难治性癫痫患者认知状况的临床分析及低剂量伽玛刀照射对癫痫大鼠认知功能影响及机制的研究
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摘要
癫痫是由各种原因引起的脑细胞群异常放电所致的发作性、暂时性的脑功能障碍综合征。癫痫的核心内容是发作,但近年来,癫痫对认知功能的影响越来越引起研究学者的关注。资料显示,约有30%～40%的癫痫患者伴有不同程度的认知功能障碍,不仅严重影响了癫痫患者的生活质量,也给患者家庭及社会带来巨大的负担和压力。
癫痫患者中约20%～30%为药物难治性癫痫,长期反复、多类型频繁的癫痫发作,使难治性癫痫患者认知功能可能更易受到损害。难治性癫痫患者的治疗方法主要为手术,尽管手术治疗可使癫痫发作得到控制,并因减少抗癫痫药物的用量而使患者认知功能获得改善,但另一方面,手术本身又可能对认知功能产生一定程度的损害。因此,重视难治性癫痫患者的认知功能损害,了解其特点及相关的影响因素,手术前后客观评价患者的认知功能状况,对评估手术的综合疗效,选择合理的治疗方案具有重要意义。
随着立体定向放射神经外科的兴起,伽玛刀逐渐成为不开颅治疗颅内病变的重要手段,目前已用于难治性癫痫的治疗。来自临床及基础研究的资料提示,亚坏死剂量的伽玛刀照射可在不损伤靶区组织功能的情况下发挥抗癫痫作用,但机理尚不明确,限制了伽玛刀治疗的进一步优化。能否借助微创的伽玛刀对癫痫进行治疗,达到既能有效控制癫痫发作,又能避免对认知的损害,甚至改善认知功能,有待进一步深入研究。
目前认为,癫痫患者的认知功能障碍与多种因素有关,但确切的生物学机制仍不明了。N-甲基-D-天氡氨酸(N-methyl-D-aspartate, NMDA)受体是离子型谷氨酸受体的一种亚型,因可介导Ca2+内流而触发不同形式的突触可塑性过程,与学习和记忆过程密切相关。细胞内Ca2+升高,可通过钙调素依赖性蛋白激酶(calmodulin dependent protein kinase, CaMK)、细胞外信号调节激酶(Extracellular signal-regulated kinase, ERK)等多种信号途径使环磷酸腺苷反应元件结合蛋白(cAMP response element binding protein, CREB)磷酸化。CREB作为一种重要的核转录因子,可在基因转录水平对学习记忆进行调控。有研究表明,NMDA受体、钙内流、信号通路相关蛋白的变化在癫痫的发生发展及持续过程中均发挥重要作用,但确切机制仍不清楚。伽玛刀是否可在抗癫痫的同时通过干预相关生物分子的变化而发挥保护认知功能的作用,有待深入探讨。
本研究一方面对难治性癫痫患者的认知功能状况及其影响因素进行了分析,并评价了外科手术治疗对癫痫患者认知功能的影响;另一方面通过建立慢性癫痫大鼠模型,应用低剂量伽玛刀对大鼠致痫皮层进行照射,对大鼠学习和记忆能力进行评测,并观察癫痫大鼠皮层及海马NMDA受体亚基、细胞内Ca2+水平、CREB信号通路蛋白表达的变化,以探讨癫痫认知功能障碍的生物学机制及低剂量伽玛刀照射的干预作用。
第一部分难治性癫痫患者认知功能状况及其影响因素的临床分析
目的:探索难治性癫痫患者认知障碍的特点,分析多种因素对认知功能的影响。
方法:选取62例难治性癫痫患者及60名健康者,分别采用瑞文推理能力测验(SPM)、艾森克人格问卷(EPQ)以及90项症状清单(SCL-90)对受试者的认知、个性、心理状况进行评测,分析年龄、病程、发作情况等多种因素对难治性癫痫患者认知功能的影响。
结果:1、难治性癫痫患者的SPM总分以及IQ值均明显偏低,存在智力缺陷的患者占53.2%,比例明显高于对照组(1.7%)(P<0.05);智力中等的患者仅有18例,占29%,比例明显低于对照组(53.3%)(P<0.05)。2、难治性癫痫患者EPQ各量表得分、个性分型所占比例与正常对照无明显差别(P>0.05)。3、难治性癫痫患者多伴有不同程度的心理障碍,SCL-90的总分及躯体化、人际关系、抑郁、焦虑、敌对等因子分均高于对照组,差异均具有显著性意义(P<0.05)。4、除性别外,起病年龄、病程、发作类型、发作频率、发作持续时间、用药种数、SCL-90总分及各因子等因素均与癫痫患者认知功能状况密切相关(P<0.05)。
结论:1、大多难治性癫痫患者的认知功能明显受损,存在智力缺陷的患者比例明显高于正常人群。2、难治性癫痫患者多伴有不同程度的心理障碍,不良的心理健康状况对患者的认知功能具有重要影响。3、起病年龄、病程、发作类型、发作频率、发作持续时间、用药种数是难治性癫痫认知功能损害的重要危险因素。
第二部分外科手术对难治性癫痫患者神经心理及认知功能的影响
目的:探讨外科手术对难治性癫痫患者个性、心理及认知状况的影响。
方法:选取30例手术治疗的难治性癫痫患者,分别采用瑞文推理能力测验(SPM)、艾森克人格问卷(EPQ)以及90项症状清单(SCL-90)对患者手术前后的认知、个性、心理状况进行评测,评估手术的综合疗效。
结果:30例难治性癫痫患者,随访10～24个月,术后无癫痫发作者21例,仅有很少的发作者5例,手术总有效率达86.67%;EPQ各量表得分与手术前无明显差别(P>0.05),而SCL-90的总分及躯体化、人际关系、抑郁、焦虑等因子分均明显低于手术前(P<0.05);SPM评分(总分及IQ值)较术前得到提高者10例(33.33%),下降13例(43.33%),无明显变化7例(23.33%)。进一步对影响癫痫患者术后认知功能的不同因素进行分析,结果表明,术前IQ≥70者术后智力下降率(60%)明显高于术前IQ<70者(26.67%)(P<0.05);左侧手术患者16例,术后智力改善4例(25%),下降8例(50%),左侧手术患者术后智力下降率明显高于右侧手术患者(35.71%)(P<0.05);颞叶及非颞叶手术均可导致术后认知障碍,两者差别并不明显(P>0.05);预后EngleⅠ-Ⅱ级的患者术后智力较术前改善10例(38.46%),下降11例(42.31%);预后EngleⅢ-Ⅳ级患者术后智力改善0例(0%),下降2例(50%);术后随访≤12个月患者术后智力改善3例(25.00%),下降7例(58.33%),术后随访>12个月的患者术后智力改善7例(38.89%),下降6例(33.33%),随着术后时间的延长,患者智力改善率得以增加。
结论:1、外科手术仍是目前治疗难治性癫痫的有效手段,可以比较满意地控制癫痫发作。2、癫痫患者术后心理状态得到不同程度的改善,部分癫痫患者术后认知功能得以改善,但仍有不少比例的患者术后认知功能受到损害。4、左侧手术、术前IQ分值较高、术后发作控制不佳的患者术后更易出现认知功能障碍,颞叶及非颞叶手术均可导致术后认知障碍;术后发作控制良好,随着术后时间的延长,患者的认知功能可得到逐步改善。
第三部分低剂量伽玛刀照射对癫痫大鼠癫痫发作及认知功能的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠的抗癫痫作用及对认知功能的影响。
