Melatonin decreases mortality following severe subarachnoid hemorrhage

Ayer, Robert; Sugawara, Takashi; Chen, Wanqiu; Tong, Wenni; Zhang, Junyi

doi:10.1111/j.1600-079x.2007.00508.x

Cited by 46 publications

(50 citation statements)

References 66 publications

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“…The well-known weakness is the poorly control of bleeding volume and variable severity of SAH, which has been reported to be correlated with the severity of brain injuries 11, 27. In this study, the average SAH grading score was similar among the groups; this indicates similar injury among compared groups, and suggests that differences in outcomes are the result of different treatments.…”

Section: Discussionsupporting

confidence: 53%

“…The endovascular perforation model has some weaknesses, although it mimics clinical mechanism of artery rupture and shows a high mortality and acute metabolic changes similar to clinical findings, and thus being the most attractive model for studies of EBI after SAH 3, 10, 11, 13, 27. The well-known weakness is the poorly control of bleeding volume and variable severity of SAH, which has been reported to be correlated with the severity of brain injuries 11, 27.…”

Section: Discussionmentioning

confidence: 99%

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Role of Interleukin-1β in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Sozen

Tsuchiyama

Hasegawa

et al. 2009

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Background and Purpose-The role of interleukin (IL)-1␤ remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1␤ has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1␤ inactivation on EBI after SAH in mice. Methods-The endovascular perforation model of SAH was produced and 112 mice were assigned to sham, SAHϩ vehicle, and SAHϩ N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-CMK, 6 and 10 mg/kg) groups. Ac-YVAD-CMK, a selective inhibitor of IL-1␤ converting enzyme, or vehicle was administered intraperitoneally 1 hour post-SAH. EBI was assessed in terms of mortality within 24 hours, neurological scores, brain water content at 24 and 72 hours, Evans blue dye extravasation and Western blot for IL-1␤, c-Jun N-Terminal kinase (JNK), matrix metalloproteinase (MMP)-9, and zonula occludens (ZO)-1 at 24 hours after SAH. Results-High-dose (10 mg/kg) but not low-dose (6 mg/kg) treatment group significantly improved neurological scores, mortality, brain water content, and Evans blue dye extravasation compared with the vehicle group. Although both dosages of Ac-YVAD-CMK attenuated the mature IL-1␤ induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation. Conclusion-IL-1␤

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Role of Interleukin-1β in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Sozen

Tsuchiyama

Hasegawa

et al. 2009

Stroke

Self Cite

167

138

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“…The endovascular perforation model of SAH was produced in male adult Sprague-Dawley rats (300–370g, Harlan, Indianapolis, IN) as previously described with slight modifications (12–14). Briefly, rats were anesthetized with 3% isoflurane in 60/40% medical air/oxygen in a small animal anesthesia induction box, followed by the subcutaneous injection of atropine (0.1mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats*

Suzuki

Ayer

Sugawara

et al. 2010

Critical Care Medicine

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Objective-Accumulated evidence suggests that the primary cause of poor outcome after subarachnoid hemorrhage (SAH) is not only cerebral arterial narrowing, but also early brain injury (EBI). Our objective was to determine the effect of recombinant osteopontin (r-OPN), a pleiotropic extracellular matrix glycoprotein, on post-SAH EBI in rats. Design-Controlled in vivo laboratory study. Setting-Animal research laboratory.Subjects-One hundred seventy-seven male adult Sprague-Dawley rats, 300-370g.Interventions-The endovascular perforation model of SAH was produced. SAH or shamoperated rats were treated with an equal volume (1μL) of pre-SAH intracerebroventricular administration of two dosages (0.02 and 0.1μg) of r-OPN, albumin or vehicle. Body weight, neurological scores, brain edema and blood-brain barrier (BBB) disruption were evaluated, and Western blot analyses were performed to determine the effect of r-OPN on matrix metalloproteinase (MMP)-9, substrates of MMP-9 (zona occludens [ZO]-1, laminin), tissue inhibitor of MMP (TIMP)-1, inflammation (interleukin-1β), and nuclear factor (NF)-κ B signaling pathways. Measurements and MainResults-Treatment with r-OPN prevented a significant loss in body weight, neurological impairment, brain edema, and BBB disruption after SAH. These effects were associated with the deactivation of NF-κB activity, inhibition of MMP-9 induction, the maintenance of TIMP-1, and the consequent preservation of the cerebral microvessel basal lamina protein laminin, and the tight junction protein ZO-1.Conclusions-These results demonstrate that r-OPN treatment is effective for post-SAH EBI. Aneurysmal subarachnoid hemorrhage (SAH) is a common and devastating neurological disorder (1). Cerebral vasospasm has been believed to be a leading cause of mortality and morbidity (2). Recent randomized clinical trials, however, showed that clazosentan significantly reduced angiographic vasospasm but failed to improve long-term neurological outcome (3,4). This means that the treatment efforts targeting only angiographic vasospasm might not be enough to achieve a better outcome. Thus, new research efforts have focused on clarifying the pathophysiology of early brain injury (EBI) following SAH, and on developing protective strategies against it (5).Osteopontin (OPN) is a secreted extracellular matrix (ECM) glycoprotein that is involved in both physiological and pathological processes in a wide range of tissue (6). The biological functions of OPN are highly variable, and often seemingly contradictory depending on the biological scenario surrounding its induction (7). However, there is compelling evidence that OPN can, in a variety of situations, help cells survive an otherwise lethal insult (8). For example, endogenous OPN induction has consistently been found to have protective effects on ischemic injuries involving the brain and other organs (9,10). Moreover, the administration of recombinant OPN (r-OPN) markedly reduced the infarct size via anti-apoptotic actions in a transient focal cerebral ischemi...

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“…Sham and SAH groups received vehicle (1.5 ml of 10% ethanol in normal saline). This concentration of ethanol was not likely to affect any of the physiologic parameters assessed during this experiment [3,5,10]. …”

Section: Methodsmentioning

confidence: 99%

Statin-Induced T-Lymphocyte Modulation and Neuroprotection Following Experimental Subarachnoid Hemorrhage

Ayer

Ostrowski

Sugawara

et al. 2012

Acta Neurochirurgica Supplement

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Introduction Statins influence immune system activities through mechanisms independent of their lipid-lowering properties. T cells can be subdivided based on cytokine secretion patterns into two subsets: T-helper cells type 1 (Th1) and type 2 (Th2). Independent laboratory studies have shown statins to be potent inducers of a Th2 switch in immune cell response and be neuroprotective in several models of central nervous system (CNS) disease. This study was the first to evaluate the immune modulating effects of statins in subarachnoid hemorrhage (SAH). Methods Simvastatin was administered to rats intraperitoneally in two dosages (1 and 20 mg/kg) 30 min after the induction of SAH using endovascular perforation. Neurological scores were assessed 24 h later. Animals were then sacrificed, and samples of cortex and brain stem were tested for expression of the T-regulatory cell cytokine transforming growth factor (TGF) β1, as well as interleukin (IL) 1β, a proinflammatory cytokine associated with Th1 immune responses. The presence of TGF-β1 secreting T cells was evaluated with the use of brain slices. Results SAH significantly impaired neurological function in all SAH groups (treated and untreated) versus sham. Animals treated with high-dose simvastatin had less neurological impairment than both untreated and low-dose groups. Cortical and brain-stem levels of TGF-β1 were significantly elevated following SAH in the high-dose group. IL-1βwas significantly elevated following the induction of SAH but was inhibited by high-dose simvastatin. Double-labeled fluorescent immunohistochemical data demonstrated the presence of lymphocytes in the subarachnoid and perivascular spaces following SAH. Expression of TGF-β1 by lymphocytes was markedly increased following treatment with high-dose simvastatin. Conclusion The present study elucidated the potential role of a Th2 immune switch in statin provided neuroprotection following SAH.

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Melatonin decreases mortality following severe subarachnoid hemorrhage

Cited by 46 publications

References 66 publications

Role of Interleukin-1β in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Role of Interleukin-1β in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats*

Statin-Induced T-Lymphocyte Modulation and Neuroprotection Following Experimental Subarachnoid Hemorrhage

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