Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage

2003 ◽  
Vol 99 (2) ◽  
pp. 383-390 ◽  
Author(s):  
Gen Kusaka ◽  
Hitoshi Kimura ◽  
Ikuyo Kusaka ◽  
Eddie Perkins ◽  
Anil Nanda ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Mitogen Activated Protein Kinase ◽  
Src Tyrosine Kinase ◽  
Content Type ◽  
Upstream Regulator ◽  
Src Inhibitor ◽  
Basilar Arteries ◽  
Fine Print

Object. Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream regulator of MAPK, is involved in cerebral vasospasm. Methods. An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2—treated, and Src inhibitor damnacanthal—treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal. Conclusions. The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.

Suramin-induced reversal of chronic cerebral vasospasm in experimental subarachnoid hemorrhage

2002 ◽  
Vol 97 (1) ◽  
pp. 129-135 ◽  
Author(s):  
Hitoshi Kimura ◽  
Toshinari Meguro ◽  
Ahmed Badr ◽  
John H. Zhang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Disulfonic Acid ◽  
Control Group ◽  
Content Type ◽  
Basilar Arteries ◽  
Blood Injection ◽  
The Mean ◽  
Fine Print

Object. The naphthylsulfonate derivative suramin is an inhibitor of growth factor receptors (receptor tyrosine kinases) and G protein—coupled P2Y receptors. Both types of these receptors are suspected of being involved in cerebral vasospasm after subarachnoid hemorrhage (SAH). In the current study, the authors examined the therapeutic effects of suramin and a selective P2X-receptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), in the reversal of vasospasm in an established canine double-hemorrhage model. Methods. Twenty-four dogs underwent double blood injection into the cisterna magna, with injections given on Days 0 and 2. The dogs were divided randomly into three groups (six animals in each group) to be treated from Days 2 through 6 with the vehicle dimethyl sulfoxide, suramin, or PPADS. An additional group of six dogs received double blood injection without any treatment and served as an SAH control group. The animals were killed on Day 7. Angiography was performed on Day 0 before blood injection and again on Day 7 before the animals were killed. After the death of the animals, the basilar arteries (BAs) were collected for morphological studies and determination of tyrosine kinase expression, and the bloody cerebrospinal fluid (CSF) produced by the hemorrhages was collected for measurement of oxyhemoglobin and adenosine triphosphate (ATP). In the SAH control group, the mean diameter of the BAs on Day 7 was 46.23 ± 6.32% of the value on Day 0 (which served as a reference of 100%). In the DMSO-treated group, the mean residual diameter of the BA was 47.77 ± 0.8% on Day 7 compared with the value on Day 0. Suramin, but not PPADS, increased the residual diameter to 74.02 ± 4.24% on Day 7. On Day 7 the level of ATP in the CSF was decreased and the level of oxyhemoglobin was increased, compared with values measured on Day 0. Suramin, but not PPADS, reduced tyrosine phosphorylation in the spastic BAs. Conclusions. By reducing tyrosine kinase activity, suramin may be useful in the treatment of cerebral vasospasm.

Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage

1997 ◽  
Vol 87 (2) ◽  
pp. 281-286 ◽  
Author(s):  
Aij-Lie Kwan ◽  
Murad Bavbek ◽  
Arco Y. Jeng ◽  
Wieslawa Maniara ◽  
Tomikatsu Toyoda ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Active Form ◽  
Delayed Cerebral Ischemia ◽  
Computer Assisted ◽  
Converting Enzyme ◽  
Content Type ◽  
Basilar Arteries ◽  
Prevention Protocol ◽  
Fine Print

✓ Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy. Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

Prevention of cerebral vasospasm after SAH with a thromboxane synthetase inhibitor, OKY-1581

1982 ◽  
Vol 57 (1) ◽  
pp. 74-82 ◽  
Author(s):  
Tomio Sasaki ◽  
Susumu Wakai ◽  
Takao Asano ◽  
Kintomo Takakura ◽  
Keiji Sano
Keyword(s):  
Cerebral Vasospasm ◽  
Morphological Changes ◽  
Content Type ◽  
Synthetase Inhibitor ◽  
Thromboxane Synthetase Inhibitor ◽  
Thromboxane Synthetase ◽  
Basilar Arteries ◽  
Blood Injection ◽  
Subarachnoid Blood ◽  
Fine Print