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③戊四氮(pentylenetetrazole,PTZ)组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,观察并记录各组大鼠伽玛刀照射前、后的癫痫发作情况及脑电图变化。于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测。
结果:大鼠于注射PTZ 12~16次后达到完全点燃标准,点燃成功率为80%。PTZ+伽玛刀组大鼠经低剂量伽玛刀照射后,随观察时间的延长,每周再次注射PTZ,与PTZ组相比,发作程度逐渐减轻,于8W~12W时,发作症状明显减轻(P<0.05),脑电图出现癫痫波的潜伏期明显延长,波幅降低,频率显著减少(P<0.05)。跳台及水迷宫实验结果显示,与对照组比较,PTZ组大鼠跳台反应时间明显延长,潜伏时间缩短,错误次数增多(P<0.05);水迷宫寻找平台逃避潜伏期时间显著延长,游泳距离增加,穿越平台的次数及在原平台象限的游泳距离的百分率减少(P<0.05),提示PTZ组大鼠学习和记忆能力明显下降;而与PTZ组相比,PTZ+伽玛刀组跳台反应时间明显缩短,潜伏时间延长,错误次数减少,水迷宫寻找平台逃避潜伏期时间缩短,游泳距离减少,穿越平台的次数及在原平台象限的游泳距离的百分率显著增加(P<0.05),提示PTZ+伽玛刀组的学习和记忆成绩得到明显改善;而伽玛刀对照组与正常对照组之间没有明显差别(P>0.05)。
结论:1、戊四氮致痫大鼠模型制备成功率较高,可造成癫痫大鼠学习和记忆功能的明显受损,是研究癫痫认知功能障碍的理想模型。2、低剂量伽玛刀照射可控制大鼠癫痫发作,并能改善癫痫对认知功能的损害。
第四部分低剂量伽玛刀照射对癫痫大鼠皮层及海马NMDA受体亚基表达的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠皮层及海马NMDA受体亚基表达的影响。
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③PTZ组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测,后留取脑组织,分别利用免疫组化及免疫蛋白印迹法对大鼠皮层及海马NMDA受体亚基NR1、NR2A和NR2B进行检测。
结果:与正常对照组相比,PTZ组大鼠额叶皮层及海马CA1、CA3区NR1、NR2A和NR2B表达均明显增强,阳性神经元数目及平均吸光度值均明显增加(P<0.05);与PTZ组比较,PTZ+伽玛刀组额叶皮层及海马CA1、CA3区NR1、NR2A和NR2B表达均明显降低,阳性神经元数目及平均吸光度值明显减少(P<0.05);伽玛刀对照组与对照组无明显差别(P>0.05)。
结论:1、PTZ诱发大鼠癫痫发作的机制可能与额叶皮层及海马NR1、NR2A及NR2B亚单位蛋白的表达增强有关,这可能是导致癫痫后出现认知功能障碍的原因之一。2、低剂量伽玛刀照射可引起癫痫大鼠皮层及海马NR1、NR2A和NR2B的表达的减少,这可能是伽玛刀抑制癫痫发作和改善认知功能的分子机制之一。
第五部分低剂量伽玛刀照射对癫痫大鼠皮层及海马神经细胞内游离Ca2+水平的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠皮层及海马神经细胞内游离Ca2+水平的影响
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③PTZ组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测,后急性分离额叶及海马神经元,应用共聚焦显微镜对神经细胞内游离Ca2+水平进行检测。
结果:正常对照组大鼠额叶皮层及海马神经细胞内Ca2+荧光强度处于基础水平;伽玛刀对照组较正常对照组轻度升高,但无统计学意义(P>0.05);与正常对照组相比,PTZ组大鼠额叶皮层及海马神经细胞内Ca2+荧光强度明显升高(P<0.05);PTZ+伽玛刀组额叶皮层及海马神经细胞内Ca2+荧光强度与PTZ组相比明显降低(P<0.05),与正常对照组相比轻度升高,但统计学无显著性差异(P>0.05)。
结论:PTZ致痫大鼠额叶皮层及海马神经细胞内高Ca2+浓度可能参与了癫痫的发病及与认知功能障碍有关,低剂量伽玛刀可能通过影响神经细胞内Ca2+浓度的变化而发挥抗癫痫和改善认知功能的作用。
第六部分低剂量伽玛刀照射对癫痫大鼠皮层及海马CREB信号通路的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠皮层及海马CREB信号通路的影响
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③PTZ组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测,后留取脑组织,分别利用免疫组化及免疫蛋白印迹法对大鼠海马及皮层CREB、α-CaMKⅡ、ERK1/2蛋白表达进行检测。
结果:PTZ组大鼠额叶皮层及海马CREB及α-CaMKⅡ的蛋白表达与正常对照组比较明显减少(P<0.05);PTZ+伽玛刀组较PTZ组CREB及α-CaMKⅡ表达明显增多(P<0.05)。PTZ组大鼠额叶皮层及海马ERK1/2蛋白表达与正常对照组比较明显增加(P<0.05);PTZ+伽玛刀组较PTZ组ERK1/2表达明显减少(P<0.05)。伽玛刀对照组CREB、α-CaMKⅡ及ERK1/2的表达与正常对照组无明显差异(P>0.05)。
结论:1、PTZ诱发癫痫的机制可能与CREB及α-CaMKⅡ蛋白的表达减少,ERK1/2表达增强有关,这可能是导致癫痫后出现认知功能障碍的重要原因。2、低剂量伽玛刀照射可引起大鼠皮层及海马CREB、α-CaMKⅡ及ERK1/2表达的变化,这可能是伽玛刀抑制癫痫发作和改善认知功能的重要的分子机制。
Epilepsy, a brain dysfunctional syndrome caused by abnormal discharge of neurons with many reasons, is characterized by recurrent and temporary disorder of brain functions. Seizure is the core content of epilepsy, but in recent years, the effect of epilepsy on cognitive function has been paid more and more attention. The data showed that about 30~40% of epileptic patients were troubled with various degrees of cognition disorders, which not only seriously affected the patients’life quality, but also brought burden and pressure to their families and society.
