Disclaimer: This dissertation has been written by a student and is not an example of our professional work, which you can see examples of here.

Any opinions, findings, conclusions, or recommendations expressed in this dissertation are those of the authors and do not necessarily reflect the views of UKDiss.com.

Role of Sex Hormones on Intracranial Aneurysm Formation & Clinical Outcomes after Cereral Vasospasm

7005 words (28 pages) Dissertation

9th Dec 2019 Dissertation Reference this

Tags: Medical

ROLE OF SEX HORMONES ON INTRACRANIAL ANEURYSM FORMATION, SUBARACHNOID HEMORRHAGE, & CLINICAL OUTCOMES AFTER CERERAL VASOSPASM

ABSTRACT

Aneurysmal subarachnoid hemorrhage (aSAH) continues to be a devastating neurological disease with few viable therapeutic treatments. Inflammation has been shown to increase the risk of complications associated with aSAH such as vasospasm and brain injury in human and animal models. The goal of this review is to explore sex hormones as therapeutic agents to prevent inflammation induced by aSAH, and to investigate potential risk factors that predispose patients to complications. Studies have shown that administration of sex steroids such as progesterone and estrogen at early stages in the inflammation process can lower the risk and magnitude of subsequent pathologies. The exact mechanism how these hormones act on the brain, as well as their role in the inflammatory cascade is not fully understood.  Moreover, conflicting results have been published on the use of sex hormone therapy in animal and human trials. This review will scrutinize the variations in these studies in order to provide a more detailed understanding of these sex hormones as therapeutic agents.

 

Introduction

Patients surviving an aneurysmal subarachnoid hemorrhage (aSAH) often develop cerebral vasospasm and delayed ischemic neurological injury. About two-thirds of patients with aSAH develop angiographic vasospasm 3-14 days after rupture of an aneurysm [1].  Following aSAH, inflammatory cells enter the CNS leading to a decrease in cerebral blood flow and endothelial cell death [1, 2]. Inflammation, increase in endothelin-1, and depletion of nitric oxide from endothelial dysfunction are associated with onset of vasospasm [2, 3]. Sex steroids such as estrogen and progesterone, on the other hand, have been shown to have some beneficial effects on inflammation and edema [4] [5] [6, 7]. Treatment with estrogen has been shown to reverse these effects by decreasing endothelin-1 and increasing nitric oxide (NO) [8]. Mortality has been shown to be significantly reduced in progesterone treated animals when compared to placebo [4]. There have been conflicting results on the different gender outcomes associated with aSAH; however, the incidence of SAH is generally found to be higher in females [9]. The purpose of this review is to explore the relationship between inflammation and vasospasm in the setting of aSAH, and the potential benefits of sex hormones as a therapeutic anti-inflammatory intervention.

Role of Inflammation on Aneurysm Formation and Cerebral Vasospasm after SAH

 

CSF Inflammatory Markers

 

Several studies have investigated various inflammatory mediators in cerebrospinal fluid (CSF) following aSAH, with some conflicting reports [10, 11].  Many studies point to the prominent role of tumor necrosis factor-alpha (TNF-α)-, though other studies have found increased levels of interleukin (IL)-6 and IL-8 but not TNFα [11-13].  One recent study found detectable levels of TNFα in 30% of patients after SAH, this suggests that the amount and type of inflammation may very considerably in different patients [14].  In animal models of SAH, blockage of TNF-α has been shown to reduce apoptosis in the hippocampus after SAH [15]. Another inflammatory marker found throughout many studies is endothelin-1 (ET-1) [16, 17].  As with many other pro-inflammatory molecules, the expression of ET-1 is highly variable. In one study, ET-1 levels were found to be present in 46% of patients with SAH versus none detectable in the CSF of control subjects [16].  A study from a different group, however,  failed to detect ET-1 after SAH [18]. The variation found in these inflammatory markers reflects the similar heterogeneity of complications associated with aSAH [19, 20]. The conflicting findings in these studies may stem from the time following injury that CSF levels were measured or the method of injury experienced by each subject.

Inflammation has also been suggested to play a role in aneurysm formation due to endothelial injury and remodeling based on human and animal studies [21, 22].  One such study showed increased levels of cyclooxygenase within the walls of ruptured and unruptured aneurysms, as well as a reduction in rate of rupture with aspirin administration [23-25].

 

Peripheral Inflammatory Markers 

Inflammatory markers increase in the systemic circulation as well as in CSF following SAH and are predictive of poor outcomes [10, 26, 27]. This has led to an increasing interest in the development of biomarkers to predict the outcome of SAH, with conflicting results [28]. High body temperature and leukocytosis have also been correlated with worse outcomes after SAH, though no causal relationship was established between intracerebral and peripheral inflammation [29, 30]. This relationship, however, may be the result of the global inflammation expected in critically ill patients suffering from SAH complications. SAH patients may experience cardiopulmonary complications as part of the systemic reaction [31]. In a rat model of SAH, anti-inflammatory treatment administered systemically was able to reduce lung injury after SAH [32].

