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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.

ABSTRACT: 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.

SUBMITTER: Povlsen GK

PROVIDER: S-EPMC4426751 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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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.

Povlsen Gro K GK Edvinsson Lars L

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20141119 2

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 c ...[more]

PMID: 25407271

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Project description:Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca2+ channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1) receptors, has previously been shown to be a factor in the pathology of SAH. The aim of the study was to compare intrathecal and subcutaneous treatment regimens of nimodipine and intrathecal treatment regimens of U0126, a MEK1/2 inhibitor, in a single injection experimental rat SAH model with post 48 h endpoints consisting of wire myography of cerebral arteries, flow cytometry of cerebral arterial tissue and behavioural evaluation. Following ET-1 concentration-response curves, U0126 exposed arteries had a significantly lower ET-1max than vehicle arteries. Arteries from both the intrathecal- and subcutaneous nimodipine treated animals had significantly higher ET-1max contractions than the U0126 arteries. Furthermore, Ca2+ concentration response curves (precontracted with ET-1 and in the presence of nimodipine) showed that nimodipine treatment could result in larger nimodipine insensitive contractions compared to U0126. Flow cytometry showed decreased protein expression of the ETB receptor in U0126 treated cerebral vascular smooth muscle cells compared to vehicle. Only U0126 treatment lowered ET-1max contractions and ETB receptor levels, as well as decreased the contractions involving nimodipine-insensitive Ca2+ channels, when compared to both intrathecal and subcutaneous nimodipine treatment. This indicate that targeting gene expression might be a better strategy than blocking specific receptors or ion channels in future treatments of SAH.

Project description:BackgroundThe endothelin receptor antagonist (ERA) clazosentan is being investigated for the medical prevention of cerebral vasospasm and associated complications, such as delayed cerebral ischemia (DCI), after aneurysmal subarachnoid hemorrhage (aSAH). This study quantified how clinicians weigh the benefits and risks of ERAs for DCI prevention to better understand their treatment needs and expectations.MethodsAn online choice experiment was conducted to elicit preferences of neurologists, intensivists, and neurosurgeons treating aSAH in the US and UK for the use of ERAs. The design of the choice experiment was informed by a feasibility assessment (N = 100), one-on-one interviews with clinicians (N = 10), a qualitative pilot (N = 13), and a quantitative pilot (N = 50). Selected treatment attributes included in the choice experiment were: one benefit (likelihood of DCI); and three risks (lung complications, hypotension, and anemia). In the choice experiment, clinicians repeatedly chose best and worst treatment options based on a scenario of a patient being treated in the ICU after aneurism repair. A correlated mixed logit model determined the relative attribute importance (RAI) and associated highest density interval (HDI) as well as acceptable benefit-risk trade-offs.ResultsThe final choice experiment was completed by 350 clinicians (116 neurologists, 129 intensivists/intensive care clinicians, and 105 neurosurgeons; mean age, 47.4 years). Reducing the likelihood of DCI (RAI = 56.5% [HDI, 53.6-59.5%]) had the largest impact on clinicians' treatment choices, followed by avoiding the risks of lung complications (RAI = 29.6% [HDI, 27.1-32.3%]), hypotension (RAI = 9.2% [HDI, 7.5-10.8%]), and anemia (RAI = 4.7% [HDI, 3.7-5.8%]). Clinicians expected the likelihood of DCI to decrease by ≥8.1% for a 20% increase in the risk of lung complications, ≥2.4% for a 20% increase in the risk of hypotension, and ≥1.2% for a 20% increase in the risk of anemia.ConclusionsClinicians were willing to accept certain increased risks of adverse events for a reduced risk of DCI after aSAH. The likelihood of DCI occurring after aSAH can therefore be considered a clinically relevant endpoint in aSAH treatment development. Thus, evaluations of ERAs might focus on whether improvements (i.e., reductions) in the likelihood of DCI justify the risks of adverse events.

Project description:OBJECTIVE:The aim of the study was to assess the relation between cerebrovascular function early after aneurysmal subarachnoid hemorrhage onset and functional and rehabilitation outcomes. DESIGN:Observational cohort study of subarachnoid hemorrhage patients (n = 133) admitted to rehabilitation (n = 49), discharged home (n = 52), or died before discharge (n = 10). We obtained hemodynamic markers of cerebral autoregulatory function from blood flow velocities in the middle cerebral artery and arterial pressure waveforms, recorded daily on days 2-4 after symptom onset, and functional independence measure (FIM) scores and FIM efficiency for those admitted to acute rehabilitation. RESULTS:Compared to those discharged home, the range of pressures within which autoregulation is effective was lower in patients admitted to rehabilitation (4.6 [0.2] vs. 3.9 [0.2] mm Hg) and those who died (2.7 [0.4], P = 0.04). For those admitted to rehabilitation, autoregulatory range and the ability of cerebrovasculature to increase flow were related to discharge FIM score (R = 0.33 and 0.43, P < 0.01) and efficiency (R = 0.33 and 0.47 P < 0.01). The latter marker, along with subarachnoid hemorrhage severity and admission FIM, explained 84% and 69% of the variability in discharge FIM score and efficiency, respectively, even after accounting for age. CONCLUSIONS:Early cerebrovascular function is a major contributor to functional outcomes after subarachnoid hemorrhage and may represent a modifiable target to develop therapeutic approaches. TO CLAIM CME CREDITS:Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Define cerebral autoregulation; (2) Explain the importance of the integrity of cerebral autoregulation for longer-term functional and rehabilitation outcomes after aneurysmal subarachnoid hemorrhage; and (3) Theorize why treatment strategies that may be effective in reducing large-vessel vasospasms after an aneurysmal subarachnoid hemorrhage might not always translate into improved functional outcomes. LEVEL:Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Dataset Information

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.

Publications

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.

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