scholarly journals MEK1/2 Inhibitor U0126 but Not Endothelin Receptor Antagonist Clazosentan Reduces Upregulation of Cerebrovascular Contractile Receptors and Delayed Cerebral Ischemia, and Improves Outcome after Subarachnoid Hemorrhage in Rats

2014 ◽  
Vol 35 (2) ◽  
pp. 329-337 ◽  
Author(s):  
Gro K Povlsen ◽  
Lars Edvinsson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Arteries ◽  
Delayed Cerebral Ischemia ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Endothelin Receptor ◽  
Elevated Expression ◽  
Causes Of Mortality

Cerebral vasospasm and late cerebral ischemia (LCI) remain leading causes of mortality in patients experiencing a subarachnoid hemorrhage (SAH). This occurs typically 3 to 4 days after the initial bleeding and peaks at 5 to 7 days. The underlying pathophysiology is still poorly understood. Because SAH is associated with elevated levels of endothelin-1 (ET-1), focus has been on counteracting endothelin receptor activation with receptor antagonists like clazosentan, however, with poor outcome in clinical trials. We hypothesize that inhibition of intracellular transcription signaling will be an effective approach to prevent LCI. Here, we compare the effects of clazosentan versus the MEK1/2 blocker U0126 in a rat model of SAH. Although clazosentan directly inhibits the contractile responses in vivo to ET-1, it did not prevent SAH-induced upregulation of ET receptors in cerebral arteries and did not show a beneficial effect on neurologic outcome. U0126 had no vasomotor effect by itself but counteracts SAH-induced receptor upregulation in cerebral arteries and improved outcome after SAH. We suggest that because SAH induces elevated expression of several contractile receptor subtypes, it is not sufficient to block only one of these (ET receptors) but inhibition of transcriptional MEK1/2-mediated upregulation of several contractile receptors may be a viable way towards alleviating LCI.

scholarly journals Signal Transduction in Cerebral Arteries after Subarachnoid Hemorrhage—A Phosphoproteomic Approach

2013 ◽  
Vol 33 (8) ◽  
pp. 1259-1269 ◽  
Author(s):  
Benjamin L Parker ◽  
Martin Røssel Larsen ◽  
Lars IH Edvinsson ◽  
Gro Klitgaard Povlsen
Keyword(s):  
Mass Spectrometry ◽  
Subarachnoid Hemorrhage ◽  
Time Course ◽  
Cerebral Arteries ◽  
Delayed Cerebral Ischemia ◽  
Calcium Calmodulin Dependent ◽  
Intracellular Signals ◽  
Extracellular Regulated Kinase ◽  
Signaling Components

After subarachnoid hemorrhage (SAH), pathologic changes in cerebral arteries contribute to delayed cerebral ischemia and poor outcome. We hypothesize such changes are triggered by early intracellular signals, targeting of which may prevent SAH-induced vasculopathy. We performed an unbiased quantitative analysis of early SAH-induced phosphorylations in cerebral arteries and evaluated identified signaling components as targets for prevention of delayed vasculopathy and ischemia. Labeled phosphopeptides from rat cerebral arteries were quantified by high-resolution tandem mass spectrometry. Selected SAH-induced phosphorylations were validated by immunoblotting and monitored over a 24-hour time course post SAH. Moreover, inhibition of key phosphoproteins was performed. Major SAH-induced phosphorylations were observed on focal adhesion complexes, extracellular regulated kinase 1/2 (ERK1/2), calcium calmodulin-dependent kinase II, signal transducer and activator of transcription (STAT3) and c-Jun, the latter two downstream of ERK1/2. Inhibition of ERK1/2 6-hour post SAH prevented increases in cerebrovascular constrictor receptors, matrix metalloprotease-9, wall thickness, and improved neurologic outcome. STAT3 inhibition partially mimicked these effects. The study shows that quantitative mass spectrometry is a strong approach to study in vivo vascular signaling. Moreover, it shows that targeting of ERK1/2 prevents delayed pathologic changes in cerebral arteries and improves outcome, and identifies SAH-induced signaling components downstream and upstream of ERK1/2.