Evidence for inflammation as cause of vasospasm

Several clinical studies have attempted to correlate fever and inflammation in the absence of infection with vasospasm [33-42]. Pro-inflammatory agents, such as lipopolysaccharide (LPS) [43], have been administered using the intracisternal route to show that vasospasm can occur in the absence of blood. This has demonstrated that the presence of red blood cells (RBCs) or hemoglobin (Hgb) are not necessary for the induction of vasospasm. Among the cellular adhesion molecules, E-selectin has also been shown to correlate well with the patients’ response to SAH. E-selectin was found to be in higher concentrations in the CSF of SAH patients who develop moderate or severe vasospasm [44]. Additionally, inhibition of E-selectin with an inhibitory antibody was shown to decrease vasospasm in rodent models [45].  Other adhesion molecules have been implicated as well. In one study Mac-1 monoclonal antibodies and anti-LFA-1 antibodies were administered systemically, and shown to reduce vasospasm in rat [46], rabbit [47], and primate [48] SAH models. Similar results have been shown with anti-ICAM1 monoclonal antibodies in a rodent model [49]. Among other pro-inflammatory cytokines, TNF-α levels in patients with lower grade SAH were shown to correlate with severity of vasospasm [50].  This has been further studied as TNF-α inhibitors were shown to attenuate vasospasm in animal models [51]. Similar results were described for other inflammatory cytokines including: IL-1B, IL-6, IL-8, and MCP-1 [13, 52-59]. Signaling pathways have been examined as well in the induction of vasospasm, namely mitogen-activated protein-kinase (MAPK) and nuclear factor kappa-B (NfKB) [60]. Other studies have suggested oxidative stress [61], and complement pathway activation [62] could play a large role in the induction of vasospasm as well.

Recent work has been done to explore a possible genetic predisposition to vasospasm.  One promising avenue has been the study of haptoglobin proteins, which are responsible for removal of free hemoglobin from CSF that may be the cause of inflammation.  hHaptoglobin (Hp) have three known distinct phenotypes in humans: Hp 1-1, Hp 2-1, and Hp 2-2 [63] In humans, the haptoglobin proteins with α-2 subunits are associated with higher rates of vasospasm as compared to other haptoglobin types (α1- α1) [64].  This is consistent with animal models that demonstrate more severe vasospasm and worst outcome after SAH in genetically altered hp 2-2 rodents [65].

Changes in nitric oxide (NO) have been extensively studied in the induction of vasospasm as well. Increase in endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) levels were detected in mice after SAH, and this physiological response to SAH is decreased in pro-inflammatory Hp 2-2 transgenic mice compared with Hp 1-1 mice [66, 67].  This further supports the evidence that Hp 2-2 genotypes are associated with a worse outcome in SAH, as these subjects would have less NO, which is involved in signaling pathways that lead to vasodilation and cytoprotection [34].  Studies have also suggested that an alteration dubbed “eNOS uncoupling”[68] may lead to production of superoxides instead of NO following SAH [67]. ET-1, a potent vasoconstrictor is thought to play a role in the inflammatory response after SAH [69-71].  Increase in ET-1 levels in in patients with SAH and symptomatic vasospasm has been documented in several studies, and he amount of blood found within the cisterns corolated well with the level of ET-1 in CSF [69-71].  Other studies, however, found no significant elevation of ET-1 after SAH and similarly, no correlation between ET-1 levels and vasospasm [71]. Similarly, administration of anti-ET-1 monoclonal antibodies were effective in decreasing vasospasm in some studies [72] [73, 74]. A rodent study suggested that transgenic mice over-expressing ET-1 experienced more severe vasospasm and edema [75]. Some studies have attempted the use of clasozentan, a synthetic endothelin receptor antagonist (ETRA)c, to reduce vasospasm in aSAH models of rodents, but the overall morbidity from vasospasm was unchanged [76].

 

Sex Steroids for the Treatment of Subarachnoid Hemorrhage

 

Estrogen

Estrogen is found in both females and males, but it is the primary female sex hormone that is responsible for the development and regulation of the female reproductive system [77].  Estrogens readily diffuse across the cell membrane because of their steroidal characteristics. Once inside the cell, they bind to and activate estrogen receptors [78]. At the molecular level, two main genes, estrogen receptor-alpha (ER-) and estrogen receptor-beta (ER-), encode the vascular estrogen receptors (ER) inside the nuclear membrane. The binding of the estrogen to the ER ligand binding domain induces a receptor conformational change and dimerization.

Evidence obtained from animal studies suggests that continuous estrogen treatment in SAH-induced rats may decrease rate and severity of vasospasm by inhibiting endothelin-1 production, increasing iNOS expression and preserving eNOS expression[8]. Mechanistically, estrogen’s attenuation of cerebral vasospasm may be related to its potent vasodilatory action, described in detail by Ding, et al. [79].

