Effects of intrathecal administration of nicardipine and nifedipine on chronic cerebral vasospasm in dogs.

Chronic cerebral vasospasm after subarachnoid haemorrhage (SAH) responds poorly to systemic administration of dihydropyridine calcium antagonists. However, the spastic arteries can be dilated by the topical (intrathecal) administration of the drugs. We examined by angiography the spasmolytic effects of intrathecal (cisternal) administration of nicardipine (0.1 mg 1 ml ) or nifedipine (0.1 mg 1 ml ) on day 7 of SAH made by the two-haemorrhage model in dogs. Both drugs dilated the spastic basilar artery from 15 min till 4 hours after the drug administration. The increase in the diameter of the basilar artery between 1 and 3 hours was statistically significant in both groups. Intrathecal administration of nicardipine which is water soluble, may be useful in the treatment of chronic cerebral vasospasm in patients.     

Impact of cerebral microcirculatory changes on cerebral blood flow during cerebral vasospasm after aneurysmal subarachnoid hemorrhage

BACKGROUND AND PURPOSE: Cerebral microcirculatory changes during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) are still controversial and uncertain. The aim of this study was to investigate the changes of cerebral microcirculation during cerebral vasospasm and to clarify the roles of microcirculatory disturbances in cerebral ischemia by measuring cerebral circulation time (CCT) and regional cerebral blood flow (rCBF). METHODS: In 24 cases with aneurysmal SAH, rCBF studies by single-photon emission CT and digital subtraction angiography (DSA) were performed on the same day between 5 and 7 days after SAH and/or within 4 hours after the onset of delayed ischemic neurological deficits. CCT was obtained by analyzing the time-density curve of the contrast media on DSA images and was divided into proximal CCT, which was the circulation time through the extraparenchymal large arteries, and peripheral CCT, which was the circulation time through the intraparenchymal small vessels. They were analyzed in association with rCBF and angiographic vasospasm. RESULTS: Severe angiographic vasospasm statistically decreased rCBF, and correlation between the degree of angiographic vasospasm and rCBF was seen (r=0.429, P=0.0006). Peripheral CCT showed strong inverse correlation with rCBF (r=-0.767, P<0.0001). Even in none/mild or moderate angiographic vasospasm, prolonged peripheral CCT was clearly associated with decreased rCBF. CONCLUSIONS: In addition to the marked luminal narrowing of large arteries detected as severe angiographic vasospasm, microcirculatory changes detected as prolonged peripheral CCT affected cerebral ischemia during cerebral vasospasm. These results suggested that impaired autoregulatory vasodilation or decreased luminal caliber in intraparenchymal vessels may take part in cerebral ischemia during cerebral vasospasm.     

Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage.

Apoptosis in the endothelium of major cerebral arteries may play a role in the initiation and maintenance of cerebral vasospasm after subarachnoid hemorrhage (SAH). We tested the therapeutic effect of caspase inhibitors on endothelial apoptosis and on cerebral vasospasm in an established dog double-hemorrhage model. Thirty-one mongrel dogs were divided into five groups: control; SAH; SAH treated with vehicle [DMSO]; SAH treated with Ac-DEVD-CHO [a specific caspase-3 inhibitor]; and SAH treated with Z-VAD-FMK [a broad caspase inhibitor]. The inhibitors (100 microM) were injected into the cisterna magna daily from Day 0 through Day 3. Angiography was performed on Day 0 and Day 7. Histology, TUNEL staining, and immunohistochemistry were conducted on basilar arteries collected on Day 7 after SAH. Positive staining of TUNEL, poly(ADP)-ribose polymerase (PARP), caspase-3, and caspase-8 was observed in the endothelial cells of the spastic arteries. Double fluorescence labeling demonstrated co-localization of TUNEL with caspase-3 and TNFalpha receptor-1 (TNFR1). Ac-DEVD-CHO and Z-VAD-FMK prevented endothelial apoptosis and reduced angiographic vasospasm. The mechanism of apoptosis in endothelial cells involves TNFR1 and the caspase-8 and caspase-3 pathways. Caspase inhibitors may have potential in the treatment of cerebral vasospasm.     

