Effect of N-arachidonoyl-l-serine on human cerebromicrovascular endothelium

AbstractN-arachidonoyl-l-serine (ARA-S) is an endogenous lipid, chemically related to the endocannabinoid, N-arachidonoyl ethanolamine (i.e., anandamide) and with similar physiologic and pathophysiologic functions. Reports indicate that ARA-S possesses vasoactive and neuroprotective properties resembling those of cannabinoids. However, in contrast to cannabinoids, ARA-S binds weakly to its known classical receptors, CB1 and CB2, and is therefore considered to be a ‘cannabinoid-like’ substance. The originally described ARA-S induced-endothelial-dependent vasorelaxation was not abrogated by CB1, CB2 receptor antagonists or TRPV1 competitive inhibitor. The present report demonstrates that ARA-S enhances the fluorescence staining of both cannabinoid receptors (CB1 and CB2) in human brain endothelial cells (HBEC). This reaction is specific since it was reduced by respective selective receptor antagonist (SR141716A and SR141728A). ARA-S alone or in the presence of ET-1 was shown to alter the cytoskeleton (actin). Both ARA-S stimulated phosphorylation of various kinases (MAPK, Akt, JNK and c-JUN) and alteration of cytoskeleton are mediated via CB1, CB2 and TRPV1 receptors. The findings also showed the involvement of Rho/Rock and PI3/Akt/NO pathways in the ARA-S-induced phosphorylation of kinases and actin reorganization in HBEC. All of the above mentioned ARA-S-induced effects were reduced by the treatment with LY294002 (inhibitor of PI3/Akt kinase), except MAPK kinase. In addition, MAPK, JNK, c-JUN phosphorylation were inhibited by H1152 (inhibitor of Rho/ROCK kinase), except Akt kinase. Furthermore, PI3/Akt pathway was inhibited by pretreatment with l-NAME (inhibitor of NOS). The findings suggest that ARA-S is a modulator of Rho kinase and may play a critical role in the regulation of its activity and subsequent effects on the cytoskeleton and its role in supporting essential cell functions like vasodilation, proliferation and movement

Treatment of experimental aneurysms with a GPX embolic agent prototype: preliminary angiographic and histological results

Background Recently, liquid embolic agents have emerged for the endovascular treatment of cerebral aneurysms. Here we describe the in vivo performance of a novel liquid embolization agent (GPX Embolic Device). Methods Elastase-induced aneurysms were embolized with a GPX prototype under balloon assistance. Digital subtraction angiography was performed pre-deployment and immediately after, and at 5, 10, and 30min postdeployment in 10 rabbits and at 1month in 8 rabbits. The early post-deployment intra-aneurysmal flow was graded as unchanged, moderately diminished, or completely absent. At 1month the status of aneurysm occlusion was evaluated. Adhesion to catheter material and migration of GPX was assessed. Results The mean aneurysm neck diameter, width, and height were 3.6±1.0mm, 3.0±0.8mm, and 7.4±1.4mm, respectively. The mean dome-to-neck ratio was 0.9±0.2. Complete stagnation of intra-aneurysmal flow was observed in 9 of 10 aneurysms (90%) within 30min of device deployment. One aneurysm showed moderately diminished intra-aneurysmal flow at 30min. At 1month, 8 aneurysms were completely occluded. There was no evidence of GPX adhesion to the catheter material. Histologically, a leukocyte and foreign body reaction to GPX was detectable 28 days after embolization. Conclusions This is the first preclinical study reporting the performance of a protype version of the GPX Embolic Device in a wide-neck aneurysm model. GPX showed promising results by achieving and maintaining high rates of complete angiographic occlusion, but may induce an inflammatory reaction

Different Rescue Approaches of Migrated Woven Endobridge (WEB) Devices: an Animal Study

Purpose Treatment of wide-necked intracranial aneurysms using the Woven Endobridge (WEB) device has become broadly accepted. Feared complications with the potential of increased poor clinical outcome include dislocations and migration of the device. This study was carried out to determine the effectiveness of a variety of different strategies to rescue migrated WEB devices. Methods In a porcine model, WEB devices of different sizes (SL [single layer] 3.5 × 2mm and SL 4.0 × 3mm, SL 8 × 5mm and SLS 8mm [single layer spherical]) were placed into both the subclavian and axillary arteries. A total of 32 rescue maneuvers (8 per rescue device) were performed. Small WEBs were rescued using reperfusion catheters (RC) (SOFIA Plus and JET 7), larger WEBs were rescued using dedicated rescue devices (Microsnare and Alligator). Rescue rates, times, attempts and complications were assessed. Results Rescue attempts of migrated WEBs were successful in all cases (100%). Rescue time (p= 0.421) and attempts (p= 0.619) of small WEBs using RCs were comparable without significant differences. Aspiration alone was not successful for larger WEBs. Rescue of larger WEBs was slightly faster (122.75 ± 41.15 s vs. 137.50 ± 54.46 s) with fewer attempts (1 vs. 1.37) when using the Microsnare compared to the Alligator device. Complications such as entrapment of the WEB in the RCs, vasospasm, perforation, or dissection were not observed. Conclusion Rescue of migrated WEB devices is a feasible and effective method and 100% successful rescue rates and appropriate rescue times can be achieved for small WEBs using RCs and for larger WEBs using dedicated rescue devices (Microsnare and Alligator)