About 20~30% of epilepsy is medically intractable. With long-term and recurrent seizures, the patients’cognitive function may be damaged easily. The primary treatment method for patients with intractable epilepsy is operation. Although operation may control seizure and lessen the dosage of antiepileptic drugs, which could improve cognitive function of the patient, at the same time, the operation itself may cause harm to cognition in some degree. Therefore, it is very important to pay attention to cognition disorders of patients with intractable epilepsy and to understand their characteristic and influencing factors. Making an objective assessment of cognitive condition before and after operation has significance to evaluate comprehensive efficacy for operation and select reasonable treatment protocols.
With the development of stereotactic radiosurgery, gamma knife surgery (GKS) has turned to be a promising alternative technology for intracranial lesions without invasive operation, which has been used in treatment of intractable epilepsy. The data from clinical and basic research suggested that, sublethal dose of gamma knife could produce an antiepileptic effect without causing subsequent functional impairment in target areas, but its mechanism remains unclear, which limits further optimization of treatment. Whether gamma knife surgery could treat epilepsy without damage to cognitive function and even improve cognition, needs further study.
At present, cognition disorder of epileptic patients is considered to be related with many factors, but its exact biologic mechanism is still debatable. N-methyl-D-aspartate receptor (NMDAR), a subtype of ionotropic receptors for glutamate, is highly permeable for Ca2+ and could mediate variety of physiological processes, such as synaptic plasticity and synaptic transmission, which is closely associated with learning and memory. The increased intracellular Ca2+ may phosphorylate cAMP response element binding protein (CREB) through several signal transduction pathways such as calmodulin dependent protein kinase (CaMK) and extracellular signal-regulated kinase (ERK). As an important nuclear transcription factor, CREB could regulate the process of learning and memory on gene transcription level. Several study showed that NMDAR, influx of Ca2+ and proteins of signal pathways play important roles in the development and maintenance of epilepsy, but the pathogenic mechanism is unclear. Whether gamma knife surgery could protect cognitive function of epileptic patients by intervening the change of biological molecules, remains to be deeply researched.
Our study, on the one hand, analyzed the cognition and influencing factors of patients with intractable epilepsy, and then evaluated the effect of surgery on their cognitive function; and on the other, through establishing epileptic animal model, we performed low dose of gamma knife irradiation on rats and assessed their abilities of learning and memory, and then we observed the changes of NMDAR, intracellular Ca2+ and proteins of CREB signal pathways in cortex and hippocampus, in order to explore the biologic mechanism of cognition disorders and the effects of gamma knife surgery.
Part 1 Clinical analysis of cognitive condition and influencing factors of patients with intractable epilepsy
Objective: To explore the characteristic of cognition disorders of patients with intractable epilepsy and analyses the effects of various influencing factors on cognitive function.
Methods: 62 patients with intractable epilepsy and 60 healthy persons were chosen in the study. The methods of SPM, EPQ and SCL-90 were used respectively to evaluate their intelligence, personality and mentality, and the effects of various influencing factors on cognitive function were analyzed.
Results: 1.Compared with control group, the total score and IQ of SPM of the epilepsy group decreased significantly. There were 53.2% of mental deficiency in patients with intractable epilepsy, and the proportion was higher than that of control group(1.7%)(P<0.05). There were only 18 patients with middle intelligence, and the proportion was 29%, which was lower than that of control group(53.3%)(P<0.05). 2. There were no significant differences on scores of EPQ and the proportion of personality type in two groups(P>0.05). 3. Many patients with intractable epilepsy had various degrees of psychological barriers. The total score of SCL-90 and the factor scores, such as somatization, interpersonal sensitivity, depression, anxiety and hostility in patients were higher than those in control group. 4. Various factors, including the onset age, course of disease, seizure types, frequency, duration, number of drug, total score and the factor scores of SCL-90 were correlated to the cognitive functions of epileptic patients, except sex(P<0.05).
Conclusion: 1.The cognitive functions of many patients with intractable epilepsy were damaged, and the proportion of patients with mental deficiency was higher significantly than that of healthy people. 2. Many patients with intractable epilepsy had various degrees of psychological barriers, and which had much important effects on the cognitive function. 3. The onset age, course of disease, seizure types, frequency, duration and number of drug were important risky factors of cognitive disorders of epileptic patients.
Part 2 Effects of surgery on neuropsychology and cognitive functions of patients with intractable epilepsy
Objective: To investigate the effects of surgery on neuropsychology and cognitive functions of patients with intractable epilepsy.
Methods: 30 patients with intractable epilepsy were chosen in the study. The methods of SPM, EPQ and SCL-90 were used respectively to evaluate their intelligence, personality and mentality of pre-operation and post-operation, and the comprehensive efficacy of surgery was assessed.
Results: 30 patients were followed up from 10 to 24 months. 21 patients had no seizure after the operation, and 5 patients had only a few seizures. The total effective rate of surgery was 86.67%. There were no significant differences on scores of EPQ between pre-operation and post-operation (P>0.05), while the total score of SCL-90 and the factor scores of somatization, interpersonal sensitivity, depression and anxiety decreased obviously after operation. The total score and IQ in SPM of 10 cases (33.33%) improved significantly after operation, 13 cases (43.33%) declined, and 7 cases (23.33%) remained unchanged. Further analysis showed that, the decline rate of intelligence of patients with preoperative IQ≥70 (60%) was significantly higher than that with IQ<70 (26.67%) after operation, and left side operation (50%) was higher than right side operation (35.71%) (P<0.05). Of 26 patients with EngleⅠ-Ⅱ, 10 (38.46%) improved in the postoperative intelligence, and 11 (42.31%) suffered from a decrease . Of 4 patients with EngleⅢ-Ⅳ, 0 improved in the postoperative intelligence, and 2 (50%) decreased. Temporal lobe and non-temporal lobe operation could both lead to cognitive disorders, and there were no significant differences in two groups (P>0.05).
