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.     

Metabolic alterations in cerebrospinal fluid from double hemorrhage model of dogs

Even though cerebral vasospasm after subarachnoid hemorrhage (SAH) causes cerebral ischemia or infarction, the metabolic alterations in cerebrospinal fluids (CSF) after SAH have not been studied. This study was undertaken to measure the levels of glucose, lactate, pyruvate and glutamate in CSF from double hemorrhage dog models. Thirty-two mongrel dogs of either sex, weighing 18-24 kg, underwent double hemorrhage by percutaneous needle puncture of the cistema magna and injection of autologous blood on day 0 and day 2. The dogs were then sacrificed on day 3, 5 and 7, after collecting CSF. In another study, the dogs were treated with mitogen-activated protein kinase (MAPK) inhibitors PD98059 and U0126, and caspase-2 and caspase-3 inhibitors from day 3 to day 6 after initial blood injection. CSF was collected on day 7 before dogs were sacrificed. The concentration of glucose, lactate, pyruvate and glutamate in CSF was measured by photometrical method. Compared with CSF collected on day 0, glucose was decreased on days 5-7, lactate was increased on days 2-7, pyruvate was increased on days 2-7, and glutamate was increased on days 3-7 (p < 0.05). In the groups treated with MAPK or caspase inhibitors, most of the metabolic alterations remained unchanged as compared with CSF from untreated dogs. Clinically, caspase inhibitors-2 and -3, and MAPK inhibitor U0126 all failed to prevent vasospasm. MAPK inhibitor PD98059 partially prevented vasospasm. Our data demonstrated a metabolic alteration of glucose, glutamate, lactate and pyruvate in CSF during cerebral vasospasm. This metabolic change in consistent with the time course of cerebral vasospasm. This study suggests that brain energy metabolites and excitative amino acids are altered during cerebral vasospasm.     

Role of p53 and apoptosis in cerebral vasospasm after experimental subarachnoid hemorrhage.

Our previous studies indicate that apoptosis in endothelial cells of major cerebral arteries contributes to cerebral vasospasm after subarachnoid hemorrhage (SAH). This study examined the pathologic roles of tumor suppressor p-53 in cerebral vasospasm using an established dog double-hemorrhage model. Twenty mongrel dogs were divided into four groups: (1) control, (2) SAH, (3) SAH+DMSO (vehicle), and (4) SAH+pifithrin-alpha (PFT) (p53 inhibitor). The p53 inhibitor (200 nmol/L) was injected into the cisterna magna daily from Day 0 through Day 3. Angiogram was performed on Day 0 and Day 7. Western blot, cell proliferation assay, histology, and TUNEL staining were conducted on the basilar arteries collected on Day 7 after SAH. The arterial diameter on Day 7 was 42%+/-4%, 40%+/-5%, and 59%+/-4% for SAH, SAH+DMSO, and SAH+PFT, respectively. In addition, positive staining of TUNEL and increased protein expression of p53, Bax, and PCNA in the basilar artery were observed on Day 7. PFT suppressed apoptosis in endothelial cells and proliferation in smooth muscle cells, and attenuated angiographic vasospasm. In conclusion, p53 may be a key factor in endothelial apoptosis and smooth muscle proliferation after SAH. Inhibition of p53 may potentially reduce or even prevent cerebral vasospasm.     

Haemoglobin and ATP levels in CSF from a dog model of vasospasm.

Haemoglobin and adenosine 5'-triposphate (ATP) released from lysed erythrocytes have been postulated to be responsible for delayed cerebral vasospasm after subarachnoid haemorrhage (SAH). However, the concentrations of haemoglobin and ATP in cerebrospinal fluid (CSF) in patients or in an animal model of vasospasm have not been reported. In this study, 12 mongrel dogs underwent a double blood injection via the cisterna magna on day 0 and 2, after an initial collection of CSF. On day 3, 5 or 7, the dogs were sacrificed after a second collection of CSF. An angiogram was recorded on day 0 and on the day of sacrifice. Results showed that the diameter of the dog's basilar artery was reduced 20% on day 3 (P > 0.05), 35% on day 5 (P < 0.05) and 45% on day 7 (P < 0.05). The concentrations of OxyHb, deOxyHb and MetHb in CSF were increased (P < 0.05), and all peaked on day 3. OxyHb and MetHb remained significantly higher than control (day 0) from day 3 to day 7, while deOxyHb remained at a high level on day 5 but returned to normal on day 7. In contrast, ATP was decreased (P < 0.05) on days 5 and 7 after SAH compared with day 0. The results indicate that haemoglobin might be involved in the development of cerebral vasospasm. The possible role of ATP in vasospasm remains unclear.     

