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.     

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.     

促红细胞生成素缓解蛛网膜下腔出血后脑血管痉挛的实验研究

目的 研究早期全身使用促红细胞生成素(EPO)对蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)的作用并探索其作用机理. 方法 将30只雄性新西兰白兔按照随机数字表法等分为5组:(1)空白组;(2)对照组;(3)SAH组;(4)SAH+安慰剂组;(5)SAH+重组人促红细胞生成素(rHuEPO)组.后三组采用枕大池注血法建立兔SAH模型.注血后48 h采用灌注同定法处死动物,留取基底动脉标本.通过测定基底动脉血管横截面积判断有无CVS,并用原位细胞凋亡检测法(TUNEL)检测血管内皮细胞凋亡情况. 结果 基底动脉横截面积测定的结果 提示空白组和对照组、SAH组和SAH+安慰剂组比较,差异无统计学意义(p>0.05);SAH组和SAH+安慰剂组较空白组和对照组明显缩小,差异有统计学意义(P<0.05)SAH+rHuEPO组较SAH组和SAH+安慰剂组明显增大,差异有统计学意义(P<0.05).但小于空白组和对照组.TUNEL染色显示SAH+rHuEPO组血管内皮细胞凋亡程度较SAH组和SAH+安慰剂组减轻,差异有统计学意义(P<0.05). 结论 早期全身使用rHuEPO能减少兔SAH模型基底动脉血管内皮细胞凋亡并部分缓解CVS.     

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。     

黄芪甲苷对大鼠蛛网膜下腔出血后脑血管痉挛的影响

目的 探讨黄芪甲苷对大鼠蛛网膜下腔出血（SAH）后脑血管痉挛（CVS）的作用。方法 将成年雄性SD大鼠40只随机分为正常组、SAH组、二甲基亚砜组（DMSO,腹腔注射等体积0.1% DMSO）和黄芪甲苷组（腹腔注射用0.1% DMSO助溶的黄芪甲苷溶悬液,2 mg/ml）,每组10只。采用血管内刺破法制作SAH模型。HE染色观察基底动脉形态改变;免疫组化染色分析基底动脉Toll样受体4（TLR4）、核转录因子kappa B（NF-κB）的表达。结果 与正常组相比,SAH组和DMSO组基底动脉管壁明显增厚（P<0.05）,而管腔横截面积明显缩小（P<0.05）;SAH组和DMSO组无明显差异（P>0.05）。黄芪甲苷组基底动脉管壁厚度较DMSO组明显变薄（P<0.05）,管腔横截面积较DMSO组明显增大（P<0.05）。与正常组相比,SAH组和DMSO组基底动脉TLR4、NF-κB阳性率明显增高（P<0.05）,而SAH组和DMSO组无明显差异（P>0.05）。黄芪甲苷组基底动脉TLR4、NF-κB阳性率较DMSO组明显下降（P<0.05）。结论 黄芪甲苷可能通过干预TLR4、NF-κB介导的炎症信号通路来缓解大鼠SAH后CVS。     

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.     

Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm following a subarachnoid hemorrhage injury in canines

Mammalian target of rapamycin (mTOR) pathway is a serine/threonine protein kinase that plays a vital role in regulating growth, proliferation, survival, and protein synthesis among cells. In the present study, we investigated the role of the mTOR pathway following subarachnoid hemorrhage brain injury--specifically investigating its ability to mediate the activation of cerebral vasospasm. Additionally, we investigated whether key signaling pathway molecules such as the mTOR, P70S6K1, and 4E-BP1 play a role in the process. Thirty dogs were randomly divided into 5 groups: sham, SAH (subarachnoid hemorrhage), SAH+DMSO (dimethyl sulfoxide), SAH+Rapamycin and SAH+AZD8055. An established canine double-hemorrhage model of SAH was used by injecting autologous arterial blood into the cisterna magna on days 0 and 2. Angiography was performed at days 0 and 7. Clinical behavior, histology, immunohistochemistry, and Western blot of mTOR, P70S6K1, 4E-BP1 and PCNA (proliferating cell nuclear antigen) in the basilar arteries were examined. In the SAH and SAH+DMSO groups, severe angiographic vasospasm was obtained (34.3±19.8%, 38.4±10.3) compared with that in Sham (93.9±5.0%) respectively. mTOR, P70S6K1, 4E-BP1 and PCNA increased in the sample of spastic basilar arteries (p<0.05). In the SAH+RAPA and SAH+AZD8055 groups, Rapamycin and AZD8055 attenuated angiographic vasospasm (62.3±15.9% and 65.2±10.3%) while improving appetite and activity scores (p<0.05) on days 5 through 7. Rapamycin and AZD8055 significantly reduced the level and expression of mTOR, P70S6K1, 4E-BP1 and PCNA (p<0.05). In conclusion, our study suggests that the mTOR molecular signaling pathway plays a significant role in cerebral vasospasm following SAH, and that inhibition of the mTOR pathway has the potential to become an attractive strategy to treat vasospasm following SAH.     