Conclusion: 1. At present, surgery is still an effective means to treat intractable epilepsy, which could satisfactorily control epileptic seizure. 2. The mental status of epileptic patients could get improved in some degree after operation, and the cognitive function of some patients could become better, but still many patients suffered damage. 4. The patients who were performed left side operation, higher preoperative IQ and not well controlled, could occur easily cognitive disorders after operation. Temporal lobe and non-temporal lobe operation could both lead to cognitive disorders.
Part 3 Effects of low dose of gamma knife irradiation on seizure and cognitive function of epileptic rats
Objective: To investigate the effects of low dose of gamma knife irradiation on seizure and cognitive function of epileptic rats.
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control + GS group;③PTZ group;④PTZ+ GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. After irradiation, the changes of the seizure, behavior and EEG were observed and recorded. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups.
Results: The rats could be kindled completely after 12~16 injections with PTZ, and the successful kindling rate was 80%. After low dose of gamma knife irradiation, the degree of seizures gradually lightened in the rats of PTZ+GS group with time passing by. Compared with PTZ group, on the 8th~12th week, the degree of seizures significantly reduced, the latency of seizure waves prolonged, and the frequency of seizure waves decreased in rats of PTZ+GS group (P<0.05). The step-down test showed that the response time and the number of errors increased, and the latent time decreased significantly in rats of PTZ group (P<0.05). Compared with control group, the Morris water maze test showed that the escape latency and the swimming distance increased significantly (P<0.05), and the number of platform crossings and the percentage of swimming time in platform quadrant decreased obviously in rats of PTZ group (P<0.05). It showed that the abilities of learning and memory of epilepsy rats were obviously impaired. While compared with PTZ group, the results of step-down test and Morris water maze test improved significantly in rats of PTZ+GS group. There were no significant differences in step-down test and Morris water maze test between control group and control + GS group (P>0.05).
Conclusion: 1. PTZ-kindled epileptic model could be easily established, which might lead to damage to the ability of learning and memory of rats, and was an ideal model for investigate cognitive disorders of epilepsy. 2. Low dose of gamma knife irradiation could reduce seizure and improve cognitive function of epileptic rats.
Part 4 Effects of low dose of gamma knife irradiation on the expression of NMDA receptor subunits in cortex and hippocampus of epileptic rats Objective: To examine the effects of low dose of gamma knife irradiation on the expression of NMDA receptor subunits in cortex and hippocampus of epileptic rats.
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control + GS group;③PTZ group;④PTZ+ GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups. And then the rats were killed and immunohistochemstry and western blotting were used to detect the relative levels of NMDAR subunits (NR1, NR2A, and NR2B) in cortex and hippocampus.
Results: Compared with control group, the protein expression of NR1, NR2A and NR2B of the PTZ group increased significantly in the cortex and hippocampus, and the positive neurons and their average absorbance value also increased significantly (P<0.05). Compared with PTZ group, the protein expression of NR1, NR2A and NR2B of the PTZ+GS group decreased significantly in the cortex and hippocampus (P<0.05). There were no significant differences between control group and control+GS group (P>0.05).
Conclusion: 1. The mechanism of PTZ induced epilepsy might be associated with increased expression of NR1, NR2A and NR2B in the cortex and hippocampus, which also might be one of reasons to cause cognitive disorders after epileptic seizures. 2. Low dose of gamma knife irradiation could decrease expression of NR1, NR2A and NR2B in the cortex and hippocampus of epileptic rats, which might represent a possible mechanism underlying the therapeutic effects of Gamma Knife irradiation. Part 5 Effects of low dose of gamma knife irradiation on cytoplasmic calcium level of neurons in cortex and hippocampus of epileptic rats
Objective: To investigate the effects of low dose of gamma knife irradiation on cytoplasmic calcium level of neurons in cortex and hippocampus of epileptic rats.
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control + GS group;③PTZ group;④PTZ+ GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups. After that, the rats were killed and neurons of cortex and hippocampus were acutely isolated and loaded with fluorescent dye fluo-3. And then the fluorescence intensity of cytoplasmic calcium was measured with laser scanning confocal microscopy (LSCM).
Results: The cytoplasmic calcium fluorescence intensity of neurons in cortex and hippocampus in control group was in the basic level, and there was no significant difference between the control group and gamma knife control group (P>0.05). The cytoplasmic calcium fluorescence intensity of PTZ group increased significantly compared with control group (P<0.05), and that of PTZ+GS group were significantly lower than PTZ group (P<0.05). There was no significant difference between control+GS group and control group (P>0.05).
Conclusion: The increased cytoplasmic calcium fluorescence intensity of neurons in cortex and hippocampus might be associated with the mechanism of PTZ induced epilepsy and cognitive disorders after seizures. Low dose of gamma knife irradiation might control seizure and improve cognitive function through regulating calcium level of neurons.
Part 6 Effects of low dose of gamma knife irradiation on CREB signal pathways in cortex and hippocampus of epileptic rats
Objective: To observe the effects of low dose of gamma knife irradiation on CREB signal pathways in cortex and hippocampus of epileptic rats
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control+GS group;③PTZ group;④PTZ+GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups. And then the rats were killed and immunohistochemstry and western blotting were used to detect the expression of CREB,α-CaMKⅡand ERK1/2 in cortex and hippocampus.
Results: Compared with control group, the protein expression of CREB andα-CaMKⅡof the PTZ group decreased, and ERK1/2 increased significantly in the cortex and hippocampus(P<0.05). Compared with PTZ group, the protein expression of CREB andα-CaMKⅡof the PTZ+GS group increased, and ERK1/2 declined significantly in the cortex and hippocampus (P<0.05). There were no significant differences of expression of CREB,α-CaMKⅡand ERK1/2 between control group and control+GS group (P>0.05).
Conclusion: 1. The mechanism of PTZ induced epilepsy might be associated with increased expression of CREB andα-CaMKⅡ, and decreased expression of ERK1/2 in the cortex and hippocampus, which also might be the important cause of cognitive disorders after epileptic seizures. 2. Low dose of gamma knife irradiation could regulate the expression of CREB,α-CaMKⅡand ERK1/2 in the cortex and hippocampus of epileptic rats, which might represent a possible mechanism underlying the therapeutic effects of Gamma Knife irradiation.
