeedback augmented dysphagia therapy significantly enhanced hyoid displacement (3 studies, WMD=0.22cm; 95% confidence interval CI 0.04, 0.40, P=.02) but there was no significant difference in functional oral intake (WMD=1.10; 95% CI -1.69, 3.89, P=.44) or dependency on tube feeding (OR =3.19; 95% CI 0.16, 62.72, P=.45). Risk of bias was high and there was significant statistical heterogeneity between trials in measures of swallow function and number tube fed (I
70%-94%). Several nonvalidated outcome measures were used. Subgroup analyses were not possible due to a paucity of studies.
Dysphagia therapy augmented by biofeedback using sEMG and accelerometry enhances hyoid displacement but functional improvements in swallowing are not evident. However, data are extremely limited and further larger well-designed RCTs are warranted.
Cannabinoids (CBs) show promise as neuroprotectants with some agents already licensed in humans for other conditions. We systematically reviewed CBs in preclinical stroke to guide further ...experimental protocols. We selected controlled studies assessing acute administration of CBs for experimental stroke, identified through systematic searches. Data were extracted on lesion volume, outcome and quality, and analyzed using random effect models. Results are expressed as standardized mean difference (SMD) with 95% confidence intervals (CIs). In all, 144 experiments (34 publications) assessed CBs on infarct volume in 1,473 animals. Cannabinoids reduced infarct volume in transient (SMD −1.41 (95% CI −1.71), −1.11) P<0.00001) and permanent (−1.67 (−2.08, −1.27), P<0.00001) ischemia and in all subclasses: endocannabinoids (−1.72 (−2.62, −0.82), P=0.0002), CB1/CB2 ligands (−1.75 (−2.19, −1.31), P<0.00001), CB2 ligands (−1.65 (−2.09, −1.22), P<0.00001), cannabidiol (−1.20 (−1.63, −0.77), P<0.00001), Δ9-tetrahydrocannabinol (−1.43 (−2.01, −0.86), P<0.00001), and HU-211 (−2.90 (−4.24, −1.56), P<0.0001). Early and late neuroscores significantly improved with CB use (−1.27 (−1.58, −0.95), P<0.00001; −1.63 (−2.64, −0.62), P<0.002 respectively) and there was no effect on survival. Statistical heterogeneity and publication bias was present, median study quality was 4 (range 1 to 6/8). Overall, CBs significantly reduced infarct volume and improve functional outcome in experimental stroke. Further studies in aged, female and larger animals, with other co-morbidities are required.
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