Trapidil对蛛网膜下腔出血后脑血管痉挛作用的实验研究

目的 探讨蛛网膜下腔出血（SAH）后脑血管痉挛的发生机制及其可能的治疗方法。方法 利用家兔枕大池内注血构建SAH模型，观察血小板衍生生长因子（PDGF）拮抗剂trapidil对脑基底动脉的影响。结果 脑基底动脉于SAH后48h明显变细；静脉或动脉内持续灌注trapidil 15min（1．5mg／min）后，数字减影脑血管造影（DSA）显示痉挛血管已明显扩张变粗，30min时达高峰。结论 PDGF可能参与脑血管痉挛发生的病理过程，PDGF拮抗剂trapidil可有效缓解实验性SAH后脑血管痉挛，有望成为脑血管痉挛的治疗药物。     

Cisternal sustained release dihydropyridines for subarachnoid hemorrhage

Nimodipine improved outcome in patients with subarachnoid hemorrhage (SAH) although hypotension limited the dose that could be administered systemically. Subarachnoid delivery of nicardipine or nimodipine may be more efficacious. We tested the efficacy of cisternal application of sustained release nicardipine and nimodipine in SAH in monkeys and dogs, respectively. SAH was created in 13 cynomolgus macaques by placement of autologous blood clot around right middle cerebral, anterior cerebral, and internal carotid arteries. Placebo poly-D,L-lactide coglycolide (PLGA), nicardipine PLGA or mibefradil PLGA was inserted in the clots. Catheter and computed tomography angiography (CTA) were performed at baseline and 7 days later (day 7). Cerebral infarction was assessed on day 7 by magnetic resonance imaging. Six dogs underwent baseline angiography and injection of autologous blood plus PLGA or nimodipine-loaded PLGA microparticles into the cisterna magna. Blood injection was repeated 2 days later and angiography 7 and 14 days later. Animals were euthanized and brains were examined histologically. Cerebrospinal fluid and serum nimodipine concentrations were measured. Nicardipine, but not mibefradil PLGA decreased vasospasm in monkeys (paired t-tests) although there was no significant effect on infarctions see on MRI. In dogs, nimodipine-PLGA produced high local concentrations of nimodipine that were associated with reduced basilar artery vasospasm. No untoward histological effects were observed. There was no reduction in microthrombi in animals treated with nimodipine PLGA compared to placebo PLGA. Site-specific, sustained release formulations of dihydropyridines can deliver high concentrations to the cerebrospinal fluid without causing systemic side effects, and may reduce angiographic vasospasm after SAH. Since nimodipine improves outcome in patients with SAH without necessarily preventing vasospasm, further studies are warranted.     

Imatinib mesylate prevents cerebral vasospasm after subarachnoid hemorrhage via inhibiting tenascin-C expression in rats

Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH), but the mechanism remains unknown. The purpose of this study was to assess whether imatinib mesylate (imatinib), an inhibitor of the tyrosine kinases of PDGF receptors (PDGFRs), prevents cerebral vasospasm after SAH in rats, and to elucidate if tenascin-C (TNC), a matricellular protein, is involved in the mechanism. Imatinib (10 or 50 mg/kg body weight) was administered intraperitoneally to rats undergoing SAH by endovascular perforation, and the effects were evaluated by neurobehavioral tests and India-ink angiography at 24-72 h post-SAH. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms in cerebral arteries at 24h post-SAH. Recombinant TNC was administered intracisternally to imatinib-treated SAH rats, and the effects were evaluated by neurobehavioral tests, India-ink angiography and immunohistochemistry at 24 h post-SAH. Both dosages of imatinib significantly prevented post-SAH neurological impairments and vasospasm at 24-72 h. SAH caused PDGFR-β upregulation, PDGFR activation, mitogen-activated protein kinase activation, and TNC upregulation in the spastic cerebral arteries, all of which were significantly suppressed by imatinib treatment. Recombinant TNC reversed the anti-vasospastic effects and protein expression changes by imatinib. This study suggests that imatinib prevents cerebral vasospasm at least partly via inhibiting the upregulation of TNC, implying that TNC may be a new therapeutic target for post-SAH vasospasm.     