癫痫患者中约20%～30%为药物难治性癫痫,长期反复、多类型频繁的癫痫发作,使难治性癫痫患者认知功能可能更易受到损害。难治性癫痫患者的治疗方法主要为手术,尽管手术治疗可使癫痫发作得到控制,并因减少抗癫痫药物的用量而使患者认知功能获得改善,但另一方面,手术本身又可能对认知功能产生一定程度的损害。因此,重视难治性癫痫患者的认知功能损害,了解其特点及相关的影响因素,手术前后客观评价患者的认知功能状况,对评估手术的综合疗效,选择合理的治疗方案具有重要意义。
随着立体定向放射神经外科的兴起,伽玛刀逐渐成为不开颅治疗颅内病变的重要手段,目前已用于难治性癫痫的治疗。来自临床及基础研究的资料提示,亚坏死剂量的伽玛刀照射可在不损伤靶区组织功能的情况下发挥抗癫痫作用,但机理尚不明确,限制了伽玛刀治疗的进一步优化。能否借助微创的伽玛刀对癫痫进行治疗,达到既能有效控制癫痫发作,又能避免对认知的损害,甚至改善认知功能,有待进一步深入研究。
目前认为,癫痫患者的认知功能障碍与多种因素有关,但确切的生物学机制仍不明了。N-甲基-D-天氡氨酸(N-methyl-D-aspartate, NMDA)受体是离子型谷氨酸受体的一种亚型,因可介导Ca2+内流而触发不同形式的突触可塑性过程,与学习和记忆过程密切相关。细胞内Ca2+升高,可通过钙调素依赖性蛋白激酶(calmodulin dependent protein kinase, CaMK)、细胞外信号调节激酶(Extracellular signal-regulated kinase, ERK)等多种信号途径使环磷酸腺苷反应元件结合蛋白(cAMP response element binding protein, CREB)磷酸化。CREB作为一种重要的核转录因子,可在基因转录水平对学习记忆进行调控。有研究表明,NMDA受体、钙内流、信号通路相关蛋白的变化在癫痫的发生发展及持续过程中均发挥重要作用,但确切机制仍不清楚。伽玛刀是否可在抗癫痫的同时通过干预相关生物分子的变化而发挥保护认知功能的作用,有待深入探讨。
本研究一方面对难治性癫痫患者的认知功能状况及其影响因素进行了分析,并评价了外科手术治疗对癫痫患者认知功能的影响;另一方面通过建立慢性癫痫大鼠模型,应用低剂量伽玛刀对大鼠致痫皮层进行照射,对大鼠学习和记忆能力进行评测,并观察癫痫大鼠皮层及海马NMDA受体亚基、细胞内Ca2+水平、CREB信号通路蛋白表达的变化,以探讨癫痫认知功能障碍的生物学机制及低剂量伽玛刀照射的干预作用。
第一部分难治性癫痫患者认知功能状况及其影响因素的临床分析
目的:探索难治性癫痫患者认知障碍的特点,分析多种因素对认知功能的影响。
方法:选取62例难治性癫痫患者及60名健康者,分别采用瑞文推理能力测验(SPM)、艾森克人格问卷(EPQ)以及90项症状清单(SCL-90)对受试者的认知、个性、心理状况进行评测,分析年龄、病程、发作情况等多种因素对难治性癫痫患者认知功能的影响。
结果:1、难治性癫痫患者的SPM总分以及IQ值均明显偏低,存在智力缺陷的患者占53.2%,比例明显高于对照组(1.7%)(P<0.05);智力中等的患者仅有18例,占29%,比例明显低于对照组(53.3%)(P<0.05)。2、难治性癫痫患者EPQ各量表得分、个性分型所占比例与正常对照无明显差别(P>0.05)。3、难治性癫痫患者多伴有不同程度的心理障碍,SCL-90的总分及躯体化、人际关系、抑郁、焦虑、敌对等因子分均高于对照组,差异均具有显著性意义(P<0.05)。4、除性别外,起病年龄、病程、发作类型、发作频率、发作持续时间、用药种数、SCL-90总分及各因子等因素均与癫痫患者认知功能状况密切相关(P<0.05)。
结论:1、大多难治性癫痫患者的认知功能明显受损,存在智力缺陷的患者比例明显高于正常人群。2、难治性癫痫患者多伴有不同程度的心理障碍,不良的心理健康状况对患者的认知功能具有重要影响。3、起病年龄、病程、发作类型、发作频率、发作持续时间、用药种数是难治性癫痫认知功能损害的重要危险因素。
第二部分外科手术对难治性癫痫患者神经心理及认知功能的影响
目的:探讨外科手术对难治性癫痫患者个性、心理及认知状况的影响。
方法:选取30例手术治疗的难治性癫痫患者,分别采用瑞文推理能力测验(SPM)、艾森克人格问卷(EPQ)以及90项症状清单(SCL-90)对患者手术前后的认知、个性、心理状况进行评测,评估手术的综合疗效。
结果:30例难治性癫痫患者,随访10～24个月,术后无癫痫发作者21例,仅有很少的发作者5例,手术总有效率达86.67%;EPQ各量表得分与手术前无明显差别(P>0.05),而SCL-90的总分及躯体化、人际关系、抑郁、焦虑等因子分均明显低于手术前(P<0.05);SPM评分(总分及IQ值)较术前得到提高者10例(33.33%),下降13例(43.33%),无明显变化7例(23.33%)。进一步对影响癫痫患者术后认知功能的不同因素进行分析,结果表明,术前IQ≥70者术后智力下降率(60%)明显高于术前IQ<70者(26.67%)(P<0.05);左侧手术患者16例,术后智力改善4例(25%),下降8例(50%),左侧手术患者术后智力下降率明显高于右侧手术患者(35.71%)(P<0.05);颞叶及非颞叶手术均可导致术后认知障碍,两者差别并不明显(P>0.05);预后EngleⅠ-Ⅱ级的患者术后智力较术前改善10例(38.46%),下降11例(42.31%);预后EngleⅢ-Ⅳ级患者术后智力改善0例(0%),下降2例(50%);术后随访≤12个月患者术后智力改善3例(25.00%),下降7例(58.33%),术后随访>12个月的患者术后智力改善7例(38.89%),下降6例(33.33%),随着术后时间的延长,患者智力改善率得以增加。
结论:1、外科手术仍是目前治疗难治性癫痫的有效手段,可以比较满意地控制癫痫发作。2、癫痫患者术后心理状态得到不同程度的改善,部分癫痫患者术后认知功能得以改善,但仍有不少比例的患者术后认知功能受到损害。4、左侧手术、术前IQ分值较高、术后发作控制不佳的患者术后更易出现认知功能障碍,颞叶及非颞叶手术均可导致术后认知障碍;术后发作控制良好,随着术后时间的延长,患者的认知功能可得到逐步改善。
第三部分低剂量伽玛刀照射对癫痫大鼠癫痫发作及认知功能的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠的抗癫痫作用及对认知功能的影响。
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③戊四氮(pentylenetetrazole,PTZ)组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,观察并记录各组大鼠伽玛刀照射前、后的癫痫发作情况及脑电图变化。于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测。
