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1.
小鼠实验性自身免疫性脑脊髓炎的病理变化   总被引:1,自引:0,他引:1  
目的用髓鞘少突胶质细胞糖蛋白多肽(MOG35-55)诱发实验性自身免疫性脑脊髓炎(experi-m ental autoimmune encephalomyelitis,EAE)小鼠模型。方法应用MOG35-55抗原加完全弗氏佐剂免疫C57BL/6小鼠,利用光镜、电镜观察小鼠组织学改变。结果光镜下可见小血管周围炎细胞浸润,呈袖套状改变、血管周围明显脱髓鞘及神经元变性,B ieschowsky银染显示大量轴索肿胀和轴索卵形体的形成,电镜下可见髓鞘结构松散、断裂或融合,包括不同程度的髓鞘重建,脊髓病变广泛,程度重于脑部。结论EAE的病理改变为血管周围炎性细胞浸润、白质脱髓鞘及髓鞘重建。  相似文献   

2.
目的观察实验性自身免疫性脑脊髓炎(EAE)模型小鼠脑组织中丝裂原活化蛋白激酶(MAPKs)表达变化及其与神经损害的关系。方法 C57BL/6小鼠随机分为:EAE组(n=12),采用髓鞘少突胶质细胞糖蛋白35-55多肽(MOG35-55)制备成抗原乳剂免疫小鼠;对照组(n=10),用生理盐水处理小鼠。每日观察两组小鼠的行为学变化,并进行神经功能障碍评分。于高峰期处死小鼠,冰冻处理脑与脊髓,行苏木精-伊红染色观察脊髓组织的炎症细胞浸润,LFB染色观察脊髓组织的髓鞘脱失,蛋白印迹法检测小鼠脑组织中MAPKs表达。分析EAE小鼠神经功能障碍改变与中枢神经组织MAPKs表达量的相关性。结果 EAE组与对照组比较:日均神经行为学评分增加(P0.01);脊髓炎症细胞浸润增多(P0.001),髓鞘脱失增多(P0.001)。P-ERK(42)、P-ERK(44)、P-JNK(54)表达量均增多(P0.01、P0.05、P0.05)。神经功能障碍与P-ERK(42)、P-ERK(44)、P-JNK(54)表达呈正相关。结论 EAE高峰期神经损伤程度与中枢神经组织中的P-ERK(42)、P-ERK(44)、P-JNK(54)表达增加相平行,提示MOG35-55诱导的EAE中枢神经损伤可能与MAPKs所激活的信号通路有关。  相似文献   

3.
目的研究胞浆型磷脂酶A2(cPLA2)在实验性自身免疫性脑脊髓炎(EAE)小鼠发病不同时期的表达。方法8~10周龄的雌性C57BL/6小鼠30只随机分为2组,EAE组(n=20)以髓鞘少突胶质细胞糖蛋白(MOG)35-55多肽加福氏完全佐剂皮下注射诱发EAE,对照组(n=10)则用PBS液取代MOG35-55多肽。用免疫组织化学方法观察EAE小鼠发病后第0天(初期)、第7天(高峰期)及第30天(恢复期)脊髓中cPLA2的表达情况。结果cPLA2在EAE发病初期及高峰期脊髓内表达明显增多,初期在绝大多数血管内皮细胞中表达,高峰期时血管周围炎性细胞中表达相对增多,恢复期时表达下调;对照组小鼠脊髓中则没有cPLA2表达。结论cPLA2在EAE发病不同时期表达存在差异,可能与EAE发生及发展有密切联系。  相似文献   

