| 1. |
- Ahnstedt, Hilda, et al.
(author)
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U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.
- 2015
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 35:3, s. 454-460
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Journal article (peer-reviewed)abstract
- Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.217.
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| 2. |
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| 3. |
- Ansar, Saema, et al.
(author)
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Cerebrovascular ETB, 5-HT1B and AT1 Receptor Upregulation Correlates with Reduction in Regional CBF after Subarachnoid Hemorrhage.
- 2007
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In: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 293:6, s. 3750-3758
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Journal article (peer-reviewed)abstract
- We hypothesize that cerebral ischemia leads to enhanced expression of endothelin (ET), 5-hydroxytryptamine (5-HT), and angiotensin II (ANG II) receptors in the vascular smooth muscle cells. Our aim is to correlate the upregulation of cerebrovascular receptors and the underlying molecular mechanisms with the reduction in regional and global cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH). SAH was induced by injecting 250 µl blood into the prechiasmatic cistern in rats. The cerebral arteries were removed 0, 1, 3, 6, 12, 24, and 48 h after the SAH for functional and molecular studies. The contractile responses to ET-1, 5-carboxamidotryptamine (5-CT), and ANG II were investigated with myograph. The receptor mRNA and protein levels were analyzed by quantitative real-time PCR and immunohistochemistry, respectively. In addition, regional and global CBFs were measured by an autoradiographic method. As a result, SAH resulted in enhanced contractions to ET-1 and 5-CT. ANG II [via ANG II type 1 (AT1) receptors] induced increased contractile responses [in the presence of the ANG II type 2 (AT2) receptor antagonist PD-123319]. In parallel the ETB, 5-HT1B, and AT1 receptor, mRNA and protein levels were elevated by time. The regional and global CBF showed a successive reduction with time after SAH. In conclusion, the results demonstrate for the first time that SAH induces the upregulation of ETB, 5-HT1B, and AT1 receptors in a time-dependent manner both at functional, mRNA, and protein levels. These changes occur in parallel with a successive decrease in CBF. Thus there is a temporal correlation between the changes in receptor expression and CBF reduction, suggesting a linkage.
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| 4. |
- Ansar, Saema, et al.
(author)
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Elevated intracranial pressure or subarachnoid blood responsible for reduction in cerebral blood flow after SAH
- 2008
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In: Cerebral Vasospasm: New Strategies in Research and Treatment. - Vienna : Springer Vienna. - 0065-1419. - 9783211757178 ; 104, s. 231-233
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Conference paper (peer-reviewed)abstract
- Background. The pathogenesis of cerebral ischemia after subarachnoid hemorrhage (SAH) still remains elusive. The purpose of the present study was to examine whether it is the change in intracranial pressure (ICP) or the extravasated blood that is responsible for cerebral ischemia and cerebral vasoconstriction observed following SAH. Method. Three groups of animals were studied; (1) cisternal injection of 250 mu l blood (SAH), (2) injection of 250 mu l NaCl (saline) or (3) same procedure in every detail but no fluid injection (sham). Two days after the treatment, an autoradiographic technique was used to investigate the cerebral blood flow (CBF). Findings. Both SAH (blood+ ICP) and saline injection (ICP only) resulted in significantly reduced regional and global CBF after as compared to sham/control. Conclusions. This study revealed that both the elevation of ICP and A Subarachnoid blood per se contribute approximately equally to the SAH induced effects.
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| 5. |
- Ansar, Saema, et al.
(author)
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Equal contribution of increased intracranial pressure and subarachnoid blood to cerebral blood flow reduction and receptor upregulation after subarachnoid hemorrhage.
- 2009
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In: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085 .- 1933-0693. ; 111, s. 978-987
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Journal article (peer-reviewed)abstract
- Object Cerebral ischemia remains the key cause of disability and death in the late phase after subarachnoid hemorrhage (SAH), and its pathogenesis is still poorly understood. The purpose of this study was to examine whether the change in intracranial pressure or the extravasated blood causes the late cerebral ischemia and the upregulation of receptors or the cerebral vasoconstriction observed following SAH. Methods Rats were allocated to 1 of 3 experimental conditions: 1) cisternal injection of 250 mul blood (SAH Group), 2) cisternal injection of 250 mul NaCl (Saline Group), or 3) the same procedure but without fluid injection (Sham Group). Two days after the procedure, the basilar and middle cerebral arteries were harvested, and contractile responses to endothelin (ET)-1 and 5-carboxamidotryptamine (5-CT) were investigated by means of myography. In addition, real-time polymerase chain reaction was used to determine the mRNA levels for ET(A), ET(B), and 5-HT(1) receptors. Regional and global cerebral blood flow (CBF) were quantified by means of an autoradiographic technique. Results Compared with the sham condition, both SAH and saline injection resulted in significantly enhanced contraction of cerebral arteries in response to ET-1 and 5-CT. Regional and global CBF were reduced both in the Saline and SAH groups compared with the Sham Group. The mRNA levels for ET(B) and 5-HT(1B) receptors were upregulated after SAH and saline injection compared with the sham procedure. The effects in all parameters were more pronounced for SAH than for saline injection. Conclusions This study revealed that both the elevation of intracranial pressure and subarachnoid blood per se contribute approximately equally to the late CBF reductions and receptor upregulation following SAH.
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| 6. |
- Ansar, Saema, et al.
(author)
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ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat.
- 2006
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 26:Nov 2, s. 846-856
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Journal article (peer-reviewed)abstract
- Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.
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| 7. |
- Ansar, Saema, et al.