Progesterone

 

Progesterone (PROG), a neurosteroid synthesized in the CNS, is therapeutic in several experimental models of traumatic brain injury (TBI), transient and permanent ischemic stroke, neonatal hypoxic brain injury, diabetic neuropathy and demyelinating disorders.[80-85] Besides its hypothalamic receptors, PROG receptors are constitutively expressed in cerebral cortex, basal ganglia, hippocampus, midbrain and cerebellum.[86] A growing body of evidence suggests that PROG and its metabolite allopregnanolone have strong anti-inflammatory, anti-apoptotic and neuroprotective properties [80-82, 84, 85, 87] and is effective in improving functional outcomes.[81-84, 88]

Progesterone has also been shown to prevent vasospasm in SAH rat models using a similar mechanism [89]. In rats treated with progesterone one hour after experimental SAH, greater levels of eNOS were seen when compared to the control group [89]. The mechanisms for progesterone-mediated elevation of eNOS were multifactorial, but involved the Akt signaling pathway, which has also been implicated in estrogen-mediated vasodilation. Moreover, administration of progesterone was shown to be effective at increasing appetite scores of induced SAH rats and decreased intestinal levels of proinflammatory cytokines such as IL-1b, TNF-a, and IL-6 as well as ameliorating the gut structure thereby possibly preventing secondary complications of SAH [90]. Progesterone treated animals showed a significantly reduced mortality when compared to vehicle treated animals [4].

Testosterone

 

Testosterone, another gonadal sex steroid, also plays important roles in the CNS, but its direct role is still unclear [91]. Testosterone is physiologically secreted by the testes and adrenal glands and transported by the sex hormones binding globulins (SHBG) and albumins [91, 92]. It acts via the activation of androgen receptors (AR) [91], which are found in neurons throughout the brain [93]. The cellular effect of testosterone is divided into two categories, genomic and non-genomic. Nongenomic pertains the ion movements and initiation of signal transduction and occurs rapidly. On the other hand, genomic effect involves transcription and translation of new gene products, hence requires longer duration [94].

Pike’s study suggest that AR-dependent neuroprotection occurs through inhibition of apoptotic and rapid cell signaling pathways [95]. In male rodents, testosterone is also associated with increase in neuronal somal size, neuritic growth, and plasticity and synaptogenesis of motor neurons [96]. In the setting of SAH, testosterone was shown to be beneficial at preventing vasospasm in rabbits with induced SAH [97]. On the contrary, Myers et al’s findings suggest that testosterone does not have any neuroprotective effect against methamphetamine-induced neurotoxicity on the dopaminergic system in mice [98].

Remaining challenges

 

Translation from animal data to human trials 

Though there is promising data alluding to sex hormones as a potential therapeutic agent for vasospasm in aSAH patients, the gap between animal and human trials is still very large.  Growing concern for surrounding the failure of clinical trials in humans calls for more precise outcome measures [99]. A study by the SAHIT investigators discusses potential reasons for failure of randomized clinical trials in SAH including: functional ineffectiveness of the tested therapies, timing and dose of the treatment, inadequate sample size, insensitive or inappropriate outcome measures, the confounding effect of rescue therapies in placebo groups, treatment-associated side effects, and variations in practice across different centers[99].  Another study of phase III progesterone trials following TBI suggests that the testing parameters used to evaluate the efficiency of the drug are inadequate, and that outcome measures used in humans for neurological diseases need to improved [100].  Some studies have attempting to correlate human

 

REFERENCES

1. Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):44-58. Epub 2013/12/11. doi: 10.1038/nrneurol.2013.246. PubMed PMID: 24323051.

2. Miller BA, Turan N, Chau M, Pradilla G. Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed Res Int. 2014;2014:384342. Epub 2014/08/12. doi: 10.1155/2014/384342. PubMed PMID: 25105123; PubMed Central PMCID: PMC4106062.

3. Chaichana KL, Pradilla G, Huang J, Tamargo RJ. Role of inflammation (leukocyte-endothelial cell interactions) in vasospasm after subarachnoid hemorrhage. World Neurosurg. 2010;73(1):22-41. Epub 2010/05/11. doi: 10.1016/j.surneu.2009.05.027. PubMed PMID: 20452866.

4. Wang Z, Zuo G, Shi XY, Zhang J, Fang Q, Chen G. Progesterone administration modulates cortical TLR4/NF-kappaB signaling pathway after subarachnoid hemorrhage in male rats. Mediators of inflammation. 2011;2011:848309. doi: 10.1155/2011/848309. PubMed PMID: 21403869; PubMed Central PMCID: PMC3051156.

5. Yan F, Hu Q, Chen J, Wu C, Gu C, Chen G. Progesterone attenuates early brain injury after subarachnoid hemorrhage in rats. Neuroscience letters. 2013;543:163-7. doi: 10.1016/j.neulet.2013.03.005. PubMed PMID: 23499999.

6. Wunderle K, Hoeger KM, Wasserman E, Bazarian JJ. Menstrual phase as predictor of outcome after mild traumatic brain injury in women. The Journal of head trauma rehabilitation. 2014;29(5):E1-8. Epub 2013/11/14. doi: 10.1097/HTR.0000000000000006. PubMed PMID: 24220566.

7. Sun X, Ji C, Hu T, Wang Z, Chen G. Tamoxifen as an effective neuroprotectant against early brain injury and learning deficits induced by subarachnoid hemorrhage: possible involvement of inflammatory signaling. Journal of neuroinflammation. 2013;10:157. doi: 10.1186/1742-2094-10-157. PubMed PMID: 24373431; PubMed Central PMCID: PMC3881500.