4.
目的探讨载脂蛋白E(Apo E)拟肽对实验性变态反应性脑脊髓炎(EAE)小鼠基质金属蛋白酶-9(MMP-9)和基质金属蛋白酶组织抑制因子-1(TIMP-1)表达的影响。方法将30只雌性C57BL/6J小鼠随机分为Apo E拟肽组、EAE组和正常组,每组10只小鼠。EAE模型通过以髓鞘少突胶质细胞糖蛋白多肽35-55为抗原诱导。Apo E拟肽组在免疫后第2 d到30 d每隔2 d按5 mg/(kg·d)背部皮下注射Apo E拟肽。EAE组和正常组均以等体积生理盐水替代。免疫后第0~35 d每日对小鼠进行神经功能评分。免疫后第35d解剖小鼠,分离大脑和脊髓并行HE染色。采用免疫组化染色法检测各组小鼠大脑、脑干和脊髓的MMP-9和TIMP-1的表达。结果正常组小鼠均未发病。Apo E拟肽组、EAE组的小鼠全部发病,但各有1只小鼠发病后死亡。Apo E拟肽组与EAE组的发病潜伏期差异无统计学意义(P=0.72)。Apo E拟肽组的神经功能评分在峰值和慢性期(第35 d)均明显低于EAE组(均P0.05)。HE染色示,正常组未见炎症细胞浸润;EAE组小鼠大脑、脑干和脊髓均有不同程度的炎性细胞浸润,以脑干和脊髓较为明显;Apo E拟肽组小鼠CNS炎性细胞浸润相对于EAE组明显减少。EAE组小鼠大脑、脑干和脊髓的MMP-9表达均高于正常组(均P0.05)。Apo E拟肽组小鼠大脑和脊髓的MMP-9表达要明显低于EAE组(均P0.05),其中Apo E拟肽组小鼠中脑和脊髓的MMP-9表达与正常组相比无明显差异(均P0.05)。正常组小鼠脊髓TIMP-1的表达明显高于EAE组和Apo E拟肽组(均P0.05)。而Apo E拟肽组与EAE组小鼠大脑、脑干和脊髓TIMP-1表达的差异均无统计学意义(均P0.05)。结论 Apo E拟肽能通过抑制大脑和脊髓MMP-9的表达改善EAE小鼠的症状。  相似文献   

5.
目的 探讨采用分子克隆技术合成MOGIgd-TrxA融合蛋白免疫C57BL/6小鼠并建立多发性硬化(MS)动物模型实验性自身免疫性脑脊髓炎(EAE)的可行性;通过检测EAE小鼠脾脏中CD4+CD25+调节性T细胞数量初步探讨CD4+CD25+调节性T细胞在EAE发病机制中的作用.方法 (1)分子克隆技术合成MOGIgd-TrxA融合蛋白,纯化、超滤浓缩后用Bradford法测定蛋白浓度.(2)C57BL/6小鼠分为MOGIgd-TrxA组(MOG组)、豚鼠脊髓匀浆组(GPSCH组)、硫氧还蛋白组(TrxA组)及正常对照组(NC组) 4组,12只/组,各组以相应抗原乳剂免疫小鼠制作EAE模型后评估其临床神经功能、组织病理学改变(HE染色和髓鞘Luxol fast blue染色)并评价模型质量. (3)流式细胞仪(FACS)检测小鼠脾脏中CD4+CD25+调节性T细胞百分比.结果 (1)纯化浓缩后MOGIgd-TrxA蛋白纯度达98%左右,浓度约2.3 mg/mL.(2)MOG组小鼠与GPSCH组小鼠在临床神经功能评分等方面差异无统计学意义(P>0.05).两组发病动物组织切片HE染色和髓鞘染色均有不同程度病理改变.(3)CD4+CD25+调节性T细胞占CD4+ T细胞比例MOG组为(4.71±1.61)%,GPSCH组为(1.44±0.65)%,均明显低于正常对照组[(9.22±1.24)%]和TrxA组[(8.97±1.20)%](P<0.01).结论 (1)分子克隆技术合成的MOGIgd蛋白免疫C57BL/6小鼠能够成功诱导出EAE模型,且模型稳定、发病率高,这为进一步研究MS免疫发病机制并采取有效治疗措施提供了一定依据.(2)CD4+CD25+调节性T细胞数量与EAE小鼠临床表现呈相关关系.  相似文献   