2-methoxyestradiol reduces cerebral vasospasm after 48 hours of experimental subarachnoid hemorrhage in rats

2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have antiproliferative, antiangiogenic, and antiproapoptotic activities. Mechanistically, 2ME2 has been shown to downregulate hypoxia-inducible factor 1alpha (HIF-1alpha). We hypothesized that hypoxia in the major cerebral arteries might activate a unique signaling pathway, hypoxia-inducible factor-1alpha (HIF-1alpha), to produce or enhance cerebral vasospasm after subarachnoid hemorrhage (SAH). Sprague-Dawley male rats (n = 70) were randomly divided into 5 groups: Sham operated, SAH without treatment, SAH treated with vehicle (DMSO), SAH treated with two HIF-1alpha inhibitors, 2ME2, and D609 (positive control of 2ME2). SAH model was produced by middle cerebral artery perforation. 2ME2 and D609 were administered intraperitoneal at 1 h after SAH; rats were sacrificed after 48 h of SAH. Thick blood clot was observed around basilar artery under arachnoids in all animals except Sham group; severe morphological vasospasm was observed in basilar arteries in SAH and SAH+DMSO rats, and the mild vasospasm in rats treated with 2ME2 and D609; 2ME2 and D609 reduced the activity of HIF-1alpha in the basilar arteries by HIF-1alpha DuoSet ELISA; reduce the expression of HIF-1alpha, VEGF, BNIP3 and PCNA in basilar arteries by Western blotting and immunohistochemical staining. In addition, it decreased the mortality and improved the neurological deficits. In conclusion, 2ME2 is a powerful agent to reduce cerebral vasospasm by inhibiting HIF-1alpha activity and the expression of VEGF as its downstream, suppressing endothelium and VSMCs apoptosis via BNIP3 pathway, and attenuating vasoproliferation.     

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。     

Effect of melatonin on cerebral vasospasm following experimental subarachnoid hemorrhage

OBJECT: The current study was undertaken to determine whether melatonin therapy reverses vasospasm and prevents apoptosis by inhibiting lipid peroxidation in an experimental subarachnoid hemorrhage (SAH) model. MATERIALS AND METHODS: The rabbits were divided into four groups as follows: Group 1, SAH + melatonin (5 mg/kg/i.p. BID) simultaneously with SAH (n = 6); Group 2, SAH + melatonin (5 mg/kg/i.p. BID) treated 2 hours after SAH (n = 6); Group 3, control group (n = 4); Group 4, SAH only (n = 6). Light microscopic examinations of the basilar arteries were performed to demonstrate the pathophysiological changes of the arterial wall with hematoxylin- eosin. Apoptosis: Immunohistology using the ApopTag Peroxidase In Situ Apoptosis Detection Kit was used to demonstrate apoptosis in a cross section of basilary arteries. Apoptotic index was calculated as the number of the immunoreactive nuclei per total number of endothelial cells, and expressed as a percentage. RESULTS: The results of measurements of diameters of the vessels between groups were significantly different (p = 0.028). While basilar arteries of the SAH only group showed 57% constriction, Groups 1 and 2 were calculated as 33 and 26% constriction, respectively, compared with the control group (p < 0.05). And also Groups 1 and 2 showed significant protection of apoptosis compared with Group 4. The difference between the four groups was tested by Kruskal-Wallis test and the significance between the two groups was tested by Mann- Whitney U-test. CONCLUSION: Melatonin with its strong antioxidant effect can prevent SAH-induced vasospasm and apoptosis of endothelial cells of vessels.     

Nonenzymatic derived lipid peroxide, 8-iso-PGF2 alpha, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model