(author)
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Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage
- 2011
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In: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 12
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Journal article (peer-reviewed)abstract
- Background: Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage (SAH) due to reduced cerebral blood flow (CBF) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells (SMC) via activation of mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK)1/2 signal pathway. We hypothesize that SAH initiates cerebrovascular ERK1/2 activation, resulting in receptor upregulation. The raf inhibitor will inhibit the molecular events upstream ERK1/2 and may provide a therapeutic window for treatment of cerebral ischemia after SAH. Results: Here we demonstrate that SAH increases the phosphorylation level of ERK1/2 in cerebral vessels and reduces the neurology score in rats in additional with the CBF measured by an autoradiographic method. The intracisternal administration of SB-386023-b, a specific inhibitor of raf, given 6 h after SAH, aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h. This is accompanied by reduced phosphorylation of ERK1/2 in cerebrovascular SMC. SAH per se enhances contractile responses to endothelin-1 (ET-1), 5-carboxamidotryptamine (5-CT) and angiotensin II (Ang II), upregulates ETB, 5-HT1B and AT(1) receptor mRNA and protein levels. Treatment with SB-386023-b given as late as at 6 h but not at 12 h after the SAH significantly decreased the receptor upregulation, the reduction in CBF and the neurology score. Conclusion: These results provide evidence for a role of the ERK1/2 pathway in regulation of expression of cerebrovascular SMC receptors. It is suggested that raf inhibition may reduce late cerebral ischemia after SAH and provides a realistic time window for therapy.
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| 8. |
- Ansar, Saema, et al.
(author)
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MAPK signaling pathway regulates cerebrovascular receptor expression in human cerebral arteries
- 2013
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In: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 14
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Journal article (peer-reviewed)abstract
- Background: Cerebral ischemia results in enhanced expression of contractile cerebrovascular receptors, such as endothelin type B (ETB), 5-hydroxytryptamine type 1B (5-HT1B), angiotensin II type 1 (AT(1)) and thromboxane (TP) receptors in the cerebral arteries within the ischemic area. The receptor upregulation occurs via activation of the mitogen-activated protein kinases (MAPK) pathway. Previous studies have shown that inhibitors of the MAPK pathway diminished the ischemic area and contractile cerebrovascular receptors after experimental cerebral ischemia. The aim of this study was to examine if the upregulation of contractile cerebrovascular receptors after 48 h of organ culture of human cerebral arteries involves MAPK pathways and if it can be prevented by a MEK1/2 inhibitor. Human cerebral arteries were obtained from patients undergoing intracranial tumor surgery. The vessels were divided into ring segments and incubated for 48 h in the presence or absence of the specific MEK1/2 inhibitor U0126. The vessels were then examined by using in vitro pharmacological methods and protein immunohistochemistry. Results: After organ culture of the cerebral arteries the contractile responses to endothelin (ET)-1, angiotensin (Ang) II and thromboxane (TP) were enhanced in comparison with fresh human arteries. However, 5-carboxamidotryptamine (5-CT) induced decreased contractile responses after organ culture as compared to fresh arteries. Incubation with U0126 diminished the maximum contraction elicited by application of ET-1, Ang II and U46619 in human cerebral arteries. In addition, the MEK1/2 inhibitor decreased the contractile response to 5-CT. Immunohistochemistry revealed that organ culture resulted in increased expression of endothelin ETA, endothelin ETB angiotensin AT(2), 5-hydroxytryptamine 5-HT1B and thromboxane A2 receptors, and elevated levels of activated pERK1/2, all localized to the smooth muscle cells of the cerebral arteries. Co-incubation with U0126 normalized these proteins. Conclusion: The study demonstrated that there is a clear association between human cerebrovascular receptor upregulation via transcription involving activation of the MAPK pathway after organ culture. Inhibition of the MAPK pathways attenuated the vasoconstriction mediated by ET, AT and TP receptors in human cerebral arteries and the enhanced expression of their receptors. The results indicate that MAPK inhibition might be a novel target for treatment of cerebrovascular disorders.
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| 9. |
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| 10. |
- Ansar, Saema, et al.
(author)
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Neurokinin-1 receptor antagonism in a rat model of subarachnoid hemorrhage: prevention of upregulation of contractile ETB and 5-HT1B receptors and cerebral blood flow reduction
- 2007
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In: Journal of Neurosurgery. - 0022-3085. ; 106:5, s. 881-886
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Journal article (peer-reviewed)abstract
- Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced cerebral blood flow (CBF) and to cerebral ischemia, in some cases even producing infarction and long-term disability. The goal of the present study was to investigate the hypothesis that inhibition of neurokinin-1 receptors (NK1Rs) by administration of L-822429 blunts the decrease in CBF as well as cerebrovascular receptor upregulation in an animal model of SAH. Methods. Subarachnoid hemorrhage was induced in rats by injection of 250 mu l of blood into the prechiasmatic cistern. The NK1R inhibitor L-822429 was injected intracisternally 30 minutes and 24 hours after the induction of SAH. Two days after SAH induction, the basilar arteries were harvested, and contractile responses to endothelin-1 (ET-1, an ETA- and ETB-receptor agonist) and 5-carboxamidotryptamine (a 5-hydroxytryptamine-1 [5-HT1]-receptor agonist) were investigated using sensitive myographs. To determine whether NK1R inhibition had an influence on local CBF after post-SAH, a quantitative autoradiographic technique was used. After SAH, the vascular receptor phenotype was changed in cerebral arteries through upregulation of contractile ET, and 5-HT1B receptors, while regional and total CBF were markedly reduced. Treatment with the selective NK1R inhibitor L-822429 prevented both the receptor upregulation and the reduction in regional and global CBF. Conclusions. The data reveal the coregulation of vascular receptor changes and blood flow effects, and also show that interaction with a small-molecule NK1R antagonist is a promising area Of focus for the development of specific treatments for SAH.
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