6.
实验性自身免疫性脑脊髓炎动物模型的比较   总被引:1,自引:1,他引:0  
目的 比较两种不同品系大鼠及不同免疫原诱发的EAE模型特点。方法 应用MOG35-55、同种脊髓匀浆(DA-SCH)、MBP68-86、豚鼠-MBP为免疫原.分别免疫DA大鼠或Lewis大鼠制备EAE动物模型。观察比较大鼠发病过程、临床评分及病理变化。结果 应用MOG35-55或DA-SCH为免疫原致敏的DA大鼠病程呈现缓解-复发的双相病程.应用MBP68-86、豚鼠-MBP致敏Lewis大鼠而诱发的EAE模型为急性单相病程。豚鼠-MBP诱发的EAE模型发病时间匀齐、发病率最高、病情也最重.应用DA-SCH诱发的EAE模型病情其次重但发病时间不匀齐.MOG及MBP肽段引发的病情相对较轻。各实验组在发病高峰期组织病理变化以炎症反应为主。DA大鼠两个实验组第二次发病期炎症反应相对较轻而脱髓鞘较明显。结论 不同免疫原制备的EAE模型具有不同的特点.可根据研究目的不同选取所需模型。  相似文献   

7.
目的研究地塞米松对实验性自身免疫性脑脊髓炎(EAE)小鼠脑及脊髓组织中IL-17表达水平及脾组织中Th17细胞比例的影响。方法将33只C57BL/6小鼠随机分为对照组、EAE组和地塞米松组。EAE组及地塞米松组小鼠以MOG35-55进行免疫造模。地塞米松组小鼠自免疫当天至处死,隔日给予地塞米松磷酸钠注射液0.07mg·kg~(-1)腹腔注射。对照组及EAE组给予等量生理盐水。观察小鼠的发病情况及神经功能评分。应用苏木精-伊红染色、免疫组织化学染色、实时定量PCR、流式细胞学方法分别检测小鼠中枢神经系统炎症细胞浸润、IL-17阳性细胞表达、IL-17m RNA水平及脾组织Th17细胞比例。结果地塞米松组与EAE组比较,小鼠发病率及神经功能评分明显降低(P0.05)。与对照组比较,EAE组小鼠脑及脊髓组织中炎性病灶数明显增多(P0.05),IL-17阳性细胞数明显增多(P0.05),脊髓组织中IL-17m RNA水平明显升高(P0.05),脾组织Th17细胞比例明显升高(P0.05);与EAE组相比较,地塞米松组小鼠脑、脊髓及脾组织中上述指标明显降低(P0.05)。结论地塞米松可以降低EAE小鼠发病率,减轻发病时神经功能损伤程度以及脑和脊髓内炎性细胞浸润程度,并使IL-17mRNA、蛋白表达水平及Th17细胞比例下降。其神经保护作用可能是通过抑制IL-17/IL-23轴等免疫调节机制而实现。  相似文献   

8.
目的建立不仅与多发性硬化(multiple sclerosis,MS)临床表现、病理特征接近而且病程相似的较为理想的复发一缓解型实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)模型。方法应用髓鞘蛋白脂质蛋白(proteolipid potein,PLP)多肽的两种免疫优势表位肽段PLP139-151和PLP178-191免疫雌性SJL/J小鼠,制作复发缓解型EAE(relapse remitting experimental autoimmune encephalomyelitis,RR—EAE)模型,观察其体重及神经功能评分的变化,应用HE、Luxol fas tblue髓鞘染色等方法观察模型的组织形态学改变。结果两种PLP肽段免疫的小鼠发病均具有缓解一复发的特点,出现明显的神经系统体征;小鼠发病时脑和脊髓组织显示明显的血管鞘形成、卫星现象和炎性细胞浸润以及脱髓鞘改变。结论PLP两种肽段均可诱发RR-EAE模型,这与临床MS的缓解一复发病程更相似,更能表现MS的临床特点,是研究MS的较为理想的动物模型。  相似文献   