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.     

Protection by lloprost (stable analogue of prostacyclin) of endothelial damage due to chronic vasospasm in dogs: An electron microscope study

Abstract

The resolution of cerebral vasospasm and protection of endothelial damage by lloprost was evaluated with multicisternal injections. Sixteen adult mongrel dogs (18-20 kg) were assigned to one of three experimental groups. All animals received a total amount of 15 ml fresh unheparinized arterial blood via three injections into the cisterna magna. Selective vertebral angiography was performed on day 0 and subsequently blood injections were performed on the 2nd and 3rd days after the first injection. On the 7th day angiography was reperformed to determine the chronic vasospasm. The first group (5 dogs) was the control group and received intrathecal saline which was equal to the amount of saline in which lloprost was diluted. The second group (5 dogs) did not receive any treatment until the 7th day. The third group (6 dogs) received lloprost intrathecally (total 10 fig kg~1). In the first two groups angiographic vasospasm was prominent. For the second group intraarterial lloprost was given on the 7th day in order to evaluate its acute effect. However there was no evidence of resolution of vasospasm. In the third'group, resolution of vasospasm was verified on angiograms. Electron microscope studies of basilar arteries of the first two groups revealed degenerative changes of the endothelial cells which were separated from each other and the elastic lamina was irregularly arranged. In the intrathecal lloprost-treated group there was little thickening in the elastic lamina and the endothelial cells were almost normal in structure. These results can be considered as the evidence of the prophylactic effect of lloprost given by the intrathecal route in the prevention of chronic cerebral vasospasm. [Neurol Res 1995; 17: 301-306]     

血管内一氧化氮合酶基因转染预防脑血管痉挛的实验研究

目的采用血管内基因转染的方法,将重组内皮型一氧化氮合酶(eNOS)基因转染入蛛网膜下腔出血(SAH)后迟发性脑血管痉挛大鼠脑动脉,探讨防治SAH后迟发性脑血管痉挛的新方法。方法首先构建携带eNOS基因的重组腺病毒。采用小脑延髓池二次注血法建立大鼠SAH后迟发性脑血管痉挛模型。通过颈动脉微泵持续滴注方法进行基因转染,并设置对照组。结果第7天采用免疫组化证实重组eNOS基因表达,重组eNOS主要表达于内皮层。第7天显微镜下测定血管内eNOS转染组脑动脉环平均直径较单纯SAH组增大,电镜观察血管痉挛较单纯SAH组减轻。结论通过本研究证实采用颈动脉微泵持续滴注方法可在大鼠脑动脉表达重组eNOS,重组基因主要表达于动脉内皮细胞,可达到缓解SAH后迟发性脑血管痉挛的目的。     

The effect of mexiletine on the level of lipid peroxidation and apoptosis of endothelium following experimental subarachnoid hemorrhage

OBJECTIVE: The role of apoptosis in etiopathogenesis of vasospasm is not clearly understood yet. It is widely accepted that protection of the endothelial cells from the process of apoptosis could have beneficial effects on cerebral vasospasm after subarachnoid hemorrhage (SAH). Mexiletine blocks sodium and calcium channels and activates ATP-sensitive K(+) channels. Moreover, mexiletine is known to have potent antioxidant effects through inhibiting free-radical production. METHODS: Twenty-one rabbits were allocated into three groups randomly. Group I was sham operated group (n=7). SAH occurred but no medication was given to the Group II rabbits (SAH only group) (n=7). Mexiletine (50 mg/kg, b.i.d., i.p.) was administered just before SAH and continued until 48 hours following SAH to the Group III rabbits (Mexiletine treated group) (n=7). The ApopTag peroxidase in situ apoptosis detection kit (Serologicals Corporation, former Intergen) was used to demonstrate apoptosis in a cross section of basillary arteries. Thiobarbituric acid reactive material was used to determine the lipid peroxidation levels. RESULTS: There was a statistically significant difference between lipid peroxidation product levels of the control and SAH only groups (p<0.05). The level of lipid peroxidation production in Mexiletine treated group was significantly lower compared with SAH only group (p<0.05) but not significantly higher than the control group (p>0.05). DISCUSSION: In the present study we investigated the antioxidant action of mexiletine on apoptosis of endothelium following a rabbit SAH model. This experimental study directly suggested that lipid peroxidation is an important step in development of apoptosis in endothelial cells and prevention of structural integrity of endothelial cell should play a beneficial role in attenuation of cerebral vasospasm. Mexiletine treatment prevented the increase in lipid peroxidation and cerebral vasospasm. Examination of endothelial cells by staining specific for apoptosis demonstrated significant protection of cell integrity in the treated group.     

