scholarly journals Therapeutic Implications of Estrogen for Cerebral Vasospasm and Delayed Cerebral Ischemia Induced by Aneurysmal Subarachnoid Hemorrhage

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Dale Ding ◽  
Robert M. Starke ◽  
Aaron S. Dumont ◽  
Gary K. Owens ◽  
David M. Hasan ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Therapeutic Implications ◽  
Delayed Neurological Deterioration ◽  
Adenosine A2a ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cerebral vasospasm (CV) remains the leading cause of delayed morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). However, increasing evidence supports etiologies of delayed cerebral ischemia (DCI) other than CV. Estrogen, specifically 17β-estradiol (E2), has potential therapeutic implications for ameliorating the delayed neurological deterioration which follows aneurysmal SAH. We review the causes of CV and DCI and examine the evidence for E2-mediated vasodilation and neuroprotection. E2 potentiates vasodilation by activating endothelial nitric oxide synthase (eNOS), preventing increased inducible NOS (iNOS) activity caused by SAH, and decreasing endothelin-1 production. E2 provides neuroprotection by increasing thioredoxin expression, decreasing c-Jun N-terminal kinase activity, increasing neuroglobin levels, preventing SAH-induced suppression of the Akt signaling pathway, and upregulating the expression of adenosine A2a receptor. The net effect of E2 modulation of these various effectors is the promotion of neuronal survival, inhibition of apoptosis, and decreased oxidative damage and inflammation. E2 is a potentially potent therapeutic tool for improving outcomes related to post-SAH CV and DCI. However, clinical evidence supporting its benefits remains lacking. Given the promising preclinical data available, further studies utilizing E2 for the treatment of patients with ruptured intracranial aneurysms appear warranted.

Cerebrospinal fluid macrophage migration inhibitory factor: a potential predictor of cerebral vasospasm and clinical outcome after aneurysmal subarachnoid hemorrhage

2020 ◽  
Vol 133 (6) ◽  
pp. 1786-1791 ◽  
Author(s):  
Kevin Kwan ◽  
Orseola Arapi ◽  
Katherine E. Wagner ◽  
Julia Schneider ◽  
Heustein L. Sy ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Vasospasm ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Significant Difference

OBJECTIVEIn patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration.METHODSIn this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures.RESULTSTwenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119).CONCLUSIONSPreliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.

scholarly journals Endothelial Nitric Oxide Synthase Gene Single-Nucleotide Polymorphism Predicts Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage

2008 ◽  
Vol 28 (6) ◽  
pp. 1204-1211 ◽  
Author(s):  
Robert M Starke ◽  
Grace H Kim ◽  
Ricardo J Komotar ◽  
Zachary L Hickman ◽  
Eric M Black ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Nitric Oxide Synthase ◽  
Cerebral Vasospasm ◽  
Endothelial Nitric Oxide Synthase ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Enos Gene ◽  
Single Nucleotide ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Studies have shown a link between single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (eNOS) gene and the incidence of coronary spasm and aneurysms. Alterations in the eNOS T-786 SNP may lead to an increased risk of post-aSAH cerebral vasospasm. In this prospective clinical study, 77 aSAH patients provided genetic material and were followed for the occurrence of vasospasm. In multivariate logistic regression analysis, genotype was the only factor predictive of vasospasm. The odds ratio (OR) for symptomatic vasospasm in patients with one T allele was 3.3 (95% confidence interval (CI): 1.1 to 10.0, P=0.034) and 10.9 for TT. Patients with angiographic spasm were 3.6 times more likely to have a T allele (95% CI: 1.3 to 9.6, P=0.013; for TT: OR 12.6). Patients with severe vasospasm requiring endovascular therapy were more likely to have a T allele (OR 3.5, 95% CI: 1.3 to 9.5, P=0.016; for TT: OR 12.0). Patients with the T allele of the eNOS gene are more likely to have severe vasospasm. Presence of this genotype may allow the identification of individuals at high risk for post-aSAH vasospasm and lead to early treatment and improved outcome.

scholarly journals The Role of the Microcirculation in Delayed Cerebral Ischemia and Chronic Degenerative Changes after Subarachnoid Hemorrhage

2013 ◽  
Vol 33 (12) ◽  
pp. 1825-1837 ◽  
Author(s):  
Leif Østergaard ◽  
Rasmus Aamand ◽  
Sanja Karabegovic ◽  
Anna Tietze ◽  
Jakob Udby Blicher ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Vasogenic Edema ◽  
Delayed Cerebral Ischemia ◽  
Tissue Hypoxia ◽  
Brain Oxygenation ◽  
Metabolic Derangement ◽  
Therapeutic Implications ◽  
Potential Sources

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

scholarly journals Role of SIRT1 in Isoflurane Conditioning-Induced Neurovascular Protection against Delayed Cerebral Ischemia Secondary to Subarachnoid Hemorrhage

2021 ◽  
Vol 22 (8) ◽  
pp. 4291
Author(s):  
Meizi Liu ◽  
Keshav Jayaraman ◽  
Tusar Giri ◽  
Gregory J. Zipfel ◽  
Umeshkumar Athiraman
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Mrna Expression ◽  
Delayed Cerebral Ischemia ◽  
Activity Levels ◽  
Neurological Outcomes ◽  
Neurovascular Protection ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.

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