Animal model Of cerebral aneurysms: Pathology and pathogenesis of induced cerebral aneurysms in rats

Saccular cerebral aneurysms are induced in rats treated with ligation of one or both of the common carotid arteries, experimental hypertension, and β-aminopropionitrile feeding. Combination of ligation of the carotid artery and experimental hypertension is the minimal requirement for inducing aneurysms within a few months. β-aminopropionitrile makes the arterial wall fragile, increasing the incidence of aneurysmal development. Induced aneurysms are strongly related to haemodynamic stresses. They ere located on the large arteries at the base of the brain. Some of them apparently originate from the apex of bifurcation. The macroscopic and microscopic findings are generally in accordance with those of spontaneous lesions in man. The results of electron microscope and histochemical studies indicate the participation of leukocytes and their lysosomal enzymes in the development and growth of aneurysms. Adventitial cells are also suggested to be responsible for the growth of aneurysms.     

Basilar artery giant fusiform aneurysms caused by congenital defect of the internal elastic lamina and media

Giant fusiform aneurysms of the basilar artery were found in a 6-year-old boy who subsequently died after rupture of the aneurysm, and in a 64-year-old man who showed signs of ischemia and compression of the brain stem. Autopsy disclosed strikingly similar abnormalities of the wall of the basilar artery, consisting of a defect of the internal elastic lamina and absence of the media. A congenital anomaly may play a role in the pathogenesis of this abnormality, in both young and some elderly patients.     

Rupture of the internal elastic lamina and vascular fragility in stroke-prone spontaneously hypertensive rats

We studied a possible relation between stroke and an enhanced susceptibility to rupture of the arterial internal elastic lamina by comparing stroke-prone spontaneously hypertensive rats with spontaneously hypertensive rats, which have a very low incidence of stroke. We quantified interruptions in the internal elastic lamina in certain arteries and studied the effect of beta-aminopropionitrile, an inhibitor of cross-link formation in collagen and elastic fibers, on rupture of the internal elastic lamina and on mortality in these two substrains. To eliminate any influence of higher blood pressure in the stroke-prone rats on the parameters studied, we used antihypertensive treatment to obtain equivalent blood pressures in the two substrains. Results showed that stroke sensitivity was associated with an enhanced early spontaneous rupture of the internal elastic lamina in the caudal artery, an increased susceptibility to beta-aminopropionitrile-induced rupture of the internal elastic lamina, and earlier mortality, mainly from aortic rupture, under beta-aminopropionitrile treatment. These findings suggest that stroke-prone rats have an enhanced minor connective tissue defect that is expressed by rupture of the internal elastic lamina and may be related, at least in part, to their greater vascular fragility and increased susceptibility to stroke.     

Defects of elastic lamina in middle cerebral artery

Summary Circumscribed defects in the elastic lamina as a possible cause of intracerebral hemorrhage are reported. The abnormality was present in the right middle cerebral artery of a 24-year-old woman. The patient died of large intracerebral hemorrhage which extended into the lateral ventricle on the same side and to the subarachnoid space. In the absence of vascular malformation and secondary degenerative changes attributed to hypertension these defects of the internal elastic lamina associated with the rise of the blood pressure appear to lead ultimately to bleeding.     

Early changes of experimentally induced cerebral aneurysms in rats: scanning electron microscopic study

To obtain information about the early changes of experimentally induced cerebral aneurysms in rats, the luminal surface of branching areas of their cerebral arteries was examined with a scanning electron microscope. At the branching sites of major cerebral arteries in the control animals, the intima just distal to the apex markedly protruded into the lumen forming a linear bank-like intimal pad. Along and distal to this pad, there was a shallow long groove (juxta-apical groove). Such grooves were much deeper and wider in experimental animals than those in the control rats. By studying various stages of early aneurysmal changes, cerebral aneurysms were proven to develop from such grooves. In deep juxta-apical grooves and small aneurysms, round regenerated endothelial cells with a large number of microvilli were diffusely present. Degenerated cells with balloons and craters were observed intermingled with such regenerated cells. Interendothelial gaps were also seen. The present study showed the complex structure of the apex of arterial bifurcation in rats, including bank-like intimal pads. Such complex structures of the branching sites were considered to be responsible for the initiation of cerebral aneurysms due to endothelial injury possibly caused by turbulent flow there.     