8. Lin CL, Shih HC, Dumont AS, Kassell NF, Lieu AS, Su YF, et al. The effect of 17beta-estradiol in attenuating experimental subarachnoid hemorrhage-induced cerebral vasospasm. J Neurosurg. 2006;104(2):298-304. Epub 2006/03/03. doi: 10.3171/jns.2006.104.2.298. PubMed PMID: 16509505.

9. Ayala C, Croft JB, Greenlund KJ, Keenan NL, Donehoo RS, Malarcher AM, et al. Sex differences in US mortality rates for stroke and stroke subtypes by race/ethnicity and age, 1995-1998. Stroke; a journal of cerebral circulation. 2002;33(5):1197-201. Epub 2002/05/04. PubMed PMID: 11988590.

10. Kaynar MY, Tanriverdi T, Kafadar AM, Kacira T, Uzun H, Aydin S, et al. Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2004;101(6):1030-6. PubMed PMID: 15597765.

11. Kikuchi T, Okuda Y, Kaito N, Abe T. Cytokine production in cerebrospinal fluid after subarachnoid haemorrhage. Neurological research. 1995;17(2):106-8. Epub 1995/04/01. PubMed PMID: 7609845.

12. Xie X, Wu X, Cui J, Li H, Yan X. Increase ICAM-1 and LFA-1 expression by cerebrospinal fluid of subarachnoid hemorrhage patients: involvement of TNF-alpha. Brain research. 2013;1512:89-96. Epub 2013/04/04. doi: 10.1016/j.brainres.2013.03.041. PubMed PMID: 23548604.

13. Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schutt S, et al. Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry. 2001;70(4):534-7. Epub 2001/03/20. PubMed PMID: 11254783; PubMed Central PMCID: PMC1737308.

14. Hopkins SJ, McMahon CJ, Singh N, Galea J, Hoadley M, Scarth S, et al. Cerebrospinal fluid and plasma cytokines after subarachnoid haemorrhage: CSF interleukin-6 may be an early marker of infection. Journal of neuroinflammation. 2012;9:255. Epub 2012/11/28. doi: 10.1186/1742-2094-9-255. PubMed PMID: 23176037; PubMed Central PMCID: PMC3526412.

15. Jiang Y, Liu DW, Han XY, Dong YN, Gao J, Du B, et al. Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2012;19(6):866-72. Epub 2012/04/21. doi: 10.1016/j.jocn.2011.08.038. PubMed PMID: 22516550.

16. Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schutt S, et al. Endothelin-1 in subarachnoid hemorrhage: An acute-phase reactant produced by cerebrospinal fluid leukocytes. Stroke. 2000;31(12):2971-5. Epub 2000/01/11. PubMed PMID: 11108758.

17. Masaoka H, Suzuki R, Hirata Y, Emori T, Marumo F, Hirakawa K. Raised plasma endothelin in aneurysmal subarachnoid haemorrhage. Lancet. 1989;2(8676):1402. PubMed PMID: 2574350.

18. Hamann G, Isenberg E, Strittmatter M, Schimrigk K. Absence of elevation of big endothelin in subarachnoid hemorrhage. Stroke. 1993;24(3):383-6. PubMed PMID: 8446974.

19. Sozen T, Tsuchiyama R, Hasegawa Y, Suzuki H, Jadhav V, Nishizawa S, et al. Immunological response in early brain injury after SAH. Acta neurochirurgica Supplement. 2011;110(Pt 1):57-61. Epub 2010/12/01. doi: 10.1007/978-3-7091-0353-1_10. PubMed PMID: 21116915.

20. Claassen J, Carhuapoma JR, Kreiter KT, Du EY, Connolly ES, Mayer SA. Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome. Stroke; a journal of cerebral circulation. 2002;33(5):1225-32. Epub 2002/05/04. PubMed PMID: 11988595.

21. Aoki T, Nishimura M. Targeting chronic inflammation in cerebral aneurysms: focusing on NF-kappaB as a putative target of medical therapy. Expert opinion on therapeutic targets. 2010;14(3):265-73. Epub 2010/02/05. doi: 10.1517/14728221003586836. PubMed PMID: 20128708.

22. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke; a journal of cerebral circulation. 2009;40(3):942-51. Epub 2009/01/24. doi: 10.1161/STROKEAHA.108.532556. PubMed PMID: 19164781.

23. Hasan D, Hashimoto T, Kung D, Macdonald RL, Winn HR, Heistad D. Upregulation of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in wall of ruptured human cerebral aneurysms: preliminary results. Stroke; a journal of cerebral circulation. 2012;43(7):1964-7. Epub 2012/05/17. doi: 10.1161/STROKEAHA.112.655829. PubMed PMID: 22588264; PubMed Central PMCID: PMC3383865.

24. Hasan DM, Chalouhi N, Jabbour P, Magnotta VA, Kung DK, Young WL. Imaging aspirin effect on macrophages in the wall of human cerebral aneurysms using ferumoxytol-enhanced MRI: preliminary results. Journal of neuroradiology Journal de neuroradiologie. 2013;40(3):187-91. Epub 2013/02/23. doi: 10.1016/j.neurad.2012.09.002. PubMed PMID: 23428244.

