scholarly journals The Role of Losartan as a Potential Neuroregenerative Pharmacological Agent after Aneurysmal Subarachnoid Haemorrhage

2020 ◽  
Vol 21 (18) ◽  
pp. 6496
Author(s):  
Stefan Wanderer ◽  
Lukas Andereggen ◽  
Jan Mrosek ◽  
Sepide Kashefiolasl ◽  
Serge Marbacher ◽  
...  
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Cerebral Vasospasm ◽  
Pharmacological Agent ◽  
Control Group ◽  
High Morbidity ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Maximal Contraction ◽  
Endothelin 1 ◽  
B1 Receptor ◽  
Dose Dependent

Background: Cerebral vasospasm (CVS) remains a major cause of delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage (SAH), making it a life-threatening type of stroke with high morbidity and mortality. Endothelin-1 is known as key player mediating a strong vasocontractile effect. Interestingly, losartan restores the impaired vasorelaxative ET(B1) receptor function in a non-competitive direct fashion. With this study, we aimed to investigate a potential losartan-dependent vasodilatory effect vice versa by inhibiting NO release through L-NAME, thus pushing forward concepts to alleviate vasospasm and possibly prevent ischaemia and neurodegeneration. Methods: Cerebral vasospasm was induced by the use of an established double-injection rat model. Sprague-Dawley rats were culled on Day 3 after the ictus, and the vasospastic basilar artery was harvested for isometric investigations of the vessel tone. Ring segments were preincubated with and without L-NAME and/or losartan. Results: Preincubation with L-NAME induced dose-dependent vasoconstriction via endothelin-1 in the non-SAH cohort, which was dose-dependently reduced by losartan. After SAH and dose-dependent endothelin-1 administration, maximal contraction was achieved in the control group without losartan. Furthermore, this maximal contraction was significantly decreased in the losartan group and was reversed by L-NAME. Conclusions: After SAH, losartan was shown to positively influence the ET(B1) receptor pathway in a non-competitive direct agonistic and indirect fashion. Losartan alleviated the maximum contraction triggered by endothelin-1. This effect was resolved due to NO inhibition by L-NAME. Considering this spasmolytic effect of losartan besides its already well-known effects (attenuating cerebral inflammation, restoring cerebral autoregulation and reducing epileptogenic activity) and alleviating early brain injury, losartan seems to have potential as a promising pharmacological agent after SAH.

scholarly journals Increase of Soluble RAGE in Cerebrospinal Fluid following Subarachnoid Haemorrhage

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Bartosz Sokół ◽  
Norbert Wąsik ◽  
Roman Jankowski ◽  
Marcin Hołysz ◽  
Witold Mańko ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Haemorrhage ◽  
Control Group ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Pronounced Difference ◽  
Significance Threshold ◽  
Soluble Rage ◽  
Inflammatory Mechanism ◽  
Glycation End Products ◽  
Csf Levels

Receptors for advanced glycation end-products (RAGE) mediate the inflammatory reaction that follows aneurysmal subarachnoid haemorrhage. Soluble RAGE (sRAGE) may function as a decoy receptor. The significance of this endogenous anti-inflammatory mechanism in subarachnoid haemorrhage (SAH) remains unknown. The present study aims to analyse sRAGE levels in the cerebrospinal fluid (CSF) of SAH patients. sRAGE levels were assayed by ELISA kit in 47 CSF samples collected on post-SAH days 0–3, 5–7, and 10–14 from 27 SAH patients with acute hydrocephalus. CSF levels of sRAGE were compared with a control group and correlated with other monitored parameters. In the control group, the CSF contained only a trace amount of sRAGE. By contrast, the CSF of 20 SAH patients collected on post-SAH days 0–3 was found to contain statistically significant higher levels of sRAGE (mean concentration 3.91 pg/mL, p<0.001). The most pronounced difference in CSF sRAGE levels between good and poor outcome patients was found on days 0–3 post-SAH but did not reach the significance threshold (p=0.234). CSF sRAGE levels did not change significantly during hospitalisation (p=0.868) and correlated poorly with treatment outcome, systemic inflammatory markers, and other monitored parameters. Our study revealed an early and constant increase of sRAGE level in the CSF of SAH patients.

scholarly journals The Role of Nitric Oxide in Resolution of Vasospasam Corresponding with Cerebral Vasospasms after Subarachnoid Haemorrhage: Animal Model