结果:大鼠于注射PTZ 12~16次后达到完全点燃标准,点燃成功率为80%。PTZ+伽玛刀组大鼠经低剂量伽玛刀照射后,随观察时间的延长,每周再次注射PTZ,与PTZ组相比,发作程度逐渐减轻,于8W~12W时,发作症状明显减轻(P<0.05),脑电图出现癫痫波的潜伏期明显延长,波幅降低,频率显著减少(P<0.05)。跳台及水迷宫实验结果显示,与对照组比较,PTZ组大鼠跳台反应时间明显延长,潜伏时间缩短,错误次数增多(P<0.05);水迷宫寻找平台逃避潜伏期时间显著延长,游泳距离增加,穿越平台的次数及在原平台象限的游泳距离的百分率减少(P<0.05),提示PTZ组大鼠学习和记忆能力明显下降;而与PTZ组相比,PTZ+伽玛刀组跳台反应时间明显缩短,潜伏时间延长,错误次数减少,水迷宫寻找平台逃避潜伏期时间缩短,游泳距离减少,穿越平台的次数及在原平台象限的游泳距离的百分率显著增加(P<0.05),提示PTZ+伽玛刀组的学习和记忆成绩得到明显改善;而伽玛刀对照组与正常对照组之间没有明显差别(P>0.05)。
结论:1、戊四氮致痫大鼠模型制备成功率较高,可造成癫痫大鼠学习和记忆功能的明显受损,是研究癫痫认知功能障碍的理想模型。2、低剂量伽玛刀照射可控制大鼠癫痫发作,并能改善癫痫对认知功能的损害。
第四部分低剂量伽玛刀照射对癫痫大鼠皮层及海马NMDA受体亚基表达的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠皮层及海马NMDA受体亚基表达的影响。
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③PTZ组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测,后留取脑组织,分别利用免疫组化及免疫蛋白印迹法对大鼠皮层及海马NMDA受体亚基NR1、NR2A和NR2B进行检测。
结果:与正常对照组相比,PTZ组大鼠额叶皮层及海马CA1、CA3区NR1、NR2A和NR2B表达均明显增强,阳性神经元数目及平均吸光度值均明显增加(P<0.05);与PTZ组比较,PTZ+伽玛刀组额叶皮层及海马CA1、CA3区NR1、NR2A和NR2B表达均明显降低,阳性神经元数目及平均吸光度值明显减少(P<0.05);伽玛刀对照组与对照组无明显差别(P>0.05)。
结论:1、PTZ诱发大鼠癫痫发作的机制可能与额叶皮层及海马NR1、NR2A及NR2B亚单位蛋白的表达增强有关,这可能是导致癫痫后出现认知功能障碍的原因之一。2、低剂量伽玛刀照射可引起癫痫大鼠皮层及海马NR1、NR2A和NR2B的表达的减少,这可能是伽玛刀抑制癫痫发作和改善认知功能的分子机制之一。
第五部分低剂量伽玛刀照射对癫痫大鼠皮层及海马神经细胞内游离Ca2+水平的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠皮层及海马神经细胞内游离Ca2+水平的影响
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③PTZ组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测,后急性分离额叶及海马神经元,应用共聚焦显微镜对神经细胞内游离Ca2+水平进行检测。
结果:正常对照组大鼠额叶皮层及海马神经细胞内Ca2+荧光强度处于基础水平;伽玛刀对照组较正常对照组轻度升高,但无统计学意义(P>0.05);与正常对照组相比,PTZ组大鼠额叶皮层及海马神经细胞内Ca2+荧光强度明显升高(P<0.05);PTZ+伽玛刀组额叶皮层及海马神经细胞内Ca2+荧光强度与PTZ组相比明显降低(P<0.05),与正常对照组相比轻度升高,但统计学无显著性差异(P>0.05)。
结论:PTZ致痫大鼠额叶皮层及海马神经细胞内高Ca2+浓度可能参与了癫痫的发病及与认知功能障碍有关,低剂量伽玛刀可能通过影响神经细胞内Ca2+浓度的变化而发挥抗癫痫和改善认知功能的作用。
第六部分低剂量伽玛刀照射对癫痫大鼠皮层及海马CREB信号通路的影响
目的:观察低剂量伽玛刀照射对癫痫大鼠皮层及海马CREB信号通路的影响
方法:根据动物是否致痫及接受伽玛刀照射,将60只大鼠分为4组:①对照组;②伽玛刀对照组;③PTZ组;④PTZ+伽玛刀组。大鼠按35mg/kg经腹腔注射PTZ溶液制备癫痫动物模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,照射中心剂量为30Gy,于伽玛刀照射后12周,应用跳台及水迷宫对各组大鼠学习和记忆能力进行评测,后留取脑组织,分别利用免疫组化及免疫蛋白印迹法对大鼠海马及皮层CREB、α-CaMKⅡ、ERK1/2蛋白表达进行检测。
结果:PTZ组大鼠额叶皮层及海马CREB及α-CaMKⅡ的蛋白表达与正常对照组比较明显减少(P<0.05);PTZ+伽玛刀组较PTZ组CREB及α-CaMKⅡ表达明显增多(P<0.05)。PTZ组大鼠额叶皮层及海马ERK1/2蛋白表达与正常对照组比较明显增加(P<0.05);PTZ+伽玛刀组较PTZ组ERK1/2表达明显减少(P<0.05)。伽玛刀对照组CREB、α-CaMKⅡ及ERK1/2的表达与正常对照组无明显差异(P>0.05)。
结论:1、PTZ诱发癫痫的机制可能与CREB及α-CaMKⅡ蛋白的表达减少,ERK1/2表达增强有关,这可能是导致癫痫后出现认知功能障碍的重要原因。2、低剂量伽玛刀照射可引起大鼠皮层及海马CREB、α-CaMKⅡ及ERK1/2表达的变化,这可能是伽玛刀抑制癫痫发作和改善认知功能的重要的分子机制。
Epilepsy, a brain dysfunctional syndrome caused by abnormal discharge of neurons with many reasons, is characterized by recurrent and temporary disorder of brain functions. Seizure is the core content of epilepsy, but in recent years, the effect of epilepsy on cognitive function has been paid more and more attention. The data showed that about 30~40% of epileptic patients were troubled with various degrees of cognition disorders, which not only seriously affected the patients’life quality, but also brought burden and pressure to their families and society.