蛛网膜下腔出血大鼠基底动脉血小板源性生长因子的表达变化

目的探讨血小板源性生长因子(PDGF)在大鼠蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)血管壁的表达及关系。方法将30只大鼠按照枕大池二次注血的方法建立模型,然后分别于建立模型后的1 d、3 d、5 d、7 d、14 d将大鼠处死,取出基底动脉制作石蜡切片在光镜下观察。采用免疫组化法检测大鼠基底动脉血管壁PDGF的表达水平。结果模型组中PDGF在基底动脉血管壁上的表达,3 d和5 d组最明显,与脑血管痉挛程度的变化是一致的。结论通过枕大池二次注血能够成功的模拟SAH后CVS的发生。PDGF参与了SAH后CVS的过程,并可能起了重要的作用。     

大鼠蛛网膜下腔出血后迟发性脑血管痉挛和血管壁增殖关系的实验研究

目的探讨大鼠蛛网膜下腔出血(SAH)后迟发性脑血管痉挛(DCV)的发生和血管壁增殖之间的关系。方法SD大鼠78只,随机分为SAH组(A组,36只)、生理盐水组(B组,36只)和正常对照组(C组,6只)。A组采用枕大池二次注血法建立SAH模型,B组同法注射等量生理盐水。A、B组分别在首次注血(或生理盐水)后4、7、10、13、16、20d取基底动脉(BA)行HE染色后测量其内径周长、血管壁厚度,观察血管结构改变;免疫组化染色后检测BA增殖细胞核抗原(PCNA)蛋白表达。结果B、C组BA血管结构正常、无DCV发生,A组第4天出现DCV,第7天达到高峰,高峰期持续至第10天,后逐渐缓解,20d基本恢复正常;A组除20d外,各时相有不同程度的内膜增厚皱折、平滑肌层增厚等改变。PCNA在B组及C组BA中无表达,A组各时相均有表达,第7天有较强表达(P<0.05)。结论SAH后DCV的发生和严重程度与血管壁增殖程度密切相关。     

Assessment of cerebral blood flow velocities in pre and post angiographic states with transcranial doppler

The frequency of complications resulting from angiograms reported in the literature vary between 0.2-5 percent. This study was planned to determine the changes in cerebral blood flow velocity before and after angiography, using transcranial doppler in patients of subarachnoid hemorrhage (SAH) undergoing angiographies. Thirty patients with subarachnoid hemorrhage underwent transcranial doppler ultrasonography immediately before and after angiography. Nonionic water-soluble agents were used during the angiograms. The mean flow velocity (MFV) and pulsatility index (PI) at the M1 segment of both middle cerebral arteries was simultaneously measured. When the patients (11 male, 19 female, mean age+SD; 52.45+12.06) were compared according to changes in MFV and PI, pre and post-angiography, there was no statistical difference in MFV (p=0.51 and p=0.99, left and right side respectively), and in PI (p=0.48 and p=0.66) pre and post angiography. Although angiogram can be used to detect vasospasm in SAH, it can also be cause of vasospasm, partially due to the effect of the contrast agent on the cerebral arteries. This study proposes that the angiographic method is still safe and TCD can be used to follow up any possible changes in diameter of cerebral arteries before and after angiography.     

实验性迟发性脑血管痉挛时痉挛动脉的自由基代谢

为探讨蛛网膜下腔出血（ＳＡＨ）后迟发性脑血管痉挛（ＤＣＶＳ）时痉挛动脉的自由基代谢变化。通过了对ＤＣＶＳ时痉挛动脉的自由基含量、自由基清除酶超氧化物岐化酶（Ｃｕ－ＺｎＳＯＤ）与过氧化氢酶（Ｃａｔ）活性以及自由基代谢产物脂质过氧化物（ＬＰＯ）含量的测定。结果显示：（１）痉挛动脉的自由基含量比对照组明显升高（Ｐ＜０．０１）；（２）Ｃｕ－ＺｎＳＯＤ活性明显降低（Ｐ＜０．０５），Ｃａｔ活性明显升高（Ｐ＜０．０１）；（３）ＬＰＯ含量明显升高（Ｐ＜０．０１）。本实验结果证实ＳＡＨ后ＤＣＶＳ时痉挛动脉存在自由基的代谢紊乱，自由基介导的病理作用可能在ＤＣＶＳ发病机理中起重要作用。     

基底动脉中Caspase3、8的表达与蛛网膜下腔出血后脑血管痉挛的关系

目的探讨天冬氨酸特异性半胱氨酸蛋白酶3、8(Caspase3、8)在蛛网膜下腔出血(SAH)后在基底动脉中的表达及其与脑血管痉挛的关系。方法新西兰大白兔36只,随机分成对照组(n=6)和实验组(n=30),后者再随机分为SAH后1、3、5、7、10d等5个亚组,每亚组各6只。采用枕大池二次注血法建立SAH模型,应用免疫组化和末端脱氧核苷酸转移酶介导的dUTP原位切口末端标记法分别检测基底动脉内皮细胞Caspase3、8表达和凋亡。结果凋亡细胞在实验组SAH后第1天出现,第7天凋亡水平达到最高。实验组Caspase3、8表达水平明显高于与对照组(P<0.05)。Caspase3、8的表达在SAH后第1天就可观察致到,第5天和第7天出现强烈表达,第l0天表达明显减弱。结论本结果提示在兔脑血管痉挛的基底动脉中存在细胞凋亡;Caspase3、8可能参与了SAH后脑血管痉挛的发生和发展。     