✓ The efficacy of thromboxane synthetase inhibitor in the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH) was evaluated in a prolonged experiment using dogs. Changes in the diameter of the basilar artery were followed by angiography, and morphological changes were studied by photomicroscopy and electron microscopy. As a thromboxane synthetase inhibitor, OKY-1581 (sodium-(E)-3-(4(-3-pyridylmethyl)phenyl)-2-methylacrylate)was used. Dogs received intravenous injections of 160 mg of OKY-1581 dissolved in 2 ml of physiological saline immediately after subarachnoid blood injection. Subsequently, the animals received continuous intravenous infusion of the drug at the rate of 4 gm/50 ml/24 hours until sacrifice 4 days after induction of SAH. Control dogs received subarachnoid blood injection without treatment with OKY-1581. Angiographic examination revealed that the late spasm was almost completely abolished by the treatment with OKY-1581. Early spasm was also prevented, but the drug's effect was less prominent than it was on the late spasm. Morphological study revealed degenerative changes in the endothelium and myonecrotic changes in the tunica media following SAH in the basilar arteries of the treated as well as the untreated dogs. However, corrugation of the internal elastic lamina was almost completely absent in the treated dogs. The above results indicate that a disproportionate synthesis of thromboxane A2 plays an important role in the evolution of chronic cerebral vasospasm following SAH, and that drugs such as OKY-1581 that selectively inhibit thromboxane synthetase might be useful in the prevention of vasospasm.

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.

Antisense preproendothelin-oligoDNA therapy for vasospasm in a canine model of subarachnoid hemorrhage

1999 ◽  
Vol 90 (6) ◽  
pp. 1105-1114 ◽  
Author(s):  
Hiroki Ohkuma ◽  
Ian Parney ◽  
Joseph Megyesi ◽  
Aziz Ghahary ◽  
J. Max Findlay
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Dna Sequences ◽  
Combined Treatment ◽  
Canine Model ◽  
Clot Lysis ◽  
Therapeutic Effects ◽  
Causative Role ◽  
Content Type ◽  
Basilar Arteries ◽  
Fine Print

Object. The purpose of this study is twofold: 1) to test antisense genetic techniques used in the prevention of cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH), targeting the endothelin-1 (ET-1) gene; and 2) to determine if fibrinolysis of subarachnoid clot with recombinant tissue plasminogen activator (rtPA) could enhance the effect of antisense treatment.Methods. A total of 39 dogs were studied in this experiment. Placebo (six animals), rtPA (six animals), antisense preproET-1 oligodeoxynucleotide (ASOD; five animals), or rtPA plus ASOD (combined treatment; six animals) was injected into the cisterna magna 30 minutes after a second SAH was induced on the 2nd day of the experiment. The animals were observed until Day 7, when they underwent follow-up angiography and then were killed; their basilar arteries were removed for analysis. Control animals included in this study (two animals in each group) received placebo, rtPA, ASOD, or rtPA plus ASOD without induction of SAH, or rtPA with mismatched (nonsense) preproET-1 oligodeoxynucleotide following SAH. Six additional dogs were analyzed earlier following SAH.Dogs that received placebo developed severe vasospasm (51 ± 8% of baseline caliber). Administration of ASOD alone resulted in a mild reduction in vasospasm (64 ± 13% of baseline caliber) and rtPA alone resulted in a moderate reduction in vasospasm (81 ± 5% of baseline caliber); however, the combined therapy of rtPA plus ASOD almost completely prevented vasospasm (95 ± 6% of baseline caliber), which was significantly different from all other groups (p < 0.05). Morphological analysis of the basilar arteries yielded results similar to angiography with respect to vasospasm severity. The ASOD treatment combined with rtPA resulted in reduced ET-1 expression, as demonstrated by immunohistochemical staining of the arteries, and reduced preproET-1 levels on Day 4, as measured by reverse transcription—polymerase chain reaction. Nonsense DNA sequences had no effect on the vessels.Conclusions. Antisense preproET-1 oligodeoxynucleotide treatment, when combined with clot lysis caused by rtPA, reduced vasospasm in the canine model of SAH, and this effect appeared to be related to reduced ET-1 synthesis. The results of this experiment support a causative role for ET-1 early in the course of vasospasm development in dogs. The apparent additive therapeutic effects of antisense and fibrinolytic treatments could be due to clot lysis, which allows better delivery of oligodeoxynucleotides to arteries within the subarachnoid space.