About 20~30% of epilepsy is medically intractable. With long-term and recurrent seizures, the patients’cognitive function may be damaged easily. The primary treatment method for patients with intractable epilepsy is operation. Although operation may control seizure and lessen the dosage of antiepileptic drugs, which could improve cognitive function of the patient, at the same time, the operation itself may cause harm to cognition in some degree. Therefore, it is very important to pay attention to cognition disorders of patients with intractable epilepsy and to understand their characteristic and influencing factors. Making an objective assessment of cognitive condition before and after operation has significance to evaluate comprehensive efficacy for operation and select reasonable treatment protocols.
With the development of stereotactic radiosurgery, gamma knife surgery (GKS) has turned to be a promising alternative technology for intracranial lesions without invasive operation, which has been used in treatment of intractable epilepsy. The data from clinical and basic research suggested that, sublethal dose of gamma knife could produce an antiepileptic effect without causing subsequent functional impairment in target areas, but its mechanism remains unclear, which limits further optimization of treatment. Whether gamma knife surgery could treat epilepsy without damage to cognitive function and even improve cognition, needs further study.
At present, cognition disorder of epileptic patients is considered to be related with many factors, but its exact biologic mechanism is still debatable. N-methyl-D-aspartate receptor (NMDAR), a subtype of ionotropic receptors for glutamate, is highly permeable for Ca2+ and could mediate variety of physiological processes, such as synaptic plasticity and synaptic transmission, which is closely associated with learning and memory. The increased intracellular Ca2+ may phosphorylate cAMP response element binding protein (CREB) through several signal transduction pathways such as calmodulin dependent protein kinase (CaMK) and extracellular signal-regulated kinase (ERK). As an important nuclear transcription factor, CREB could regulate the process of learning and memory on gene transcription level. Several study showed that NMDAR, influx of Ca2+ and proteins of signal pathways play important roles in the development and maintenance of epilepsy, but the pathogenic mechanism is unclear. Whether gamma knife surgery could protect cognitive function of epileptic patients by intervening the change of biological molecules, remains to be deeply researched.
Our study, on the one hand, analyzed the cognition and influencing factors of patients with intractable epilepsy, and then evaluated the effect of surgery on their cognitive function; and on the other, through establishing epileptic animal model, we performed low dose of gamma knife irradiation on rats and assessed their abilities of learning and memory, and then we observed the changes of NMDAR, intracellular Ca2+ and proteins of CREB signal pathways in cortex and hippocampus, in order to explore the biologic mechanism of cognition disorders and the effects of gamma knife surgery.
Part 1 Clinical analysis of cognitive condition and influencing factors of patients with intractable epilepsy
Objective: To explore the characteristic of cognition disorders of patients with intractable epilepsy and analyses the effects of various influencing factors on cognitive function.
Methods: 62 patients with intractable epilepsy and 60 healthy persons were chosen in the study. The methods of SPM, EPQ and SCL-90 were used respectively to evaluate their intelligence, personality and mentality, and the effects of various influencing factors on cognitive function were analyzed.
Results: 1.Compared with control group, the total score and IQ of SPM of the epilepsy group decreased significantly. There were 53.2% of mental deficiency in patients with intractable epilepsy, and the proportion was higher than that of control group(1.7%)(P<0.05). There were only 18 patients with middle intelligence, and the proportion was 29%, which was lower than that of control group(53.3%)(P<0.05). 2. There were no significant differences on scores of EPQ and the proportion of personality type in two groups(P>0.05). 3. Many patients with intractable epilepsy had various degrees of psychological barriers. The total score of SCL-90 and the factor scores, such as somatization, interpersonal sensitivity, depression, anxiety and hostility in patients were higher than those in control group. 4. Various factors, including the onset age, course of disease, seizure types, frequency, duration, number of drug, total score and the factor scores of SCL-90 were correlated to the cognitive functions of epileptic patients, except sex(P<0.05).
Conclusion: 1.The cognitive functions of many patients with intractable epilepsy were damaged, and the proportion of patients with mental deficiency was higher significantly than that of healthy people. 2. Many patients with intractable epilepsy had various degrees of psychological barriers, and which had much important effects on the cognitive function. 3. The onset age, course of disease, seizure types, frequency, duration and number of drug were important risky factors of cognitive disorders of epileptic patients.
Part 2 Effects of surgery on neuropsychology and cognitive functions of patients with intractable epilepsy
Objective: To investigate the effects of surgery on neuropsychology and cognitive functions of patients with intractable epilepsy.
Methods: 30 patients with intractable epilepsy were chosen in the study. The methods of SPM, EPQ and SCL-90 were used respectively to evaluate their intelligence, personality and mentality of pre-operation and post-operation, and the comprehensive efficacy of surgery was assessed.
Results: 30 patients were followed up from 10 to 24 months. 21 patients had no seizure after the operation, and 5 patients had only a few seizures. The total effective rate of surgery was 86.67%. There were no significant differences on scores of EPQ between pre-operation and post-operation (P>0.05), while the total score of SCL-90 and the factor scores of somatization, interpersonal sensitivity, depression and anxiety decreased obviously after operation. The total score and IQ in SPM of 10 cases (33.33%) improved significantly after operation, 13 cases (43.33%) declined, and 7 cases (23.33%) remained unchanged. Further analysis showed that, the decline rate of intelligence of patients with preoperative IQ≥70 (60%) was significantly higher than that with IQ<70 (26.67%) after operation, and left side operation (50%) was higher than right side operation (35.71%) (P<0.05). Of 26 patients with EngleⅠ-Ⅱ, 10 (38.46%) improved in the postoperative intelligence, and 11 (42.31%) suffered from a decrease . Of 4 patients with EngleⅢ-Ⅳ, 0 improved in the postoperative intelligence, and 2 (50%) decreased. Temporal lobe and non-temporal lobe operation could both lead to cognitive disorders, and there were no significant differences in two groups (P>0.05).