Elastic skeleton of intracranial cerebral aneurysms in rats

In an attempt to clarify the developmental mechanism of cerebral aneurysms, we studied the elastic skeleton of experimentally induced cerebral aneurysms in rats under scanning electron microscopy after hot formic acid extraction followed by freeze-drying. We produced cerebral aneurysms in 19 rats by unilaterally ligating the common carotid artery, inducing renal hypertension, and feeding beta-aminopropionitrile fumarate. The first noted change was the loss of folds protruding from the internal elastic lamina. Morphologic changes of the internal elastic lamina, considered to be primarily responsible for aneurysmal formation, occurred after the loss or disintegration of the elastic skeleton of first the intima, then the media. In large aneurysms with thick domes, we found proliferation of elastic lamellae that may reduce the risk of rupture. It seems probable that the complex elastic skeleton of the arterial wall may account for the mechanical properties of the artery and that growth of an aneurysm occurs due to disintegration of the elastic skeleton and not simply to rupture of the internal elastic lamina. We believe that such changes in the elastic skeleton are a property of the functional state of the cells that produce elastin.     

Bilateral hypoplastic internal carotid arteries with multiple cerebral aneurysms

A 60-year-old man with massive subarachnoid hemorrhage is reported. Radiologically, bilateral occlusion of the internal carotid arteries and multiple cerebral aneurysms of the saccular type were detected. Postmortem examination revealed that the internal carotid arteries were markedly diminutive and completely occluded by mesenchymal fibrous tissue. The pathogenesis of the diminutive internal carotid arteries and the cerebral aneurysms were briefly discussed.     

Experimentally induced cerebral aneurysms as model for non-surgical treatment

This article summarizes the results of our experimental studies on the pathogenesis of cerebral aneurysm. Experimentally induced aneurysms in rats and in monkeys resemble those of human cases both in location and in microscopic structure. By studying early changes of aneurysm development, it is proposed that degenerative changes in the intima caused by haemodynamic stress at vessel branches are the basis for aneurysm formation and aneurysms develop, at least partly, because of defective or decreased healing processes there. By giving the experimental animals blood coagulation factor XIII, which is known to enhance wound healing, a significant amount of intimal proliferation occurred in and around aneurysms. Some aneurysms were completely obliterated. This fact may indicate a possibility of non-surgical treatment of the disease in the future. Suggestive findings in human autopsy cases are also presented.     

Hyperbaric oxygen reduces basal lamina degradation after transient focal cerebral ischemia in rats

Hyperbaric oxygen (HBO) has been shown to preserve the integrity of the blood-brain barrier after cerebral ischemia. However, the underlying molecular mechanisms are currently unknown. We examined the effect of HBO on postischemic expression of the basal laminar component laminin-5 and on plasma matrix metalloproteinase-9 (MMP) levels. Wistar rats underwent occlusion of the middle cerebral artery (MCAO) for 2 h. With a delay of 45 min after filament introduction, animals breathed either 100% O2 at 1.0 atmosphere absolute (ata; NBO) or at 3.0 ata (HBO) for 1 h in an HBO chamber. Laminin-5 expression was quantified on immunohistochemical sections after 24 h of reperfusion. Plasma MMP-9 levels were measured using gelatin zymography before MCAO as well as 0, 6 and 24 h after reperfusion. Immunohistochemistry 24 h after ischemia revealed a decrease of vascular laminin-5 staining in the ischemic striatum to 43 +/- 26% of the contralateral hemisphere in the NBO group which was significantly attenuated to 73 +/- 31% in the HBO group. Densitometric analysis of zymography bands yielded significantly larger plasma MMP-9 levels in the NBO group compared to the HBO group 24 h after ischemia. In conclusion, HBO therapy attenuates ischemic degradation of cerebral microvascular laminin-5 and blocks postischemic plasma MMP-9 upregulation.     