Subarachnoid hemorrhage—induced upregulation of the 5-HT1B receptor in cerebral arteries in rats

2003 ◽  
Vol 99 (1) ◽  
pp. 115-120 ◽  
Author(s):  
Jacob Hansen-Schwartz ◽  
Natalie Løvland Hoel ◽  
Cang-Bao Xu ◽  
Niels-Aage Svendgaard ◽  
Lars Edvinsson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Real Time ◽  
Cerebral Vasospasm ◽  
Cerebral Arteries ◽  
Specific Treatment ◽  
Content Type ◽  
Sequence Of Events ◽  
Arterial Blood ◽  
Receptor Phenotype ◽  
Fine Print

Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced blood flow in the brain. Inspired by organ culture—induced changes in the receptor phenotype of cerebral arteries, the authors investigated possible changes in the 5-hydroxytryptamine (HT) receptor phenotype after experimental SAH. Methods. Experimental SAH was induced in rats by using an autologous prechiasmatic injection of arterial blood. Two days later, the middle cerebral artery (MCA), posterior communicating artery (PCoA), and basilar artery (BA) were harvested and examined functionally with the aid of a sensitive in vitro pharmacological method and molecularly by performing quantitative real-time reverse transcription—polymerase chain reaction (PCR). In the MCA and BA the 5-HT1B receptor was upregulated, as determined through both functional and molecular analysis. In response to selective 5-HT1 receptor agonists both the negative logarithm of the 50% effective concentration was increased (one log unit in the MCA and one half unit in the BA), as was the agonist's potency (increased by 50% in the MCA and doubled in the BA). In addition, the authors found an approximately fourfold increase in the number of copies of messenger RNA coding for the 5-HT1B receptor as determined by quantitative real-time PCR. In the PCoA no upregulation of the 5-HT1B receptor was observed. Conclusions. Changes in the receptor phenotype in favor of contractile receptors may well represent the end stage in a sequence of events leading from SAH to the actual development of cerebral vasospasm. Insight into the mechanism of upregulation may provide new targets for developing specific treatment against cerebral vasospasm.

Treatment of cerebral vasospasm from subarachnoid hemorrhage with isoproterenol and lidocaine hydrochloride

1973 ◽  
Vol 38 (5) ◽  
pp. 557-560 ◽  
Author(s):  
Thoralf M. Sundt ◽  
Burton M. Onofrio ◽  
John Merideth
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Lidocaine Hydrochloride ◽  
Initial Experience ◽  
Treatment Results ◽  
Content Type ◽  
Major Complications ◽  
Fine Print ◽  
Severe Spasm

✓ Initial experience with intravenously administered isoproterenol and lidocaine hydrochloride in 14 patients with severe spasm from subarachnoid hemorrhage is summarized. All patients were actively deteriorating from progressive spasm without other major complications; 12 of 14 improved, and two died. The method of treatment, results, and rationale for this method of therapy are discussed.

Efficacy of transluminal angioplasty for the management of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage

2000 ◽  
Vol 92 (2) ◽  
pp. 284-290 ◽  
Author(s):  
Richard S. Polin ◽  
Volker A. Coenen ◽  
Carolyn Apperson Hansen ◽  
Peter Shin ◽  
Mustafa K. Baskaya ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Scale Score ◽  
Cerebral Vasospasm ◽  
Medical Management ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Conditional Logistic Regression ◽  
Study Drug ◽  
Transluminal Angioplasty ◽  
Content Type ◽  
Fine Print

Object. Transluminal angioplasty has become a widely used adjunct therapy to medical management of symptomatic cerebral vasospasm following subarachnoid hemorrhage (SAH). Despite anecdotal reports of universal, angiographically confirmed reversal of vasospasm and high rates of clinical improvement, no rigorous examination of the efficacy of this procedure has been conducted. In this study the authors assess the efficacy of the aforementioned procedure.Methods. Thirty-eight patients enrolled as part of the North American trial of tirilazad in aneurysmal SAH underwent transluminal angioplasty for symptomatic cerebral vasospasm. Fifty-three percent of these patients showed good recovery or moderate disability based on their 3-month Glasgow Outcome Scale score.Among the 38 patients who underwent angioplasty, the severity and type of vasospasm, use of papaverine in addition to balloon angioplasty, timing of treatment, and dose of study drug did not have an effect on the outcome. The results of their neurological examinations improved in only four of the 38 patients immediately after the procedure. A conditional logistic regression analysis was performed in which these patients were compared with individuals matched for age, sex, dose of study drug, admission neurological grade, and modified Glasgow Coma Scale score at the time of angioplasty. No effect on favorable outcomes was found for this procedure.Conclusions. Transluminal cerebral angioplasty is very effective in reversing angiographically confirmed vasospasm, and anecdotal reports of its clinical utility are numerous. However, in this report the authors conclude that its superiority to medical management for symptomatic cerebral vasospasm is questionable.