Fasudil,a protein kinase inhibitor,prevents the development of endothelial injury and neutrophil infiltration in a two-haemorrhage canine subarachnoid model

We examined the possible prophylactic potential of fasudil, a protein kinase inhibitor, on the development of endothelial injury and neutrophil infiltration after subarachnoid haemorrhage (SAH). Using the two haemorrhage canine model, fasudil (3 mg/kg) was infused intravenously for 30 min twice daily (days 1–7) and related histological changes were observed by light and electron microscopy. On day 7 characteristic features of the basilar arteries included corrugation of the elastic lamina and endothelial disruption; fasudil inhibited this endothelial damage. Marked neutrophil infiltration into the subarachnoid space was not detected until day 3. On day 7 a large number of neutrophils was observed in the subarachnoid space around all the basilar arteries examined; fasudil treatment significantly inhibited neutrophil infiltration. Our findings suggest that: (1) endothelial injury and neutrophils play a major role in the pathogenesis of cerebral vasospasm; and (2) fasudil inhibited both endothelial damage and neutrophil infiltration, and therefore protein kinase pathways may have a role in these pathological events.     

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.     

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.     

兔蛛网膜下腔出血后脑血管痉挛与脑细胞外液相关性实验研究

目的探讨蛛网膜下腔出血(SAH)后脑血管痉挛的脑代谢变化规律及其与脑血管痉挛程度的相关性。方法 16只成年新西兰白兔随机分为:枕大池2次注生理盐水组(NS组)8只,枕大池2次注血组(SAH组)8只。两组均采用微透析仪于注血(或生理盐水)前、后第1,3,5,7天检测脑细胞外液的葡萄糖、乳酸、丙酮酸、谷氨酸及天冬氨酸的浓度,并计算乳酸与丙酮酸(L/P)比值。经颅多普(TCD)测定两组兔基底动脉血流速度;DSA测定两组兔基底动脉直径。结果与注血前相比,SAH组注血后各指标均有不同程度变化。基底动脉直径显著缩小及血流速度明显增快均于第3天开始(P0.05),并于第5天达高峰;且轻度和中度脑血管痉挛血流速度与管径呈负相关(γ轻=0.673,P0.01;γ中=0.613,P0.01)。乳酸和L/P比值均于第1天明显升高(P0.05),第5天达高峰;且与基底动脉直径变化呈负相关(γ乳酸=0.624,P0.01;γL/P=0.713,P0.01)。谷氨酸第1天显著升高(P0.05),后急剧下降。结论 TCD可通过检测血流速度变化判断兔脑血管痉挛情况,但痉挛程度的判断存在局限性。脑细胞外液乳酸和L/P比值变化可预测兔脑血管痉挛的发生并判断其痉挛程度。     

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。     

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。     

The effect of mexiletine on the level of lipid peroxidation and apoptosis of endothelium following experimental subarachnoid hemorrhage

Abstract

Objective: The role of apoptosis in etiopathogenesis of vasospasm is not clearly understood yet. It is widely accepted that protection of the endothelial cells from the process of apoptosis could have beneficial effects on cerebral vasospasm after subarachnoid hemorrhage (SAH). Mexiletine blocks sodium and calcium channels and activates ATP-sensitive K+ channels. Moreover, mexiletine is known to have potent antioxidant effects through inhibiting free-radical production.