Abstract P350: Early Transcranial Doppler Velocity Changes as a Predictor for Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Matthew Triano ◽  
Maite J Corbin ◽  
Sameer Desale ◽  
Ai-Hsi Liu ◽  
Daniel R Felbaum ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Transcranial Doppler ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Cerebral Arteries ◽  
Delayed Cerebral Ischemia ◽  
Multivariate Logistic Regression Analysis ◽  
Absolute Velocity ◽  
Doppler Velocity ◽  
Velocity Change

Introduction: Although transcranial Doppler (TCD) evaluation for vasospasm remains an important study in aneurysmal subarachnoid hemorrhage (aSAH) management, its precise role in predicting delayed cerebral ischemia (DCI) remains unclear. Hypothesis: We evaluated optimal measures for evaluating TCD velocities and hypothesized that TCD velocity change would be the best predictor for DCI in patients with aSAH. Methods: Patients with aSAH over a two-year period were retrospectively analyzed. Baseline characteristics, outcomes, and TCD velocities in bilateral middle cerebral arteries (MCA) for hospital days 2 to14 were recorded. TCD variables, including absolute velocity and change in velocity, were obtained by creating a smoothing curve. A variable representing change in TCD velocity was then created through a linear regression model that confirmed greatest change in velocity associated with DCI occurred at days 2-7. Multivariate logistic regression analysis using DCI as outcome was then completed. Results: 95 patients with aSAH were evaluated. Increased TCD velocity at days 2-7 proved to be a better predictor for DCI than absolute velocity with an optimal cutoff of 8.9 cm/sec/day ( p = 0.019) and AUC 0.651. Multivariate logistic analysis using DCI as the outcome showed that poor admission Hunt-Hess scores (OR 5.02, 95%CI 1.22-22.67, p = 0.028) and increase in TCD velocity during days 2-7 (OR 5.32, 95%CI 1.41-23.33, p = 0.018) were independently associated with DCI. Conclusions: We found that relative increases in TCD velocities in the MCAs during the first 7 days (threshold increase of 8.9 cm/sec/day or 53.4 cm/sec from days 2-7) after aSAH were independently associated with DCI. Our findings suggest that vasospasm should be confirmed and treated aggressively when detected via increased TCD velocities during the first seven days in order to minimize DCI. This association requires independent confirmation.

scholarly journals Role of Pial Microvasospasms and Leukocyte Plugging for Parenchymal Perfusion after Subarachnoid Hemorrhage Assessed by In Vivo Multi-Photon Microscopy

2021 ◽  
Vol 22 (16) ◽  
pp. 8444
Author(s):  
Julian Schwarting ◽  
Kathrin Nehrkorn ◽  
Hanhan Liu ◽  
Nikolaus Plesnila ◽  
Nicole Angela Terpolilli
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Fluorescent Dyes ◽  
Delayed Cerebral Ischemia ◽  
Tissue Imaging ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Cranial Window ◽  
Pial Arterioles

Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia. We suggested spasms of pial arterioles as a possible mechanism; however, it remained unclear whether and how pial microvasospasms (MVSs) induce cerebral ischemia. Therefore, we used in vivo deep tissue imaging by two-photon microscopy to investigate MVSs together with the intraparenchymal microcirculation in a clinically relevant murine SAH model. Male C57BL/6 mice received a cranial window. Cerebral vessels and leukocytes were labelled with fluorescent dyes and imaged by in vivo two-photon microscopy before and three hours after SAH induced by filament perforation. After SAH, a large clot formed around the perforation site at the skull base, and blood distributed along the perivascular space of the middle cerebral artery up to the cerebral cortex. Comparing the cerebral microvasculature before and after SAH, we identified three different patterns of constrictions: pearl string, global, and bottleneck. At the same time, the volume of perfused intraparenchymal vessels and blood flow velocity in individual arterioles were significantly reduced by more than 60%. Plugging of capillaries by leukocytes was observed but infrequent. The current study demonstrates that perivascular blood is associated with spasms of pial arterioles and that these spasms result in a significant reduction in cortical perfusion after SAH. Thus, the pial microvasospasm seems to be an important mechanism by which blood in the subarachnoid space triggers cerebral ischemia after SAH. Identifying the mechanisms of pial vasospasm may therefore result in novel therapeutic options for SAH patients.