25. Hasan DM, Mahaney KB, Brown RD, Jr., Meissner I, Piepgras DG, Huston J, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke; a journal of cerebral circulation. 2011;42(11):3156-62. Epub 2011/10/08. doi: 10.1161/STROKEAHA.111.619411. PubMed PMID: 21980208; PubMed Central PMCID: PMC3432499.

26. Horstmann S, Su Y, Koziol J, Meyding-Lamade U, Nagel S, Wagner S. MMP-2 and MMP-9 levels in peripheral blood after subarachnoid hemorrhage. Journal of the neurological sciences. 2006;251(1-2):82-6. Epub 2006/11/08. doi: 10.1016/j.jns.2006.09.005. PubMed PMID: 17087971.

27. Mocco J, Mack WJ, Kim GH, Lozier AP, Laufer I, Kreiter KT, et al. Rise in serum soluble intercellular adhesion molecule-1 levels with vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg. 2002;97(3):537-41. PubMed PMID: 12296636.

28. Kubo Y, Ogasawara K, Kakino S, Kashimura H, Tomitsuka N, Sugawara A, et al. Serum inflammatory adhesion molecules and high-sensitivity C-reactive protein correlates with delayed ischemic neurologic deficits after subarachnoid hemorrhage. Surgical neurology. 2008;69(6):592-6; discussion 6. Epub 2008/05/20. doi: 10.1016/j.surneu.2008.02.014. PubMed PMID: 18486699.

29. Dhar R, Diringer MN. The burden of the systemic inflammatory response predicts vasospasm and outcome after subarachnoid hemorrhage. Neurocritical care. 2008;8(3):404-12. Epub 2008/01/16. doi: 10.1007/s12028-008-9054-2. PubMed PMID: 18196475; PubMed Central PMCID: PMC2538678.

30. Tam AK, Ilodigwe D, Mocco J, Mayer S, Kassell N, Ruefenacht D, et al. Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: exploratory analysis of CONSCIOUS-1 database. Neurocritical care. 2010;13(2):182-9. Epub 2010/07/02. doi: 10.1007/s12028-010-9402-x. PubMed PMID: 20593247.

31. Wartenberg KE, Mayer SA. Medical complications after subarachnoid hemorrhage. Neurosurgery clinics of North America. 2010;21(2):325-38. Epub 2010/04/13. doi: 10.1016/j.nec.2009.10.012. PubMed PMID: 20380973.

32. Cobelens PM, Tiebosch IA, Dijkhuizen RM, van der Meide PH, Zwartbol R, Heijnen CJ, et al. Interferon-beta attenuates lung inflammation following experimental subarachnoid hemorrhage. Crit Care. 2010;14(4):R157. Epub 2010/08/25. doi: 10.1186/cc9232. PubMed PMID: 20731855; PubMed Central PMCID: PMC2945141.

33. Rousseaux P, Scherpereel B, Bernard MH, Graftieaux JP, Guyot JF. Fever and cerebral vasospasm in ruptured intracranial aneurysms. Surg Neurol. 1980;14(6):459-65. PubMed PMID: 7221858.

34. Weir B, Disney L, Grace M, Roberts P. Daily trends in white blood cell count and temperature after subarachnoid hemorrhage from aneurysm. Neurosurgery. 1989;25(2):161-5. PubMed PMID: 2770982.

35. Oliveira-Filho J, Ezzeddine MA, Segal AZ, Buonanno FS, Chang Y, Ogilvy CS, et al. Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology. 2001;56(10):1299-304. PubMed PMID: 11376177.

36. Maiuri F, Gallicchio B, Donati P, Carandente M. The blood leukocyte count and its prognostic significance in subarachnoid hemorrhage. J Neurosurg Sci. 1987;31(2):45-8. PubMed PMID: 3668657.

37. McGirt MJ, Mavropoulos JC, McGirt LY, Alexander MJ, Friedman AH, Laskowitz DT, et al. Leukocytosis as an independent risk factor for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg. 2003;98(6):1222-6. PubMed PMID: 12816268.

38. Neil-Dwyer G, Cruickshank J. The blood leucocyte count and its prognostic significance in subarachnoid haemorrhage. Brain. 1974;97(1):79-86. PubMed PMID: 4434173.

39. Niikawa S, Hara S, Ohe N, Miwa Y, Ohkuma A. Correlation between blood parameters and symptomatic vasospasm in subarachnoid hemorrhage patients. Neurol Med Chir (Tokyo). 1997;37(12):881-4; discussion 4-5. PubMed PMID: 9465585.

40. Spallone A, Acqui M, Pastore FS, Guidetti B. Relationship between leukocytosis and ischemic complications following aneurysmal subarachnoid hemorrhage. Surg Neurol. 1987;27(3):253-8. PubMed PMID: 3810457.

41. Pellettieri L, Nilsson B, Carlsson CA, Nilsson U. Serum immunocomplexes in patients with subarachnoid hemorrhage. Neurosurgery. 1986;19(5):767-71. PubMed PMID: 3785623.

42. Walton JN. The prognosis and management of subarachnoid haemorrhage. Can Med Assoc J. 1955;72(3):165-75. PubMed PMID: 13231008.

43. Recinos PF, Pradilla G, Thai QA, Perez M, Hdeib AM, Tamargo RJ. Controlled release of lipopolysaccharide in the subarachnoid space of rabbits induces chronic vasospasm in the absence of blood. Surg Neurol. 2006;66(5):463-9; discussion 9. PubMed PMID: 17084186.

44. Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, et al. Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg. 1998;89(4):559-67. PubMed PMID: 9761049.

45. Lin CL, Dumont AS, Calisaneller T, Kwan AL, Hwong SL, Lee KS. Monoclonal antibody against E selectin attenuates subarachnoid hemorrhage-induced cerebral vasospasm. Surg Neurol. 2005;64(3):201-5; discussion 5-6. PubMed PMID: 16099244.

46. Clatterbuck RE, Oshiro EM, Hoffman PA, Dietsch GN, Pardoll DM, Tamargo RJ. Inhibition of vasospasm with lymphocyte function-associated antigen-1 monoclonal antibody in a femoral artery model in rats. J Neurosurg. 2002;97(3):676-82. PubMed PMID: 12296653.

47. Pradilla G, Wang PP, Legnani FG, Ogata L, Dietsch GN, Tamargo RJ. Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. J Neurosurg. 2004;101(1):88-92. PubMed PMID: 15255256.

48. Clatterbuck RE, Gailloud P, Ogata L, Gebremariam A, Dietsch GN, Murphy KJ, et al. Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates. J Neurosurg. 2003;99(2):376-82. PubMed PMID: 12924713.

49. Oshiro EM, Hoffman PA, Dietsch GN, Watts MC, Pardoll DM, Tamargo RJ. Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats. Stroke. 1997;28(10):2031-7; discussion 7-8. PubMed PMID: 9341715.

50. Hanafy KA, Stuart RM, Khandji AG, Connolly ES, Badjatia N, Mayer SA, et al. Relationship between brain interstitial fluid tumor necrosis factor-alpha and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Clin Neurosci. 2010;17(7):853-6. Epub 2010/05/18. doi: 10.1016/j.jocn.2009.11.041. PubMed PMID: 20471835; PubMed Central PMCID: PMC2878881.

51. Bowman G, Dixit S, Bonneau RH, Chinchilli VM, Cockroft KM. Neutralizing antibody against interleukin-6 attenuates posthemorrhagic vasospasm in the rat femoral artery model. Neurosurgery. 2004;54(3):719-25; discussion 25-6. PubMed PMID: 15028149.

52. Ni W, Gu YX, Song DL, Leng B, Li PL, Mao Y. The relationship between IL-6 in CSF and occurrence of vasospasm after subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110(Pt 1):203-8. Epub 2010/12/01. doi: 10.1007/978-3-7091-0353-1_35. PubMed PMID: 21116940.

53. Aihara Y, Kasuya H, Onda H, Hori T, Takeda J. Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage. Stroke. 2001;32(1):212-7. PubMed PMID: 11136939.

54. Gaetani P, Tartara F, Pignatti P, Tancioni F, Rodriguez y Baena R, De Benedetti F. Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Neurol Res. 1998;20(4):337-42. PubMed PMID: 9618698.

55. Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH. Neuro Endocrinol Lett. 2004;25(1-2):141-7. PubMed PMID: 15159698.

56. Nam DH, Kim JS, Hong SC, Lee WH, Lee JI, Shin HJ, et al. Expression of interleukin-1 beta in lipopolysaccharide stimulated monocytes derived from patients with aneurysmal subarachnoid hemorrhage is correlated with cerebral vasospasm. Neurosci Lett. 2001;312(1):41-4. PubMed PMID: 11578841.

57. Wang Y, Zhong M, Tan XX, Yang YJ, Chen WJ, Liu W, et al. Expression change of interleukin-8 gene in rabbit basilar artery after subarachnoid hemorrhage. Neurosci Bull. 2007;23(3):151-5. PubMed PMID: 17612593.

58. Muroi C, Seule M, Sikorski C, Dent W, Keller E. Systemic interleukin-6 levels reflect illness course and prognosis of patients with spontaneous nonaneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:77-80. Epub 2012/08/15. doi: 10.1007/978-3-7091-1192-5_17. PubMed PMID: 22890649.

59. Lu H, Shi JX, Chen HL, Hang CH, Wang HD, Yin HX. Expression of monocyte chemoattractant protein-1 in the cerebral artery after experimental subarachnoid hemorrhage. Brain Res. 2009;1262:73-80. Epub 2009/04/30. doi: 10.1016/j.brainres.2009.01.017. PubMed PMID: 19401162.

60. Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013;13(9):679-92. Epub 2013/08/21. doi: 10.1038/nri3495. PubMed PMID: 23954936.

61. Hsieh HL, Yang CM. Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases. BioMed research international. 2013;2013:484613. Epub 2014/01/24. doi: 10.1155/2013/484613. PubMed PMID: 24455696.

62. Zanier ER, Zangari R, Munthe-Fog L, Hein E, Zoerle T, Conte V, et al. Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage. Neurology. 2014;82(2):126-34. Epub 2013/12/18. doi: 10.1212/WNL.0000000000000020. PubMed PMID: 24336142.

63. Bowman BH, Kurosky A. Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation. Adv Hum Genet. 1982;12:189-261, 453-4. Epub 1982/01/01. PubMed PMID: 6751044.