2008 ◽  
Vol 8 (2) ◽  
pp. 177-182
Author(s):  
Kemal Dizdarević
Keyword(s):  
Nitric Oxide ◽  
Animal Model ◽  
Subarachnoid Haemorrhage ◽  
Cerebral Vasospasm ◽  
Subarachnoid Space ◽  
Arterial Wall ◽  
Cerebral Arteries ◽  
Control Group ◽  
Blood Products

Intracranial aneurysmal rupture is the common cause of spontaneous subarachnoid haemorrhage (SAH). This haemorrhage is typically diffuse and located in extracerebral subarachnoid space in which main cerebral arterial branches are situated. The intimate and long-term contact of arterial wall and blood products in the closed space causes the cerebral vasospasm as a serious and frequent complication of SAH. It is connected with significant morbidity and mortality due to developing of focal cerebral ischaemia and subsequently cerebral infarction. The aim of our experimental research was to create the animal model of vasospasm using the femoral artery due to examination of reduced basic dilator activity cause in arterial wall after SAH. The important characteristic of major cerebral arteries is their localization in the closed subarachnoid space which enables their to have long-term contact with blood products after haemorrhage. Thirty six femoral arteries (FA) of eighteen female rats weighing about 300 g were used. In vivo, femoral arteries are microsurgically prepared in both inguinal regions in all rats. Eighteen arteries were encompassed by polytetrafluoroethylene (PTFE) material forming closed tube and autologous blood was injected in the tube around the arterial wall. Additional eighteen arteries, as a control group, were also put in PTFE tube but without exposing to the blood. All rats are left to live for eight days. Afterwards, rats were sacrificed and their arteries were in vitro examined including an isometric tension measurement and histological changes analysis. The tension was measured during application of vasoconstrictors and vasodilatators (nitric oxide, NO). FA exposed to periadventitial blood exhibit hyper reactivity to constrictors (KCl, phenylephrine, acetylcholine) compared to control group. It was also found that NO donor (sodium nitroprusside) diminished arterial spasm induced by blood and vasoconstrictors. In conclusion, FA can be used as a model for vasospasm correlating with cerebral vasospasm after SAH and therefore this model can be utilized in future experiments assessing cerebral vasospasm. The reduced basic dilator activity of spastic femoral artery is caused by an absence of gaseous messenger NO next to the arteries but not by diminished response vasculature to NO. Absence of NO after SAH probably causes the reduced basic dilator activity of cerebral arteries as well. The guanylate-cyclase level in the arterial wall is consequently reduced after SAH primary due to absence of NO but not due to direct reduction of enzyme activities caused by process of blood degradation inside of subarachnoid space.

scholarly journals Literature Review of Aneurysmal Subarachnoid Hemorrhage from Incidence to Treatment Options

2020 ◽  
Vol 18 (1) ◽  
pp. 70-78
Author(s):  
Ieva Buce-Satoba ◽  
Daina Rozkalne ◽  
Jevgenijs Stepanovs ◽  
Biruta Mamaja ◽  
Gaida Krumina ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cerebral Ischemia ◽  
Literature Review ◽  
Glasgow Coma Scale ◽  
Subarachnoid Haemorrhage ◽  
Cerebral Vasospasm ◽  
Treatment Options ◽  
Delayed Cerebral Ischemia ◽  
Late Complications ◽  
Aneurysmal Subarachnoid Haemorrhage