Solitaire Stentectomy Using a Stent-Retriever Technique in a Porcine Model

Purpose Mechanical thrombectomy using the Solitaire device has become a standard treatment of ischemic stroke due to large vessel occlusions. Inadvertent detachment is a feared complication, which is associated with poor clinical outcome. The aim of this experimental study was to assess in a porcine model the feasibility and effectiveness of rescuing detached Solitaire devices using different stent retrievers. Methods Solitaire FR devices (4 × 15/20 mm and 6 × 20/30 mm) were placed in the axillary artery of pigs. By means of 3 different stent retrievers (Trevo ProVue; EmboTrap II revascularization device; 3D revascularization device) a total of 24 rescue maneuvers (8 per retriever) were performed by deploying the retrievers within the deployed Solitaire devices and trapping parts of the Solitaire within the microcatheter. Rescue rates, rescue time and complications were assessed. Results Overall stentectomy of the Solitaire devices was successful in all cases (100%). Time of rescue was comparable using the applied stent retrievers (Trevo ProVue; EmboTrap II revascularization device; 3D revascularization device). Complications, such as entrapment of the Solitaire-retriever complex at the intermediate catheter, Solitaire migration, vasospasm, perforation, or dissection were not observed. Conclusion Stentectomy of inadvertently detached Solitaire devices using different stent retrievers is a feasible and effective method. Rescue rates and times with the Trevo ProVue, EmboTrap II and 3D revascularization device were comparable

Vascular Response on a Novel Fibrin-Based Coated Flow Diverter

Purpose Due to thromboembolic complications and in-stent-stenosis after flow diverter (FD) treatment, the long-term use of dual antiplatelet treatment (DAPT) is mandatory. The tested nano-coating has been shown to reduce material thrombogenicity and promote endothelial cell proliferation in vitro. We compared the biocompatibility of coated (Derivo Heal) and non-coated (Derivo bare) FDs with DAPT in an animal model. Methods Derivo® bare (n = 10) and Derivo® Heal (n = 10) FD were implanted in the common carotid arteries (CCAs) of New Zealand white rabbits. One additional FD, alternately a Derivo bare (n = 5) or Derivo Heal (n = 5), was implanted in the abdominal aorta (AA) for assessment of the patency of branch arteries. Histopathological examinations were performed after 28 days. Angiography was performed before and after FD implantation and at follow-up. Results Statistical analysis of the included specimens showed complete endothelialization of all FDs with no significant differences in neointima thickness between Derivo® bare and Derivo® Heal (CCA: p = 0.91; AA: p = 0.59). A significantly reduced number of macrophages in the vessel wall of the Derivo Heal was observed for the CCA (p = 0.02), and significantly reduced fibrin and platelet deposition on the surface of the Derivo Heal was observed for the AA. All branch arteries of the stented aorta remained patent. Conclusion In this animal model, the novel fibrin-based coated FD showed a similar blood and tissue compatibility as the non-coated FD

The Japanese Clinical Practice Guideline for acute kidney injury 2016

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search

Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis

In vivo comparison of braided (Accero) and laser-cut intracranial stents (Acclino, Credo): evaluation of vessel responses at subacute and mid-term follow-up in a rabbit model

This study aimed to investigate in vivo two stent technologies, with particular emphasis on thrombogenicity and inflammatory vessel remodeling processes. The micro-stents tested in this study were developed for intracranial aneurysm treatment. In our study twelve, New Zealand white rabbits were divided into two groups: 18 laser-cut stents (LCS) and 18 braided stents (BS) were impanated without admiration of antiplatelet medication. Three stents were implanted into each animal in the common carotid artery, subclavian artery, and abdominal aorta. Digital subtraction angiography was performed before and after stent implantation and at follow-up for the visualization of occurring In-stent thromboembolism or stenosis. The Stents were explanted for histopathological examination at two different timepoints, after 3 and 28 days. Angiographically neither in-stent thrombosis nor stenosis for both groups was seen. There was a progressive increase in the vessel diameter, which was more pronounced for BS than for LCS. We detected a higher number of thrombi adherent to the foreign material on day 3 for BS. On day 3, the neointima was absent, whereas the complete formation observed was on day 28. There was no significant difference between both groups regarding the thickness of the neointima. The in vivo model of our study enabled the evaluation of blood and vessel reactions for two different stent technologies. Differences in vessel dimension and tissue around the stents were observed on day 28. Histological analysis on day 3 enabled the assessment of thrombotic reactions, representing an important complementary result in long-term studies. [GRAPHICS]

Preclinical Evaluation of the Accero Stent: Flow Remodelling Effect on Aneurysm, Vessel Reaction and Side Branch Patency

Purpose It has been hypothesized that microstents which are used to prevent coil protrusion in the treatment of cerebral aneurysms may have flow diverting and therefore occlusive effects. In a rabbit elastase aneurysm model, we investigated the aneurysm occlusion rate and vessel reaction of a braided Accero stent prototype with porosity in the lower range of other available (non-flow-diverter) microstents. Methods Ten aneurysms were induced the right subclavian artery in New Zealand white rabbits and treated with the Accero stent prototype. In each subject, a second stent was implanted in the abdominal aorta to cover the origins of branch arteries. Angiographic follow-up and explantation of the devices and aneurysms for histological analysis were performed after 3 months (n = 5) and 6 months (n = 5). Results Grades I ( 50%) occlusion rates were observed in 9 (90%) and 1 (10%) of ten aneurysms treated with the stent device. The mean reduction in contrast filling at 6 months was 42.1% (p = .02). Neointima thickness was significantly higher in the subclavian artery than in the abdominal aorta after 3 (p = .03), whereas not after 6 months (p = .1). No cases of inadequate wall apposition, branch artery occlusion or stent thrombosis were observed. Conclusion The present study showed flow remodelling properties of the device prototype with progredient aneurysm occlusion. A larger in vivo study with induced aneurysm should be done to confirm these results