Microsuture repair of intra-operative ruptures of cerebral aneurysms of the internal carotid artery

We report on two patients with intra-operative rupture of cerebral aneurysms that were managed by microsuturing. This is one of only a few reports of successful direct repair using suturing. We found that stitching remains an option to repair a tear of a saccular part of an aneurysm and a torn neck of a blister-like aneurysm, and thus this technique can be considered before sacrificing the artery.     

Segmental disruption of internal elastic lamina in spontaneous vertebral artery dissection combined with redundancy of multiple cervical arteries.

A 49-year-old man developed a spontaneous vertebral artery dissection leading to cerebellar and brain stem infarction. Cerebral angiograph demonstrated redundancy, including kinks, loops and coils, in multiple cervicocephalic arteries, in addition to the dissecting artery. Histological examination of the superficial temporal artery revealed segmental disruptions of the internal elastic lamina and intimal abnormalities. These ultrastructural abnormalities may impair vessel wall integrity and predispose to nontraumatic arterial dissection and vascular tortuosity.     

高压氧治疗颅内破裂动脉瘤血管痉挛的疗效探讨

目的探讨高压氧(HBO)综合治疗发生血管痉挛的颅内动脉瘤的效果。方法 80例发生血管痉挛的破裂动脉瘤患者,经过手术或介入治疗后,随机分为高压氧(HBO)组(40例)和对照组(40例),在治疗前、治疗后1个月,超声多普勒记录大脑中动脉平均血流速度来反映血管痉挛情况;治疗前及治疗后36 d,均采用简明精神状态检查量表(MMSE)和日常活动能力量表(ADL)评估认知功能。结果两组病例均出现有严重血管痉挛患者死亡,对照组4例,高压氧组3例;治疗后,高压氧组血管痉挛较对照组低,差异呈显著性(P0.05),MMSE、ADL评分与对照组比较,差异均显著(P0.05)。结论早期联合高压氧的综合治疗可以缓解血管痉挛,改善血管痉挛导致的认知障碍。     

动脉瘤破裂致蛛网膜下腔出血患者死亡原因分析

目的 探讨动脉瘤破裂致蛛网膜下腔出血患者住院期间死亡的原因并提出相应的对策. 方法 回顾性分析江苏大学附属人民医院神经外科自2003年1月至2010年12月收治且住院期间死亡的24例颅内动脉瘤破裂致自发性蛛网膜下腔出血患者的临床资料和死亡原因.结果 死亡原因分别为:颅内再出血11例,其中术前再出血5例,介入栓塞术中出血3例,栓塞术后颅内再次出血3例;术后脑血管痉挛或脑梗死8例,其中早期(术后3d内)CT表现为脑梗死3例,晚期(术后3d后)脑血管痉挛或脑梗死5例;椎动脉瘤栓塞术后呼吸骤停1例;肺部感染3例;肾功能衰竭1例. 结论 颅内再次出血、脑梗死或脑血管痉挛、非神经系统并发症是动脉瘤性蛛网膜下腔出血患者住院期间主要的死亡原因.     

体温升高对大鼠大脑中动脉栓塞模型脑微血管的影响

侧脑体积百分比增加至56.1%±8.4%(P<0.01).术后6h及24h,高温组中单位面积胶原蛋白Ⅳ与层粘连蛋白数量较对照组均下降(P<0.05).结论 脑梗死后体温升高可加重脑微血管破坏,增加脑梗死灶体积,从而加重神经功能损伤.     