Therapeutic effect of caspase inhibitors in the prevention of apoptosis and reversal of chronic cerebral vasospasm

One of the important histological changes in cerebral vasospasm after subarachnoid hemorrhage (SAH) is endothelial cell damage, which involves apoptosis. The current study was undertaken to determine whether anti-apoptosis therapy prevents apoptosis and reverses vasospasm in a dog SAH model. Twenty-three mongrel dogs of either sex, weighing 17-25 kg, were subjected to autologous arterial blood injection into the cisterna magna on day 0 and day 2, and sacrificed on day 7. Angiography was performed on day 0 before blood injection and on day 7 before sacrifice. Caspase-2 (Z-VDVAD-FMK, 10 microM) inhibitor, caspase-3 (Z-DEVD-FMK, 10 microM) inhibitor, or vehicle (DMSO) were injected intrathecally from day 2 to day 6. The effects of caspase inhibitors on apoptosis and vasospasm were evaluated by angiography and transmission electron microscopy. The residual diameter of the basilar artery on day 7 in SAH dogs without treatment was 53.4+/-5.5% of the day 0 diameter. Marked damage to the endothelial cells, including apoptotic like changes, was observed in these arteries. Both caspase inhibitors prevented apoptosis in the endothelial cells. Only caspase-3 inhibitor, however, had a near-significant effect on reducing 13.3% of angiographic vasospasm. Higher doses and early treatment, as well as other more potent apoptosis inhibitors, are recommended for future studies.     

实验性蛛网膜下腔出血后脑血管痉挛兔基底动脉Cx43蛋白表达的时相变化

目的 通过建立兔二次蛛网膜下腔出血实验模型,观察兔蛛网膜下腔出血后基底动脉缝隙连接蛋白Cx43表达的时相变化特点,初步探讨蛛网膜下腔出血后脑血管痉挛的形成机制.方法 选择健康新西兰大白兔30只,随机分为5组:正常对照组(n=6)和蛛网膜下腔出血模型组(1d、3d、7d和14d,n=6):建立兔二次蛛网膜下腔出血后脑血管痉挛实验模型,脑血管造影分析基底动脉的直径变化并应用Western Blot检测基底动脉Cx43蛋白的表达变化.对血管直径与Cx43表达变化情况进行相关分析.结果 成功建立兔二次蛛网膜下腔出血模型;脑血管造影显示注血后1d基底动脉即出现痉挛(85.7%±8.6%,P<0.05);7d时达高峰(66.5%±7.6%,P<0.01);14d时仍有痉挛(78.4%±8.2%,P<0.05)但程度较前缓解.Cx43蛋白表达在建立SAH模型后1d(38.6%±5.6%,P<0.05)、3d(50.2%±5.7%,P<0.05)、7d(57.8%±5.3%,P<0.01)、14d(32.4%±3.6%.P<00.05)均升高,其中7d为高峰,14d开始下降.Cx43蛋白表达的时相性变化与SAH后基底动脉直径的时相性变化相关系数为0.914.结论 实验结果 显示蛛网膜下腔出血后兔基底动脉缝隙连接蛋白Cx43的表达发生了时相性变化,并且Cx43蛋白表达强弱与蛛网膜下腔出血后脑血管痉挛程度在时程上存在正相关关系,表明缝隙连接蛋白Cx43可能参与蛛网膜下腔出血后脑血管痉挛的形成.

Abstract：

Objective The study was designed to explore the change of expression of connexin43(Cx43)protien in the model of subarachnoid hemorrhage(SAH)of rabbits,hoping to provide the basis to study the mechanism of cerebral vasospasm(CVS).Methods 30 New Zealand rabbits were divided into 5 groups:SAH group(1d,3d,7d,14d,n=6)and control group(n=6).The model of CVS following SAH was established.Digital subtraction angiography was performed to detect the change of the basilar arteries diameter.The expression of Cx43 protien in basilar arteries tissue at different time points following experimental SAH was examined by using western blotting analysis.The data were statistically analyzed using the bivariate correlations test.Results The model of SAH in rabbits was successfully established.All 30 rabbits were analyzed.Cerebral angiograms on 1d,3d,7d and 14d showed severe narrowing of the BAs,and on 7d showed the most narrowing and on 14d began to Relieve.Western blotting showed that the expression of Cx43 protein were detected in normal rabbit basilar arteries tissue.However,the expression of Cx43 protein increased gradually and significantly in models compared with that of control(P<0.05),which reached peak on 7d(P<0.01)and then decreased on 14d(P<0.05).There was positive correlation between expression of Cx43 and cerebral vasospasm.Conclusions The above results demonstrates at the first time that the Cx43 protein expression is altered after the SAH,and exhibits a time-dependent change.which might be connected with the development of CVS.In summary,our data demonstrates gap junctions may play an important role in the pathogenesis of cerebral vasospasm after SAH.     

Magnetic resonance angiographic assessment after extracranial-intracranial bypass surgery.

Extracranial-intracranial (EC-IC) bypass operation may be performed to augment the distal cerebral circulation. The bypass patency is usually assessed postoperatively with conventional cerebral angiography. Six patients are reported in whom the bypass patency was assessed using magnetic resonance angiography (MRA): Two had intracavernous carotid aneurysms, three had base of skull tumours encompassing the internal carotid artery, and one had occlusion of the right internal carotid artery with poor collateral reserve as confirmed by an acetazolamide stimulation test. Postoperative conventional cerebral angiography was also obtained in three patients for comparison. The MRA correlated reasonably well with conventional cerebral angiography in showing bypass patency, although conventional cerebral angiography was superior in demonstrating small vessels; MRA has the added advantage of showing the relative flow contribution and flow direction under physiological conditions by using targeted presaturation pulses.     

蛛网膜下腔出血后白细胞介素-8基因在兔脑基底动脉中表达的变化

目的探讨实验性蛛网膜下腔出血（SAH）诱发脑血管痉挛时,白细胞介素-8（IL-8）基因在兔脑基底动脉中表达的变化及在诱发脑血管痉挛中的作用。方法35只健康日本大耳白兔随机分为生理盐水组、SAH组。SAH组根据第一次注血时间又分为四组,分别为第一次注血后第1、4、7、14天。以枕大池二次注血法构建迟发性脑血管痉挛模型,采用RT—PCR法观察兔基底动脉中细胞因子IL-8mRNA表达的变化。结果IL-8mRNA在SAH组第一次注血后第4—7天升高,14天趋于正常。SAH组IL-8的表达水平与基底动脉的狭窄程度呈正相关（r=0．642,P〈0．01）。结论IL．8在基底动脉中的表达水平与脑血管痉挛的程度紧密相关,提示IL-8可能作为免疫／炎症因素因素参与了SAH后迟发性脑血管痉挛的发生。     

Neurologic evaluation in a canine model of single and double subarachnoid hemorrhage

The pathophysiology of cerebral vasospasm is complex and multifactorial. The present study sought to identify the degree of correlation between cerebral vasospasm as observed angiographically and clinical evaluation of an animal's neurologic status in the canine model following a single and double experimental subarachnoid hemorrhage (SAH) protocol. Nineteen mongrel dogs underwent single or double experimental SAH by percutaneous needle puncture of the cisterna magna and placement of a subarachnoid blood clot in the basal cistern on day 1 and day 4, respectively. At 72 h after each experimental SAH, vertebral angiography was performed and compared to control angiography. Basilar artery diameter measured at multiple positions was expressed as percentage of control diameter. Clinical evaluation of the animals was performed every day throughout the experiments. To assess the degree of neurologic impairment we developed a coma scale that efficiently estimated motor ability, eye response and eating habits of the animals. Vasoconstriction after experimental SAH reduced mean basilar artery diameter to 79.1% (±5.4) of control diameter following single SAH and to 69.0% (±2.1) of control diameter following double SAH. No changes were observed in the neurologic behavior of the animals throughout the experiment. Since a principal characteristic of human cerebral vasospasm is the close correlation between arterial constriction and neurological deficit, we believe that the canine model of SAH, although good in creating cerebral arterial vasoconstriction, does not fully represent the best model of human cerebral vasospasm.     