64. Borsody M, Burke A, Coplin W, Miller-Lotan R, Levy A. Haptoglobin and the development of cerebral artery vasospasm after subarachnoid hemorrhage. Neurology. 2006;66(5):634-40. PubMed PMID: 16436647.

65. Chaichana KL, Levy AP, Miller-Lotan R, Shakur S, Tamargo RJ. Haptoglobin 2-2 genotype determines chronic vasospasm after experimental subarachnoid hemorrhage. Stroke. 2007;38(12):3266-71. PubMed PMID: 17962599.

66. Pradilla G, Garzon-Muvdi T, Ruzevick JJ, Bender M, Edwards L, Momin EN, et al. Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage. Neurosurgery. 2012;70(3):747-56; discussion 56-7. Epub 2011/09/15. doi: 10.1227/NEU.0b013e3182363c2f. PubMed PMID: 21915076.

67. Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X, et al. Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2011;31(1):190-9. Epub 2010/06/03. doi: 10.1038/jcbfm.2010.76. PubMed PMID: 20517322; PubMed Central PMCID: PMC3049483.

68. Yang YM, Huang A, Kaley G, Sun D. eNOS uncoupling and endothelial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol. 2009;297(5):H1829-36. Epub 2009/09/22. doi: 10.1152/ajpheart.00230.2009. PubMed PMID: 19767531; PubMed Central PMCID: PMC2781386.

69. Mascia L, Fedorko L, Stewart DJ, Mohamed F, terBrugge K, Ranieri VM, et al. Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2001;32(5):1185-90. PubMed PMID: 11340231.

70. Seifert V, Loffler BM, Zimmermann M, Roux S, Stolke D. Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage. Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma. J Neurosurg. 1995;82(1):55-62. PubMed PMID: 7815135.

71. Jung CS, Lange B, Zimmermann M, Seifert V. The CSF concentration of ADMA, but not of ET-1, is correlated with the occurrence and severity of cerebral vasospasm after subarachnoid hemorrhage. Neurosci Lett. 2012;524(1):20-4. Epub 2012/07/17. doi: 10.1016/j.neulet.2012.06.076. PubMed PMID: 22796469.

72. Yamaura I, Tani E, Maeda Y, Minami N, Shindo H. Endothelin-1 of canine basilar artery in vasospasm. J Neurosurg. 1992;76(1):99-105. PubMed PMID: 1727175.

73. Clozel M, Breu V, Burri K, Cassal JM, Fischli W, Gray GA, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature. 1993;365(6448):759-61. PubMed PMID: 8413655.

74. Zuccarello M, Boccaletti R, Romano A, Rapoport RM. Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 1998;29(9):1924-9. PubMed PMID: 9731620.

75. Yeung PK, Shen J, Chung SS, Chung SK. Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage. BMC Neurosci. 2013;14(1):131. Epub 2013/10/26. doi: 10.1186/1471-2202-14-131. PubMed PMID: 24156724; PubMed Central PMCID: PMC3815232.

76. Chen G, Tariq A, Ai J, Sabri M, Jeon HJ, Tang EJ, et al. Different effects of clazosentan on consequences of subarachnoid hemorrhage in rats. Brain Res. 2011;1392:132-9. Epub 2011/04/07. doi: 10.1016/j.brainres.2011.03.068. PubMed PMID: 21466789.

77. Moreno P, Beisken S, Harsha B, Muthukrishnan V, Tudose I, Dekker A, et al. BiNChE: a web tool and library for chemical enrichment analysis based on the ChEBI ontology. BMC Bioinformatics. 2015;16:56. Epub 2015/04/17. doi: 10.1186/s12859-015-0486-3. PubMed PMID: 25879798; PubMed Central PMCID: PMCPMC4349482.

78. Nussey S, Whitehead S.  Endocrinology: An Integrated Approach. Oxford2001.

79. Ding D, Starke RM, Dumont AS, Owens GK, Hasan DM, Chalouhi N, et al. Therapeutic implications of estrogen for cerebral vasospasm and delayed cerebral ischemia induced by aneurysmal subarachnoid hemorrhage. BioMed research international. 2014;2014:727428. doi: 10.1155/2014/727428. PubMed PMID: 24724095; PubMed Central PMCID: PMC3958795.

80. Peterson BL, Won S, Geddes RI, Sayeed I, Stein DG. Sex-related differences in effects of progesterone following neonatal hypoxic brain injury. Behav Brain Res. 2015;286:152-65. Epub 2015/03/10. doi: 10.1016/j.bbr.2015.03.005. PubMed PMID: 25746450.

81. Wali B, Ishrat T, Stein DG, Sayeed I. Progesterone improves long-term functional and histological outcomes after permanent stroke in older rats. Behav Brain Res. 2016;305:46-56. Epub 2016/02/28. doi: 10.1016/j.bbr.2016.02.024. PubMed PMID: 26921692.

82. Webster KM, Wright DK, Sun M, Semple BD, Ozturk E, Stein DG, et al. Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury. J Neuroinflammation. 2015;12:238. Epub 2015/12/20. doi: 10.1186/s12974-015-0457-7. PubMed PMID: 26683475; PubMed Central PMCID: PMC4683966.