Neuropeptide Y in the primate model of subarachnoid hemorrhage

1992 ◽  
Vol 77 (3) ◽  
pp. 417-423 ◽  
Author(s):  
Ryszard M. Pluta ◽  
Anna Deka-Starosta ◽  
Alois Zauner ◽  
Jay K. Morgan ◽  
Karin M. Muraszko ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neuropeptide Y ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Peripheral Plasma ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Plasma ◽  
Fine Print

✓ The cause of cerebral vasospasm after subarachnoid hemorrhage (SAH) remains unknown. Recently, an association between the potent vasoconstricting peptide, neuropeptide Y, and delayed cerebral vasospasm after SAH has been postulated. This was based on the findings of increased neuropeptide Y levels in the cerebrospinal fluid (CSF) and plasma after SAH in animals and humans. For this study, the primate model of SAH was used to assess the possible role of neuropeptide Y in delayed vasospasm after SAH. Fifteen cynomolgus monkeys underwent placement of a clot of either whole blood or red blood cells in the subarachnoid space around the middle cerebral artery (MCA). Sequential arteriography for assessment of MCA diameter and sampling of blood and CSF for neuropeptide Y were performed: before SAH (Day 0); 7 days after SAH, when signs of delayed cerebral vasospasm peak in this model and in humans; 12 days after SAH; and 28 days after SAH. Subarachnoid hemorrhage did not evoke changes in CSF or plasma levels of neuropeptide Y. Nine monkeys had arteriographic evidence of vasospasm on Day 7, but no change in neuropeptide Y levels occurred in plasma or CSF. In addition, neuropeptide Y levels did not change, even after resolution of vasospasm on Day 12 or Day 28. Neuropeptide Y levels were substantially higher in CSF than in arterial plasma (p < 0.003 at each interval). No correlation was found between neuropeptide Y levels in CSF and in plasma. These results do not confirm a relationship between neuropeptide Y levels in the CSF or peripheral plasma and delayed cerebral vasospasm in SAH.

Natriuretic peptide system and endothelin in aneurysmal subarachnoid hemorrhage

1997 ◽  
Vol 87 (2) ◽  
pp. 275-280 ◽  
Author(s):  
Eelco F. M. Wijdicks ◽  
Wouter I. Schievink ◽  
John C. Burnett
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Natriuretic Peptide ◽  
Cerebral Vasospasm ◽  
Fluid Balance ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Content Type ◽  
Peptide System ◽  
Natriuretic Peptide System ◽  
Fine Print

✓ The natriuretic peptide system consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The system is implicated in the control of body fluid homeostasis, causes natriuresis and diuresis (ANP and BNP), and regulates vascular tone (CNP). A reciprocal relationship between ANP and endothelin (ET) has been suggested, and earlier studies have documented a possible role of ET in cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The authors studied plasma ANP, BNP, CNP, and ET for 6 consecutive days in 13 patients with SAH by using radioimmunoassay. The median admission values for ANP were 31.5 pg/ml (range 16.8–323 pg/ml [normal 15 ± 7 pg/ml]); for BNP, 45.3 pg/ml (range 2.2–80.2 pg/ml [normal 12 ± 9 pg/ml]); for CNP, 7.7 pg/ml (range < 2–20 pg/ml [normal 5.2 ± 3 pg/ml]); and for ET, 11 pg/ml (range 6.5–25.1 pg/ml [normal 7.2 ± 4 pg/ml]). Additional increases (defined as > 100% increase on two consecutive measurements) were noted in ANP (11 patients), BNP (10 patients), and CNP (three patients), and resulted in a negative fluid balance in 10 of the 13 patients. The CNP increased in three of four patients with cerebral vasospasm and in one of nine patients without cerebral vasospasm (Fisher's exact test, p = 0.2). No major fluctuations in plasma ET were noted. In seven patients, the plasma ET level did not increase beyond 10 pg/ml during the days of measurement. In six patients, only an occasional sample showed an increase to a maximum of 25 pg/ml. Changes in BNP, ANP, and CNP were independent of each other. The authors conclude that both plasma ANP and BNP increase after SAH and often result in a negative fluid balance. Plasma ANP and BNP seem differentially regulated in the presence of SAH but not by the level of the plasma ET. The possible role of CNP as a regulatory response to cerebral vasospasm needs further exploration.

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