Methods: Twenty-one rabbits were allocated into three groups randomly. Group I was sham operated group (n=7). SAH occurred but no medication was given to the Group II rabbits (SAH only group) (n=7). Mexiletine (50 mg/kg, b.i.d., i.p.) was administered just before SAH and continued until 48 hours following SAH to the Group III rabbits (Mexiletine treated group) (n=7). The ApopTag peroxidase in situ apoptosis detection kit (Serologicals Corporation, former Intergen) was used to demonstrate apoptosis in a cross section of basillary arteries. Thiobarbituric acid reactive material was used to determine the lipid peroxidation levels.

Results: There was a statistically significant difference between lipid peroxidation product levels of the control and SAH only groups (p<0.05). The level of lipid peroxidation production in Mexiletine treated group was significantly lower compared with SAH only group (p<0.05) but not significantly higher than the control group (p>0.05).

Discussion: In the present study we investigated the antioxidant action of mexiletine on apoptosis of endothelium following a rabbit SAH model. This experimental study directly suggested that lipid peroxidation is an important step in development of apoptosis in endothelial cells and prevention of structural integrity of endothelial cell should play a beneficial role in attenuation of cerebral vasospasm. Mexiletine treatment prevented the increase in lipid peroxidation and cerebral vasospasm. Examination of endothelial cells by staining specific for apoptosis demonstrated significant protection of cell integrity in the treated group.     

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.     

CCK-8对家兔SAH后迟发性脑血管痉挛病理变化的影响

目的:利用胆囊收缩素-8(CCK-8)的抗炎作用,观察其对自发性蛛网膜下腔出血后迟发性脑血管痉挛病理改变的影响。方法:雄性新西兰白兔60只随机分为四组(n=15)。①假手术组:仅进行枕大池穿刺和假注血;②SAH组:经家兔枕大池二次注射自体动脉血(0．8ml／kg)制作SAH模型;③SAH+CCK-8组:对SAH模型自day 0开始经枕大池注入 CCK-8(8μg／kg,0．5ml),每日一次直到动物处死;④SAH+生理盐水组:对SAH模型自day 0开始经枕大池注入等量37℃生理盐水,每日一次直到动物处死。各组分别在day 4、day 7和day 14分三批处死动物,每批5只。结果:假手术组动物基底动脉组织结构正常。SAH组动物基底动脉在day4、day7时出现血管痉挛,以day 7时最为显著,day 14血管痉挛得到缓解。CCK-8治疗组动物的血管痉挛程度有不同程度缓解,血管壁NF-κB、TNF-a表达明显减弱,与同时段SAH组和SAH+ 生理盐水组比较以day7时最为显著(P<0．05)。结论:CCK-8对SAH后迟发性脑血管痉挛具有一定的预防作用。     

尼莫地平对蛛网膜下腔出血大鼠额叶转化生长因子-β1表达的影响

目的：探讨尼莫地平对蛛网膜下腔出血（SAH）大鼠额叶转化生长因子-β1（TGF—β1）表达和血管痉挛的影响。方法：枕大池二次注血法制作SAH模型。54只成年健康雄性SD大鼠随机分为对照组（n=6）、SAH组（n=24）和尼莫地平处理组（n=24），其中SAH组和尼莫地平处理组随机均分为1、3、5和7d等4组（n=6）。尼莫地平处理组于二次注血后30min时经股静脉注入尼莫地平2mg／kg，此后每天经腹腔注射尼莫地平2mg／kg。HE染色光镜下观察基底动脉病理学变化，测定内径；免疫组化法检测各组大鼠额叶TGF—β1表达。结果：SAH组和尼莫地平处理组基底动脉内径显著小于对照组（P〈0．01），而SAH组与尼莫地平处理组无显著差异。SAH1d时，TGF—β1表达增加，3d时达高峰，5d和7d时显著低于1d和3d时（P〈0．01），但仍照著高于对照组（P〈0．01）。与SAH组相比，尼莫地平处理组1d和3d时TGF-β1表达无显著差异，5d和7d时显著增加。结论：SAH后额叶TGF—β1表达发生改变，与脑血管痉挛有关，提示TGF-β1参与了脑血管痉挛的病理学过程。尼莫地平可能通过增加SAH后啮组织中TGF-β1表达对缺血脑组织起着保护作用。     

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。