83. Yousuf S, Sayeed I, Atif F, Tang H, Wang J, Stein DG. Delayed progesterone treatment reduces brain infarction and improves functional outcomes after ischemic stroke: a time-window study in middle-aged rats. J Cereb Blood Flow Metab. 2014;34(2):297-306. Epub 2013/12/05. doi: 10.1038/jcbfm.2013.198. PubMed PMID: 24301297; PubMed Central PMCID: PMC3915207.

84. Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura LM, et al. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience. 2007;144(4):1293-304. Epub 2006/12/26. doi: 10.1016/j.neuroscience.2006.11.014. PubMed PMID: 17187935.

85. El-Etr M, Rame M, Boucher C, Ghoumari AM, Kumar N, Liere P, et al. Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia. 2015;63(1):104-17. Epub 2014/08/06. doi: 10.1002/glia.22736. PubMed PMID: 25092805; PubMed Central PMCID: PMC4237628.

86. Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, et al. Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors. Prog Neurobiol. 2013. Epub 2013/11/01. doi: 10.1016/j.pneurobio.2013.09.004. PubMed PMID: 24172649.

87. Sayeed I, Stein DG. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog Brain Res. 2009;175:219-37. Epub 2009/08/08. doi: 10.1016/S0079-6123(09)17515-5. PubMed PMID: 19660659.

88. Allen RS, Olsen TW, Sayeed I, Cale HA, Morrison KC, Oumarbaeva Y, et al. Progesterone treatment in two rat models of ocular ischemia. Invest Ophthalmol Vis Sci. 2015;56(5):2880-91. Epub 2015/05/30. doi: 10.1167/iovs.14-16070. PubMed PMID: 26024074; PubMed Central PMCID: PMC4419778.

89. Chang CM, Su YF, Chang CZ, Chung CL, Tsai YJ, Loh JK, et al. Progesterone attenuates experimental subarachnoid hemorrhage-induced vasospasm by upregulation of endothelial nitric oxide synthase via Akt signaling pathway. BioMed research international. 2014;2014:207616. doi: 10.1155/2014/207616. PubMed PMID: 24949428; PubMed Central PMCID: PMC4052693.

90. Zhao XD, Zhou YT. Effects of progesterone on intestinal inflammatory response and mucosa structure alterations following SAH in male rats. J Surg Res. 2011;171(1):e47-53. Epub 2011/09/20. doi: 10.1016/j.jss.2011.07.018. PubMed PMID: 21924739.

91. Bialek M, Zaremba P, Borowicz KK, Czuczwar SJ. Neuroprotective role of testosterone in the nervous system. Pol J Pharmacol. 2004;56(5):509-18. PubMed PMID: WOS:000227152600002.

92. Iqbal MJ, Dalton M, Sawers RS. Binding of testosterone and oestradiol to sex hormone binding globulin, human serum albumin and other plasma proteins: evidence for non-specific binding of oestradiol to sex hormone binding globulin. Clin Sci (Lond). 1983;64(3):307-14. Epub 1983/03/01. PubMed PMID: 6681600.

93. Belle MD, Lea RW. Androgen receptor immunolocalization in brains of courting and brooding male and female ring doves (Streptopelia risoria). Gen Comp Endocrinol. 2001;124(2):173-87. Epub 2001/11/13. doi: 10.1006/gcen.2001.7693. PubMed PMID: 11703083.

94. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions of steroid hormones–a focus on rapid, nongenomic effects. Pharmacol Rev. 2000;52(4):513-56. Epub 2000/12/21. PubMed PMID: 11121509.

95. Pike CJ. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res. 2001;919(1):160-5. Epub 2001/11/02. PubMed PMID: 11689174.

96. Matsumoto A. Hormonally induced neuronal plasticity in the adult motoneurons. Brain Res Bull. 1997;44(4):539-47. Epub 1997/01/01. PubMed PMID: 9370222.

97. Gurer B, Turkoglu E, Kertmen H, Karavelioglu E, Arikok AT, Sekerci Z. Attenuation of cerebral vasospasm and secondary injury by testosterone following experimental subarachnoid hemorrhage in rabbit. Acta Neurochir (Wien). 2014;156(11):2111-20; discussion 20. Epub 2014/09/10. doi: 10.1007/s00701-014-2211-9. PubMed PMID: 25194970.

98. Myers RE, Anderson LI, Dluzen DE. Estrogen, but not testosterone, attenuates methamphetamine-evoked dopamine output from superfused striatal tissue of female and male mice. Neuropharmacology. 2003;44(5):624-32. Epub 2003/04/02. PubMed PMID: 12668048.

99. Macdonald RL, Jaja B, Cusimano MD, Etminan N, Hanggi D, Hasan D, et al. SAHIT Investigators–on the outcome of some subarachnoid hemorrhage clinical trials. Transl Stroke Res. 2013;4(3):286-96. Epub 2013/12/11. doi: 10.1007/s12975-012-0242-1. PubMed PMID: 24323299.

100. Stein DG. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015;29(11):1259-72. Epub 2015/08/15. PubMed PMID: 26274493.

Cite This Work

To export a reference to this article please select a referencing stye below:

Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.

Related Services

View all

DMCA / Removal Request

If you are the original writer of this dissertation and no longer wish to have your work published on the UKDiss.com website then please: