scholarly journals Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats

2021 ◽  
Vol 22 (11) ◽  
pp. 5975
Author(s):  
Chieh-Hsin Wu ◽  
Yi-Cheng Tsai ◽  
Tai-Hsin Tsai ◽  
Keng-Liang Kuo ◽  
Yu-Feng Su ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Subarachnoid Hemorrhage ◽  
Dentate Gyrus ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Histone H3 ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Cross Sectional ◽  
Delayed Cerebral Vasospasm ◽  
Basilar Arteries

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (p < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.

scholarly journals Levosimendan as a therapeutic strategy to prevent neuroinflammation after aneurysmal subarachnoid hemorrhage?

2021 ◽  
pp. neurintsurg-2021-017504
Author(s):  
Stefan Wanderer ◽  
Lukas Andereggen ◽  
Jan Mrosek ◽  
Sepide Kashefiolasl ◽  
Gerrit Alexander Schubert ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Severe Heart Failure ◽  
Prostaglandin F2alpha ◽  
Sprague Dawley ◽  
Delayed Cerebral Vasospasm ◽  
Sprague Dawley Rats ◽  
Solvent Control ◽  
Anti Inflammatory

BackgroundPoor patient outcomes after aneurysmal subarachnoid hemorrhage (SAH) occur due to a multifactorial process, mainly involving cerebral inflammation (CI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia, followed by neurodegeneration. CI is mainly triggered by enhanced synthesis of serotonin (5-HT), prostaglandin F2alpha (PGF2a), and cytokines such as interleukins. Levosimendan (LV), a calcium-channel sensitizer, has already displayed anti-inflammatory effects in patients with severe heart failure. Therefore, we wanted to elucidate its potential anti-inflammatory role on the cerebral vasculature after SAH.MethodsExperimental SAH was induced by using an experimental double-hemorrhage model. Sprague Dawley rats were harvested on day 3 and day 5 after the ictus. The basilar artery was used for isometric investigations of the muscular media tone. Vessel segments were either preincubated with LV or without, with precontraction performed with 5-HT or PGF2a followed by application of acetylcholine (ACh) or LV.ResultsAfter preincubation with LV 10−4 M and 5-HT precontraction, ACh triggered a strong vasorelaxation in sham segments (LV 10−4 M, Emax 65%; LV 10−5 M, Emax 48%; no LV, Emax 53%). Interestingly, SAH D3 (LV 10−4, Emax 76%) and D5 (LV 10−4, Emax 79%) segments showed greater vasorelaxation compared with sham. An LV series after PGF2a precontraction showed significantly enhanced relaxation in the sham (P=0.004) and SAH groups (P=0.0008) compared with solvent control vessels.ConclusionsLV application after SAH seems to beneficially influence DCVS by antagonizing 5-HT- and PGF2a-triggered vasoconstriction. Considering this spasmolytic effect, LV might have a role in the treatment of SAH, additionally in selected patients suffering takotsubo cardiomyopathy.

scholarly journals Risk factors for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 598-604
Author(s):  
Valentina Opancina ◽  
Snezana Lukic ◽  
Slobodan Jankovic ◽  
Radisa Vojinovic ◽  
Milan Mijailovic
Keyword(s):  
Risk Factors ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Medical Center ◽  
White Blood Cells ◽  
Cerebral Aneurysms ◽  
International Normalized Ratio ◽  
Cross Sectional Study ◽  
Cross Sectional

AbstractIntroductionAneurysmal subarachnoid hemorrhage is a type of spontaneous hemorrhagic stroke, which is caused by a ruptured cerebral aneurysm. Cerebral vasospasm (CVS) is the most grievous complication of subarachnoid hemorrhage (SAH). The aim of this study was to examine the risk factors that influence the onset of CVS that develops after endovascular coil embolization of a ruptured aneurysm.Materials and methodsThe study was designed as a cross-sectional study. The patients included in the study were 18 or more years of age, admitted within a period of 24 h of symptom onset, diagnosed and treated at a university medical center in Serbia during a 5-year period.ResultsOur study showed that the maximum recorded international normalized ratio (INR) values in patients who were not receiving anticoagulant therapy and the maximum recorded white blood cells (WBCs) were strongly associated with cerebrovascular spasm, increasing its chances 4.4 and 8.4 times with an increase of each integer of the INR value and 1,000 WBCs, respectively.ConclusionsSAH after the rupture of cerebral aneurysms creates an endocranial inflammatory state whose intensity is probably directly related to the occurrence of vasospasm and its adverse consequences.