We studied whether 8-iso-PGF2alpha, nonenzymatic arachidonyl peroxide, participated in the pathogenesis of delayed vasospasm using a canine subarachnoid hemorrhage (SAH) model. Fourteen adult mongrel dogs were divided into two groups, two-hemorrhage SAH group (n = 8) and control group (n = 6). The contents of 8-iso-PGF2alpha in CSF, the basilar artery segment, and subarachnoid clot were measured by enzyme immunoassay kit. The CSF 8-iso-PGF2alpha content on Day 7 in the SAH group was 67.9+/-29.9 pg ml(-1) (n = 8), which was significantly higher than 27.1+/-13.8 (n = 8) on Day 0 in the SAH group, and 33.2+/-14.4 pg ml(-1) (n = 5) on Day 7 in the control group. The 8-iso-PGF2alpha content in the basilar artery segment with spasm on Day 7 in the SAH group was 13.5+/-1.9 pg mg(-1) wet weight (n = 8), significantly higher than 8.7+/-1.9 (n = 6) in the control group. The 8-iso-PGF2alpha content in subarachnoid clot was 1.7+/-1.4 ng g(-1) wet weight (n = 8). Significant elevation of the 8-iso-PGF2alpha contents in the CSF and the basilar artery segment occurred on Day 7 in the SAH group. The subarachnoid clot enclosed the basilar artery on Day 7, contained a considerable amount of 8-iso-PGF2alpha. These results suggested that 8-iso-PGF2alpha could play a crucial role in the pathogenesis of the delayed cerebral vasospasm.     

Molecular profile of vascular ion channels after experimental subarachnoid hemorrhage.

Cerebral vasospasm is a transient, delayed constriction of cerebral arteries that occurs after subarachnoid hemorrhage (SAH). Smooth muscle cells show impaired relaxation after SAH, which may be caused by a defect in the ionic mechanisms regulating smooth muscle membrane potential and Ca(2+) permeability. We tested this hypothesis by examining changes in expression of mRNA and protein for ion channels in the basilar arteries of dogs after SAH using quantitative real-time polymerase chain reaction (PCR) and western blotting. SAH was associated with a significant reduction in basilar artery diameter to 41 +/- 8% of pre-SAH diameter (P < 0.001) after 7 days. There was significant downregulation of the voltage-gated K(+) channel K(v) 2.2 (65% reduction in mRNA, P < 0.001; 49% reduction in protein, P < 0.05) and the beta1 subunit of the large-conductance, Ca(2+) - activated K(+) (BK) channel (53% reduction in mRNA, P < 0.02). There was no change in BK beta1 subunit protein. Changes in mRNA levels of K(v) 2.2 and the BK-beta1 subunit correlated with the degree of vasospasm (r(2) = 0.490 and 0.529 respectively, P < 0.05). The inwardly rectifying K(+) (K(ir)) channel K(ir) 2.1 was upregulated (234% increase in mRNA, P < 0.001; 350% increase in protein, P < 0.001). There was no significant change in mRNA expression of L- type Ca(2+) channels and the BK-alpha subunit. These data suggest that K(+) channel dysfunction may contribute to the pathogenesis of cerebral vasospasm.     

Therapeutic potential of peroxisome proliferator-activated receptor γ agonist rosiglitazone in cerebral vasospasm after a rat experimental subarachnoid hemorrhage model

The pathogenesis of cerebral vasospasm is closely associated with inflammation and immune response in arterial walls. Recently, the authors proved the key role of Toll-like receptor (TLR)4 in the development of vasospasm in experimental subarachnoid hemorrhage (SAH) model. Because peroxisome proliferator-activated receptor (PPAR) gamma agonists are identified as effective inhibitors of TLR4 activation, we investigated the anti-inflammation properties of PPAR-gamma agonist rosiglitazone in basilar arteries in a rat experimental SAH model and evaluated the effects of rosiglitazone on vasospasm. Inflammatory responses in basilar arteries were assessed by immunohistochemical staining for intercellular molecule (ICAM)-1 and myeloperoxidase (MPO). Expression of TLR4 was determined by western blot analysis. The degree of cerebral vasospasm was evaluated by measuring the mean diameter and cross-sectional area of basilar arteries. Rosiglitazone suppressed the SAH-induced inflammatory responses in basilar arteries by inhibiting the TLR4 signalling. Furthermore, rosiglitazone could attenuate cerebral vasospasm following SAH. Therefore, we suggested that PPAR-gamma agonists may be potential therapeutic agents for cerebral vasospasm.     

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.     

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。     

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。     

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.     

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。     

细胞凋亡对蛛网膜下腔出血后脑血管痉挛发病机制的研究

脑血管痉挛是蛛网膜下腔出血的重要并发症,也是造成患者死亡和致残最重要的原因.脑血管痉挛已经成为临床研究的热点,尤其是近几年在发病机制、诊断和治疗方面取得了很大进展.凋亡不同于坏死,是细胞的程序性死亡.最近的研究表明蛛网膜下腔出血以后脑血管内皮细胞存在有凋亡的发生,而且此现象在血管痉挛形成机制中起着重要的作用.对脑血管痉挛凋亡机制的深入研究,必将有助于临床上防治脑血管痉挛.