SummaryIntroductionAneurysmal subarachnoid haemorrhage (SAH) is associated with high mortality and morbidity. Rebleeding, cerebral vasospasm (VS) with delayed cerebral ischemia (DCI) are major complications after SAH associated with poor neurological outcome.Aim of the studyTo summarize the existing research data on the SAH from incidence, risk factors and clinical presentation to diagnostic, monitoring and treatment options after SAH.Materials and MethodsLiterature review was carried out to identify factors associated with SAH using specific keywords (aneurysmal subarachnoid haemorrhage, rebleeding, cerebral vasospasm, delayed cerebral ischemia) in the PUBMED database. In the time period from 2000 to 2019, 34 full articles were reviewed.ResultsAccording to the literature, the key risk factors for cerebral aneurysms and the SAH are hypertension, smoking, chronic alcohol abuse, family history of intracranial aneurysms in first-degree relatives and female sex. The key risk factor for early complication - rebleeding after SAH - is hypertension. The factors responsible for late complications - cerebral VS and DCI after SAH - are initially lower Glasgow coma scale and higher grades of Fisher scale, where grade IV and III predict cerebral VS in 31–37%. Furthermore, hyperglycaemic state, hyponatremia, hypotension and cerebral hypoperfusion, increased level of Troponin correlate with the incidence of cerebral VS and DCI. Although the golden standard to detect cerebral VS is digital subtraction angiography, CT angiography has become a routine examination. Transcranial doppler sonography is recommended and regional cerebral oximetry also seems to be promising. To avoid rebleeding for wide-necked, gigantic aneurysms or when SAH is combined with intraparenchymal hematoma, surgical clipping is preferred. For posterior circulation aneurisms, poor grade SAH and patients with age >70 years superior is endovascular treatment. To avoid late complications, the pharmacological method is used with Nimodipine.ConclusionsSAH is still associated with poor clinical outcome due to the development of early and late complications. The highest risk patients are those with low Glasgow coma scale and high grades of Fisher scale. Timely performed obliteration methods of the ruptured aneurysm are crucial and Nimodipine is the main agent to prevent cerebral VS and DCI.

Symptomatic cerebral vasospasm manifested 18 days after aneurysmal subarachnoid haemorrhage

1993 ◽  
Vol 15 (3) ◽  
pp. 209-211 ◽  
Author(s):  
Takakazu Kawamata ◽  
Nobuhiko Aoki ◽  
Tatsuo Sakai ◽  
Koji Arai
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Haemorrhage

scholarly journals Study protocol for SFX-01 after subarachnoid haemorrhage (SAS): a multicentre randomised double-blinded, placebo controlled trial

BMJ Open ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. e028514 ◽  
Author(s):  
Ardalan H Zolnourian ◽  
Stephen Franklin ◽  
Ian Galea ◽  
Diederik Oliver Bulters
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Middle Cerebral Artery ◽  
Flow Velocity ◽  
Cerebral Artery ◽  
Short Form ◽  
Controlled Trial ◽  
High Morbidity ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Double Blind ◽  
South Central

IntroductionSubarachnoid haemorrhage (SAH) from a ruptured cerebral aneurysm carries high morbidity and mortality. Despite huge advances in techniques to secure the aneurysm, there has been little progress in the treatment of the deleterious effects of the haemorrhage.Sulforaphane is an Nrf2 inducer with anti-oxidant and anti-inflammatory properties. It has been shown to improve clinical outcome in experimental models of SAH, but is unstable. SFX-01 (Evgen Pharma) is a novel composition comprised of synthetic sulforaphane stabilised within an α-cyclodextrin complex. On ingestion, the complex releases sulforaphane making SFX-01 an ideal vehicle for delivery of sulforaphane.Methods and analysisThe objective of the study is to assess the safety, pharmacokinetics and efficacy of SFX-01. This is a prospective, multicentre, randomised, double-blind placebo-controlled trial in patients aged 18–80 years with aneurysmal subarachnoid haemorrhage in the previous 48 hours. 90 patients will be randomised to receive SFX-01 (300 mg) or placebo two times per day for up to 28 days.Safety will be assessed using blood tests and adverse event reporting.Pharmacokinetics will be assessed based on paired blood and cerebrospinal fluid (CSF) sulforaphane levels on day 7. A subgroup will have hourly samples taken during 6 hours post-dosing on days 1 and 7. Pharmacodynamics will be assessed by haptoglobin and malondialdehyde levels, and maximum flow velocity of middle cerebral artery will be measured by transcranial Doppler ultrasound.Clinical outcomes will be assessed at days 28, 90 and 180 with modified Rankin Scale, Glasgow Outcome Score, SAH Outcome Tool, Short Form-36, Brain Injury Community Rehabilitation Outcome Scales and Check List for Cognitive and Emotional consequences following stroke. MRI at 6 months including quantitative susceptibility mapping and volumetric T1 will measure iron deposition and cortical volume.Safety, CSF sulforaphane concentration and middle cerebral artery flow velocity will be primary outcomes and all others secondary.Ethics and disseminationEthical approval was obtained from South Central Hampshire A committee. Outcomes of the trial will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT02614742.

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