Conclusion: 1. At present, surgery is still an effective means to treat intractable epilepsy, which could satisfactorily control epileptic seizure. 2. The mental status of epileptic patients could get improved in some degree after operation, and the cognitive function of some patients could become better, but still many patients suffered damage. 4. The patients who were performed left side operation, higher preoperative IQ and not well controlled, could occur easily cognitive disorders after operation. Temporal lobe and non-temporal lobe operation could both lead to cognitive disorders.
Part 3 Effects of low dose of gamma knife irradiation on seizure and cognitive function of epileptic rats
Objective: To investigate the effects of low dose of gamma knife irradiation on seizure and cognitive function of epileptic rats.
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control + GS group;③PTZ group;④PTZ+ GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. After irradiation, the changes of the seizure, behavior and EEG were observed and recorded. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups.
Results: The rats could be kindled completely after 12~16 injections with PTZ, and the successful kindling rate was 80%. After low dose of gamma knife irradiation, the degree of seizures gradually lightened in the rats of PTZ+GS group with time passing by. Compared with PTZ group, on the 8th~12th week, the degree of seizures significantly reduced, the latency of seizure waves prolonged, and the frequency of seizure waves decreased in rats of PTZ+GS group (P<0.05). The step-down test showed that the response time and the number of errors increased, and the latent time decreased significantly in rats of PTZ group (P<0.05). Compared with control group, the Morris water maze test showed that the escape latency and the swimming distance increased significantly (P<0.05), and the number of platform crossings and the percentage of swimming time in platform quadrant decreased obviously in rats of PTZ group (P<0.05). It showed that the abilities of learning and memory of epilepsy rats were obviously impaired. While compared with PTZ group, the results of step-down test and Morris water maze test improved significantly in rats of PTZ+GS group. There were no significant differences in step-down test and Morris water maze test between control group and control + GS group (P>0.05).
Conclusion: 1. PTZ-kindled epileptic model could be easily established, which might lead to damage to the ability of learning and memory of rats, and was an ideal model for investigate cognitive disorders of epilepsy. 2. Low dose of gamma knife irradiation could reduce seizure and improve cognitive function of epileptic rats.
Part 4 Effects of low dose of gamma knife irradiation on the expression of NMDA receptor subunits in cortex and hippocampus of epileptic rats Objective: To examine the effects of low dose of gamma knife irradiation on the expression of NMDA receptor subunits in cortex and hippocampus of epileptic rats.
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control + GS group;③PTZ group;④PTZ+ GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups. And then the rats were killed and immunohistochemstry and western blotting were used to detect the relative levels of NMDAR subunits (NR1, NR2A, and NR2B) in cortex and hippocampus.
Results: Compared with control group, the protein expression of NR1, NR2A and NR2B of the PTZ group increased significantly in the cortex and hippocampus, and the positive neurons and their average absorbance value also increased significantly (P<0.05). Compared with PTZ group, the protein expression of NR1, NR2A and NR2B of the PTZ+GS group decreased significantly in the cortex and hippocampus (P<0.05). There were no significant differences between control group and control+GS group (P>0.05).
Conclusion: 1. The mechanism of PTZ induced epilepsy might be associated with increased expression of NR1, NR2A and NR2B in the cortex and hippocampus, which also might be one of reasons to cause cognitive disorders after epileptic seizures. 2. Low dose of gamma knife irradiation could decrease expression of NR1, NR2A and NR2B in the cortex and hippocampus of epileptic rats, which might represent a possible mechanism underlying the therapeutic effects of Gamma Knife irradiation. Part 5 Effects of low dose of gamma knife irradiation on cytoplasmic calcium level of neurons in cortex and hippocampus of epileptic rats
Objective: To investigate the effects of low dose of gamma knife irradiation on cytoplasmic calcium level of neurons in cortex and hippocampus of epileptic rats.
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control + GS group;③PTZ group;④PTZ+ GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups. After that, the rats were killed and neurons of cortex and hippocampus were acutely isolated and loaded with fluorescent dye fluo-3. And then the fluorescence intensity of cytoplasmic calcium was measured with laser scanning confocal microscopy (LSCM).
Results: The cytoplasmic calcium fluorescence intensity of neurons in cortex and hippocampus in control group was in the basic level, and there was no significant difference between the control group and gamma knife control group (P>0.05). The cytoplasmic calcium fluorescence intensity of PTZ group increased significantly compared with control group (P<0.05), and that of PTZ+GS group were significantly lower than PTZ group (P<0.05). There was no significant difference between control+GS group and control group (P>0.05).
Conclusion: The increased cytoplasmic calcium fluorescence intensity of neurons in cortex and hippocampus might be associated with the mechanism of PTZ induced epilepsy and cognitive disorders after seizures. Low dose of gamma knife irradiation might control seizure and improve cognitive function through regulating calcium level of neurons.
Part 6 Effects of low dose of gamma knife irradiation on CREB signal pathways in cortex and hippocampus of epileptic rats
Objective: To observe the effects of low dose of gamma knife irradiation on CREB signal pathways in cortex and hippocampus of epileptic rats
Methods: Primarily 60 rats were randomly divided into 4 groups:①control group;②control+GS group;③PTZ group;④PTZ+GS group. The rats were injected intraperitoneally with PTZ (35mg/kg) to establish the epileptic models. Gamma knife irradiation was performed on bilateral frontal cortex of rats with a maximum dose of 30Gy. On the 12th week after irradiation, the step-down test and Morris water maze were used to evaluate the ability of learning and memory of four groups. And then the rats were killed and immunohistochemstry and western blotting were used to detect the expression of CREB,α-CaMKⅡand ERK1/2 in cortex and hippocampus.
Results: Compared with control group, the protein expression of CREB andα-CaMKⅡof the PTZ group decreased, and ERK1/2 increased significantly in the cortex and hippocampus(P<0.05). Compared with PTZ group, the protein expression of CREB andα-CaMKⅡof the PTZ+GS group increased, and ERK1/2 declined significantly in the cortex and hippocampus (P<0.05). There were no significant differences of expression of CREB,α-CaMKⅡand ERK1/2 between control group and control+GS group (P>0.05).
Conclusion: 1. The mechanism of PTZ induced epilepsy might be associated with increased expression of CREB andα-CaMKⅡ, and decreased expression of ERK1/2 in the cortex and hippocampus, which also might be the important cause of cognitive disorders after epileptic seizures. 2. Low dose of gamma knife irradiation could regulate the expression of CREB,α-CaMKⅡand ERK1/2 in the cortex and hippocampus of epileptic rats, which might represent a possible mechanism underlying the therapeutic effects of Gamma Knife irradiation.
引文
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