动脉栓塞法复制局灶性脑缺血模型的影响因素探讨

目的　提高栓塞法大鼠局灶性脑缺血 (MCAO)模型的成功率和稳定性 ,探讨大鼠体重、栓子体积、插管深度与MCAO模型成功的关系。方法　采用 2× 2× 2析因设计 ,通过检测神经功能缺损评分和脑梗死体积进行分析。结果　栓子体积、插管深度的两水平之间有显著性差异 (P <0 .0 1) ,大鼠体重两水平之间无差异 (P >0 .0 5 ) ;栓子体积和插管深度之间有显著性交互作用 (P <0 .0 5 ) ,其余两两因素之间以及三者之间无交互作用 (P >0 .0 5 )。结论　最佳造模方案是大鼠体重 2 80～ 30 0g、动脉血栓子≈ 1.0 μl、导管插入颈内动脉入口 1.5cm ,该方案制作的MCAO模型成功率高 ,梗死面积稳定 ,重复性好。导管进入大脑中动脉的深度是模型成功的关键。     

Risk factors in intracranial saccular aneurysms Aspects on the formation and rupture of aneurysms, and development of cerebral vasospasm

Intracranial saccular aneurysms have been a well-known clinical and pathological entity for over two centuries. The pathophysiological events that lead to aneurysm formation and rupture are, however, poorly understood. Besides an HLA-associated genetic factor, the most widely accepted risk factors are arterial hypertension, female gender, and increasing age. Some aneurysm patients have a deficient formation of Type III collagen. This seems to interfere with the mechanical integrity of the cerebral arterial wall encouraging aneurysm formation. While some of the risk factors may be involved in the process of aneurysm formation, others may be of importance in the actual aneurysm rupture. Medical and surgical developments have only had a slight impact on mortality rates from aneurysm rupture. The principal cause of death and disability is cerebral arterial spasm. Considerable effort has been expended in investigating the etiology of this phenomenon. Previous studies have failed to yield conclusive evidence of the causative agent(s) or the nature of cerebral artery narrowing. The time course of vasospasm after the onset of subarachnoid hemorrhage is consistent with an immune-mediated response, and more recent observations suggest that immunological processes including activation of the complement system may be involved. Missed minor bleeding episodes may thus be a risk factor for aneurysm patients in respect to the development of cerebral vasospasm.     

Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats

Stroke is a major cause of mortality and disability. The management with thrombolytic therapy has to be initiated within 3-4 h and is associated with limitations like increased risk of intracranial hemorrhage and progression of cerebral injury. Immunophilin inhibitors such as cyclosporine A and tacrolimus have been shown to afford neuroprotection by improving neurological functions and infarct volume in models of ischemic stroke. In the present study, the effect of rapamycin in middle cerebral artery occlusion (MCAo) model of ischemic stroke was evaluated.Ischemic stroke was induced in rats by occluding the MCA using the intraluminal thread. After 1 h of MCAo, animals were administered rapamycin (50, 150, 250 μg/kg, i.p.). After 2 h of occlusion, reperfusion was done. Thirty minutes after reperfusion, animals were subjected to diffusion-weighted magnetic resonance imaging for assessment of protective effect of rapamycin. Twenty-four hours after MCAo, motor performance was assessed, the animals were euthanized and the brains were removed for estimation of malondialdehyde, glutathione, nitric oxide and myeloperoxidase.Significant improvement was observed with rapamycin 150 and 250 μg/kg in percent infarct area, apparent diffusion coefficient and signal intensity as compared to vehicle treated group. Rapamycin treatment ameliorated motor impairment associated with MCAo and significantly reversed the changes in levels of malondialdehyde, glutathione, nitric oxide and myeloperoxidase.The results of the present study indicate neuroprotective effect of rapamycin in MCAo model of stroke. Therefore, rapamycin might be considered as a therapeutic strategy for stroke management.