9.
目的探讨实验性自身免疫性脑脊髓炎(EAE)小鼠应用二甲双胍(MET)干预,观察MET对EAE小鼠发病情况、神经功能评分的影响及其对小鼠体内Th17细胞反应的作用。方法以MOG35-55免疫雌性C57BL/6小鼠建立EAE模型。随机分成对照组、EAE组和MET治疗组,比较不同组小鼠神经功能评分。在发病高峰期,比较小鼠脊髓中炎性细胞浸润程度,脾细胞中Th17细胞比例,脾细胞培养上清及血清中IL-17A含量以及小鼠脾及脊髓中IL-17A、RORγt mRNA转录水平。结果与EAE组相比,MET治疗组发病率减低(P0.05),疾病严重程度减轻(P0.01);脾细胞中Th17细胞比例降低(P0.01),脾细胞培养上清及血清中IL-17A含量减少(P0.01);脾及脊髓组织中IL-17A、RORγt mRNA转录水平均降低(P0.01)。结论 MET通过抑制外周免疫器官及中枢神经系统的Th17细胞反应而对EAE小鼠起到保护作用。  相似文献   

10.
目的:观察实验性自身免疫性脑脊髓炎(EAE)小鼠模型脑组织和脊髓中脑型肌酸激酶(CK-BB)、钙泵(CaATPase)和钙中性蛋白酶(calpain)的变化。方法:C57BL/6小鼠随机分为:EAE组(n=9),用髓鞘少突胶质细胞糖蛋白35-55多肽(MOG35-55)及完全弗氏佐剂混合抗原乳剂免疫小鼠;对照组(n=5),注射生理盐水。用MOG35-55诱导C57BL/6小鼠,建立(EAE)动物模型(即多发性硬化模型)。观察记录EAE小鼠行为学变化;采用苏木精-伊红染色、LFB髓鞘染色,酶标仪和分光光度计法检测发病高峰期(免疫后第19天)的中枢神经组织病理学变化、CK-BB,CaATPase和calpain酶活性的改变。结果:EAE组与对照组相比:①日均神经功能评分和日累积评分增加(P〈0.01);②苏木精-伊红染色:中枢炎症细胞浸润明显(P〈0.05);③LFB染色:髓鞘脱失较多;④CK-BB和CaATPase活性降低,calpain活性增加(P〈0.05);⑤EAE组小鼠(只)日均累积神经功能评分与CK-BB和CaATPase活性呈负相关(P〈0.05);⑥EAE组小鼠(只)日均累积神经功能评分与calpain酶活性呈正相关(P〈0.05)。结论:EAE高峰期中枢CK-BB和CaATPase活性降低、calpain活性增高是EAE发生发展的后果,提示EAE时中枢能量代谢和CaATPase、calpain的病理性损害。  相似文献   

11.
Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.  相似文献   

12.
Diagnostic Difficulties and Treatment Implications   总被引:1,自引:0,他引:1  
Robert J. Gumnit 《Epilepsia》1987,28(S3):S9-S13
Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.  相似文献   

13.
Cognitive Dysfunction Associated with Antiepileptic Drug Therapy   总被引:7,自引:5,他引:2  
Eileen P.G. Vining 《Epilepsia》1987,28(S2):S18-S22
Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.  相似文献   

14.
B. J. Wilder 《Epilepsia》1987,28(S2):S1-S7
Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.  相似文献   

15.
Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.  相似文献   

16.
Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.  相似文献   

17.
Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity   总被引:5,自引:1,他引:4  
G. Trube  R. Netzer 《Epilepsia》1994,35(S5):S62-S67
Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.  相似文献   

18.
Hepatic Considerations in the Use of Antiepileptic Drugs   总被引:5,自引:4,他引:1  
Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.  相似文献   

19.
Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.  相似文献   

20.
Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.  相似文献   

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