scholarly journals Vasa Vasorum Formation is Associated With Rupture of Intracranial Aneurysms

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Haruka Miyata ◽  
Hirokazu Koseki ◽  
Kampei Shimizu ◽  
Yu Abekura ◽  
Mieko Oka ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysms ◽  
Histopathological Examination ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Vasa Vasorum ◽  
Systemic Hypertension ◽  
External Carotid ◽  
Anterior Communicating Artery ◽  
Sprague Dawley ◽  
The Right

Abstract INTRODUCTION Subarachnoid hemorrhage has a poor outcome despite a modern advancement in medical care. The development of a novel therapeutic strategy to prevent rupture of intracranial aneurysms (IAs) or a novel diagnostic marker to predict rupture-prone lesions is thus mandatory. Therefore, in the present study, we established a rat model in which IAs spontaneously rupture and examined this model to clarify histopathological features associated with rupture of lesions. METHODS In detail, female Sprague-Dawley rats were subjected to the bilateral ovariectomy, the ligation of the left common carotid, the right external carotid, and the right pterygopalatine arteries, the induced systemic hypertension, and the administration of a lysyl oxidase inhibitor. RESULTS Aneurysmal subarachnoid hemorrhage occurred one-thirds of manipulated animals and locations of ruptured IAs were exclusively at a posterior or an anterior communicating artery. Histopathological examination using ruptured IAs, rupture-prone ones induced at a posterior or an anterior communicating artery, ones induced at an anterior cerebral artery-olfactory artery bifurcation that never rupture revealed the formation of vasa vasorum as an event associated with rupture of IAs. CONCLUSION We thus proposed the contribution of a structural change in an adventitia, vasa vasorum formation, to rupture of IAs. Findings from this study provide important insights about the pathogenesis of IAs.

scholarly journals Increased levels of lipid peroxides as predictive of symptomatic vasospasm and poor outcome after aneurysmal subarachnoid hemorrhage

2002 ◽  
Vol 97 (6) ◽  
pp. 1302-1305 ◽  
Author(s):  
Takao Kamezaki ◽  
Kiyoyuki Yanaka ◽  
Sohji Nagase ◽  
Keishi Fujita ◽  
Noriyuki Kato ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Lipid Peroxides ◽  
Medical Complication ◽  
Content Type ◽  
Poor Outcome ◽  
Symptomatic Vasospasm ◽  
Delayed Cerebral Vasospasm ◽  
Fine Print

Object. Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). Reactive oxygen species and subsequent lipid peroxidation are reported to participate in the causes of cerebral vasospasm. This clinical study was performed to investigate the relationships between levels of lipid peroxides in cerebrospinal fluid (CSF) and both delayed cerebral vasospasm and clinical outcome after SAH. Methods. Levels of phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl ester hydroperoxide (CEOOH) in the CSF were measured in 20 patients with aneurysmal SAH. The patients' CSF was collected within 48 hours of hemorrhage onset and on Day 6 or 7 post-SAH. On Day 7, angiography was performed to verify the degree and extent of the vasospasm. The relationship between the patients' clinical profiles and the levels of lipid peroxides in the CSF were investigated. Both PCOOH and CEOOH were detectable in CSF, and their levels decreased within 7 days after onset of SAH. The levels of CEOOH within 48 hours after onset of hemorrhage were significantly higher in patients in whom symptomatic vasospasm later developed than in patients in whom symptomatic vasospasm did not develop (p = 0.002). Levels of PCOOH measured within 48 hours after onset of hemorrhage were significantly higher in patients with poor outcomes than in patients with good outcomes (p = 0.043). Conclusions. Increased levels of lipid peroxides measured in the CSF during the acute stage of SAH were predictive of both symptomatic vasospasm and poor outcome. Measurements of lipid peroxides in the CSF may be useful prognostically for patient outcomes as well as for predicting symptomatic vasospasm.

Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage

1997 ◽  
Vol 3 (4) ◽  
pp. E8 ◽  
Author(s):  
John E. Wanebo ◽  
Hunter G. Louis ◽  
Adam S. Arthur ◽  
Jie Zhou ◽  
Neal F. Kassell ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Rabbit Model ◽  
Systemic Administration ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Cross Sectional ◽  
Basilar Arteries ◽  
The Mean

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ETA receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH. Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters. The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm2 in the control group to 0.106 mm2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm2 (78.1% of control) compared with the placebo BID value of 0.134 mm2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups. These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.

scholarly journals Matrix Metalloproteinases in Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Vivek Mehta ◽  
Jonathan Russin ◽  
Alexandra Spirtos ◽  
Shuhan He ◽  
Peter Adamczyk ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Matrix Metalloproteinases ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Critical Role ◽  
Morbidity And Mortality ◽  
Cellular Mechanisms ◽  
Delayed Cerebral Vasospasm ◽  
Membrane Bound ◽  
Existing Data

Delayed cerebral vasospasm is a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). While the cellular mechanisms underlying vasospasm remain unclear, it is believed that inflammation may play a critical role in vasospasm. Matrix metalloproteinasees (MMPs) are a family of extracellular and membrane-bound proteases capable of degrading the blood-rain barrier (BBB). As such, MMP upregulation following SAH may result in a proinflammatory extravascular environment capable of inciting delayed cerebral vasospasm. This paper presents an overview of MMPs and describes existing data pertinent to delayed cerebral vasospasm.

Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury

1996 ◽  
Vol 84 (2) ◽  
pp. 229-233 ◽  
Author(s):  
Sarah L. Smith ◽  
Heidi M. Scherch ◽  
Edward D. Hall
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Blood Brain Barrier ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Brain Barrier ◽  
Phase Iii ◽  
Blue Dye ◽  
Ferrous Ammonium Sulfate ◽  
Protective Effects ◽  
Blood Brain ◽  
Tirilazad Mesylate

✓ The 21-aminosteroid lipid-peroxidation inhibitor, tirilazad mesylate (U-74006F), recently was shown in a large multinational Phase III clinical trial to decrease mortality and improve neurological recovery in patients 3 months after onset of aneurysmal subarachnoid hemorrhage (SAH). A major tirilazad metabolite in animals and man, U-89678 is formed when the 4–5 double bond in the A-ring is reduced and has been postulated to contribute significantly to tirilazad's neuroprotective effects. In the first experiment of the present study, the authors compared the effects of tirilazad and U-89678 on acute blood-brain barrier (BBB) damage in rats subjected to SAH via injection of 300 µl of autologous nonheparinized blood under the dura of the left cortex. The rats were treated by intravenous administration of either 0.3 or 1.0 mg/kg of tirilazad or U-89678 10 minutes before and 2 hours after SAH, and BBB damage was quantified according to the extravasation of the protein-bound Evans' blue dye into the injured cortex 3 hours post-SAH. The results revealed that 0.3 and 1.0 mg/kg tirilazad significantly reduced SAH-induced BBB damage 35.2% (p < 0.05) and 60.6% (p < 0.0001), respectively, in comparison to treatment with vehicle. The 0.3- and 1.0-mg/kg doses of U-89678 also decreased injury by 39.1% (p < 0.05) and 21.3% (not significant), respectively. In the second experiment, the investigators assessed the relative abilities of tirilazad and U-89678 to protect cultured neurons from iron-induced lipid peroxidative injury. Fetal mouse spinal cord cells were pretreated with 3, 10, or 30 µM tirilazad or U-89678 for 1 hour and then exposed to 200 µM ferrous ammonium sulfate (FAS) for 40 minutes. Cell viability was measured in terms of the uptake of [3H]α-(methyl)-aminoisobutyric acid 45 minutes after the FAS treatment. Both compounds enhanced neuronal survival in a concentration-dependent fashion. Although the two were equally efficacious, U-89678 was slightly more potent than its parent. On the basis of these findings, the authors conclude that the tirilazad metabolite, U-89678, possesses vaso- and neuroprotective properties that are essentially equivalent to the parent 21-aminosteroid. Hence, U-89678 probably contributes to the protective effects of tirilazad in SAH and other insults to the central nervous system.

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