大鼠蛛网膜下腔出血后基底动脉病理结构的变化

目的观察大鼠蛛网膜下腔出血(SAH)后基底动脉病理结构的变化。方法采用枕大池二次注血的方法建立SAH大鼠模型,对照组同法注等量的生理盐水。观察两组大鼠基底动脉血管腔内周长、血管壁厚及其超微结构的改变。结果对照组大鼠基底动脉腔内周长、血管壁厚及其超微结构正常,SAH组大鼠血管腔内周长明显缩短,血管壁增厚,内皮细胞变性、内弹力膜增生变性、平滑肌细胞变性。结论大鼠SAH后脑血管痉挛的病理基础是血管内皮细胞通透性增高,内弹力膜增厚,平滑肌细胞变性。     

蛛网膜下腔出血后白细胞介素-8基因在兔脑基底动脉中表达的变化(英文)

目的探讨实验性蛛网膜下腔出血(SAH)诱发脑血管痉挛时,白细胞介素-8(IL-8)基因在兔脑基底动脉中表达的变化及在诱发脑血管痉挛中的作用。方法 35只健康日本大耳白兔随机分为生理盐水组、SAH组。SAH组根据第一次注血时间又分为四组,分别为第一次注血后第1、4、7、14 天。以枕大池二次注血法构建迟发性脑血管痉挛模型,采用RT-PCR法观察兔基底动脉中细胞因子IL-8 mRNA表达的变化。结果 IL-8mRNA在SAH组第一次注血后第4- 7天升高,14 天趋于正常。SAH组IL-8 的表达水平与基底动脉的狭窄程度呈正相关(r = 0.642,P < 0.01)。结论 IL-8在基底动脉中的表达水平与脑血管痉挛的程度紧密相关,提示IL-8可能作为免疫/炎症因素因素参与了SAH 后迟发性脑血管痉挛的发生。     

Intracisternal administration of SB203580, a p38 mitogen-activated protein kinase inhibitor,attenuates cerebral vasospasm via inhibition of tumor-necrosis factor-α

Tumor-necrosis factor-α (TNF-α) is critical to the development of cerebral vasospasm after subarachnoid hemorrhage (SAH). Hence, therapeutic strategies targeting TNF-α can attenuate cerebral vasospasm. This study investigated the effects of SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on TNF-α concentration in the cerebral arteries and the cerebrospinal fluid (CSF) after SAH and on subsequent cerebral vasospasm. Twenty-three rabbits were divided into four groups: (i) control (without SAH), (ii) SAH (SAH only), (iii) dimethylsulfoxide (DMSO, vehicle), and (iv) SB203580. The severity of vasospasm and the immunoreactivities of TNF-α and phosphorylated p38 MAPK in the brain vessels were determined in all animals, and the concentrations of TNF-α in the CSF were also assessed. Severe vasospasm was observed in the rabbits from the SAH and DMSO groups. SB203580 reversed vasospasm after SAH. Lower immunoreactivities of TNF-α and phosphorylated p38 MAPK were found in the basilar artery in the SB203580 group than in the DMSO group. The concentration of TNF-α in the CSF increased after SAH, but treatment with SB203080 after SAH suppressed this increase. Our data show that SB203580 reversed cerebral vasospasm by inhibiting the phosphorylation of p38 MAPK in the basilar artery and by suppressing the increase in TNF-α in the basilar artery and CSF after SAH. SB203580 could therefore potentially be used for the treatment of cerebral vasospasm after SAH.     

Potential role of Ras in cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits

Previous studies have demonstrated that mitogen-activated protein kinase (MAPK) is involved in the pathogenesis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Ras, an upstream regulator of MAPK, may be activated following SAH. The aim of this study was to investigate the role of Ras in cerebral vasospasm in a rabbit model of SAH. We first investigated the time course of Ras and ERK1/2 activation in the basilar artery after SAH. Next, for the time point at which Ras was maximally activated, we assessed the effect of FTI-277 (a Ras farnesyltransferase inhibitor) on cerebral vasospasm. SAH was induced by injecting autologous blood into the cisterna magna on both day 0 and day 2. FTI-277 was injected into the cisterna magna every 24 hours, beginning 30 minutes after blood injection to the last day of the experiment. Elevated expression of Ras-GTP and phosphorylated ERK1/2 was detected in the basilar artery after SAH and expression peaked on day 3. FTI-277 administration resulted in lower Ras-GTP and phosphorylated ERK1/2 levels and markedly attenuated vasospasm in the basilar arteries relative to animals that did not receive FTI-277. Our results suggest that Ras protein is activated in the arterial wall after SAH and contributes to vasospasm development.