scholarly journals The Role of Arterioles and the Microcirculation in the Development of Vasospasm after Aneurysmal SAH

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Masato Naraoka ◽  
Naoya Matsuda ◽  
Norihito Shimamura ◽  
Kenichiro Asano ◽  
Hiroki Ohkuma
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Relative Risk ◽  
Cerebral Ischemia ◽  
Clinical Outcome ◽  
Cerebral Arteries ◽  
Delayed Cerebral Ischemia ◽  
Microcirculatory Disturbance ◽  
Angiographic Vasospasm ◽  
Successful Reduction

Cerebral vasospasm of the major cerebral arteries, which is characterized by angiographic narrowing of those vessels, had been recognized as a main contributor to delayed cerebral ischemia (DCI) in subarachnoid hemorrhage (SAH) patients. However, the CONSCIOUS-1 trial revealed that clazosentan could not improve mortality or clinical outcome in spite of successful reduction of relative risk in angiographic vasospasm. This result indicates that the pathophysiology underlying DCI is multifactorial and that other pathophysiological factors, which are independent of angiographic vasospasm, can contribute to the outcome. Recent studies have focused on microcirculatory disturbance, such as microthrombosis and arteriolar constriction, as a factor affecting cerebral ischemia after SAH. Reports detecting microthrombosis and arteriolar constriction will be reviewed, and the role of the microcirculation on cerebral ischemia during vasospasm after SAH will be discussed.

Scavenging Free Iron Reduces Arteriolar Microvasospasms After Experimental Subarachnoid Hemorrhage

Stroke ◽  
2021 ◽  
Author(s):  
Hanhan Liu ◽  
Julian Schwarting ◽  
Nicole Angela Terpolilli ◽  
Kathrin Nehrkorn ◽  
Nikolaus Plesnila
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Delayed Cerebral Ischemia ◽  
Neurological Deficits ◽  
Free Iron ◽  
Acute Cerebral Ischemia ◽  
Experimental Subarachnoid Hemorrhage ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Background and Purpose: Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia resulting in high acute mortality and severe chronic neurological deficits. Spasms of the pial and intraparenchymal microcirculation (microvasospasms) contribute to acute cerebral ischemia after SAH; however, the underlying mechanisms remain unknown. We hypothesize that free iron (Fe 3+ ) released from hemolytic red blood cells into the subarachnoid space may be involved in microvasospasms formation. Methods: Male C57BL/6 mice (n=8/group) received 200 mg/kg of the iron scavenger deferoxamine or vehicle intravenously and were then subjected to SAH by filament perforation. Microvasospasms of pial and intraparenchymal vessels were imaged three hours after SAH by in vivo 2-photon microscopy. Results: Microvasospasms occurred in all investigated vessel categories down to the capillary level. Deferoxamine significantly reduced the number of microvasospasms after experimental SAH. The effect was almost exclusively observed in larger pial arterioles (>30 µm) covered with blood. Conclusions: These results provide proof-of-principle evidence that Fe 3+ is involved in the formation of arteriolar microvasospasms after SAH and that arteriolar and capillary microvasospasms are triggered by different mechanisms. Deciphering the mechanisms of Fe 3+ -induced microvasospasms may result in novel therapeutic strategies for SAH patients.

Sign in / Sign up

Export Citation Format

Share Document