钙稳态失衡对钙记忆相关蛋白表达的影响机制及钙离子调节剂临床疗效的荟萃分析
摘要
钙离子是细胞内重要的第二信使,在细胞分裂增殖、受精、基因转录和表达等生理过程扮演着重要的角色,钙离子稳态失衡是很多疾病的共同病理机制之一。阿尔茨海默病患者由于老年斑、神经纤维缠结等病理产物的聚集,淀粉样前体蛋白(APP)、载脂蛋白E(ApoE)、早老素(PS)等基因突变会引起神经元钙稳态失调,影响神经元的存活和学习记忆过程。目前的解释仅限于多种病理变化引起的钙超载对神经元损伤和学习记忆形成和巩固过程的影响,具体环节和通路尚不清楚,低钙状态对学习记忆影响的机制未曾涉及。本研究根据前期工作提出：钙超载和低钙均会影响学习记忆过程,其机制可能是各种病理刺激导致的钙稳态失衡抑制了钙振荡,降低了钙-记忆相关蛋白质的磷酸化水平和合成,最终影响记忆的形成和巩固。为了佐证这一设想,本研究用NMDA受体激活剂和钙螯合剂分别处理神经元,模拟不同的钙病理,检测他们对钙振荡和钙-记忆相关蛋白质表达的影响,并选用一种在不同钙病理条件下对钙流具有双向调节作用的药物雷洛昔芬进行干预,成功的逆转了这一病理过程。为了进一步论证钙调节剂治疗AD有效性和安全性,我们选用了一种对钙流有抑制作用的NMDA受体拮抗剂美金刚和雷洛昔芬进行系统综述和Meta分析,发现它们对学习记忆均有改善作用。证明：钙稳态失衡确实是AD的重要病理机制,根据患者特点选用合适的钙调节剂是AD治疗的有效方法之一。本研究共分为三部分：
第一部分钙稳态失衡对钙记忆相关蛋白表达的影响机制及雷洛昔芬的逆转效应
[背景/目的]钙稳态失衡是阿尔茨海默病重要的病理特征之一,其具体机制至今未明。本研究试图揭示钙稳态失衡对钙记忆相关蛋白的影响及与钙振荡的关联。
[方法]首先用各种浓度梯度的谷氨酸盐溶液和BAPTA-AM溶液刺激神经元来模拟细胞内钙超载和低钙状态,然后测试他们对钙振荡的影响。实验完毕,提取神经元总蛋白,用Western blotting分析钙-记忆相关蛋白的表达情况。用MTT法测试谷氨酸和BAPTA-AM刺激后神经元的活性。
[结果]研究发现1～100uM的谷氨酸盐延长了钙峰持续期并且增加Cav1.2,NR1, NR2B, PSD95, CaMKII, pCREB的表达。300uM和1uM谷氨酸盐抑制钙振荡并减少PSD93和pCREB表达。雷洛昔芬增加300uM谷氨酸盐刺激后Cav1.2,NR2B,PKC, CREB的表达。luM-50uM BAPTA-AM呈浓度依赖性的抑制钙振荡,减少NRl,PSD95, PSD93, CaMKII, pCaMKII, pCREB的表达。雷洛昔芬增加20uM BAPTA-AM刺激后PSD95, PSD93, pCaMKII, CREB的表达。高浓度的谷氨酸和BAPTA-AM降低神经元的活性,但是可以被适当浓度的雷洛昔芬所逆转。
[结论]钙稳态失调可以通过抑制钙振荡减少钙-记忆相关蛋白的表达,这可能是AD认知退变的机制之一。雷洛昔芬能够逆转钙振荡降低所致的钙-记忆相关蛋白表达下调。
第二部分：美金刚治疗阿尔茨海默病的有效性和安全性系统综述和Meta分析
[背景/目的]美金刚已经被美国食品药品监督管理局批准为治疗中重度阿尔茨海默病的治疗药物,然而,最近有几项临床研究却认为它对阿尔茨海默病并无明显的治疗益处,且存在一定的副作用。本研究将收集所有可以得到的临床研究以更新美金刚治疗阿尔茨海默病的结论。
[方法]我们检索了九个数据库,时间截止2012年9月25日。用Review Manager version5.1合并同样的研究项目,检测异质性和敏感性,用森林图表示合并效应。Cochrane Handbook (version5.0.1)用于评价纳入研究的总体偏倚。Egger's检验和漏斗图用于评价报告偏倚。同时,我们也评价了美金刚治疗AD的有效性和安全性。
[结果]一共检索到889篇文章,12篇入选。合并分析发现美金刚对阿尔茨海默病认知和临床医师总体印象有利；对精神状态,日常生活行动能力,没有明显的益处。对脑容量和代谢的结果存在争议。美金刚对失访率,不良事件导致的失访没有明显的影响,但对肥胖,思维混沌感,高血压,神经系统障碍和跌倒有更高的风险。漏斗图显示报告偏倚存在,但Egger's检验发现偏倚不显著。
[结论]美金刚对AD患者认知和临床医师总体印象有益,但是对思维混沌,肥胖,高血压,神经系统障碍和跌倒存在较高的诱发风险。
第三部分雷洛昔芬对更年期妇女认知和生活质量的影响：一个临床随机对照研究的系统综述
[背景/目的]雷洛昔芬在临床上用作绝经后妇女骨质疏松的治疗和乳腺癌的预防。然而,他对老年女性认知和更年期症状的影响存在争议。本研究将用循证医学的方法尽可能收集所有的相关研究得出一个综合性的结论,给病人一些有意义的建议。
[方法]我们检索了13个电子数据库,阅读标题和摘要以排除明显不合要求的文章,然后根据准入标准阅读全文和参考文献。如果没有全文,我们将会写信向作者索要PDF文本。将提取的数据记录在EXCEL表格中,两个作者将会根据Jadad分数和循证医学手册评价该研究的质量。
[结果]我们获得了7项合格的研究,设计、评价指标和问卷有相当大的异质性。根据Jadad分数,其中有四项研究得到5分,三项研究得3分,仅仅两项研究使用了分配掩藏方法。有两项研究(n=5599)发现60mg/ml雷洛昔芬能够改善动词记忆,120mg/ml雷洛昔芬能减少轻度认知障碍的发病风险达33%,在一定程度上降低AD的发病率,其他两项研究则没有发现显著差异。有三项研究发现雷洛昔芬并不能减轻抑郁,其他研究则发现能够减轻抑郁。从现有的研究来看,没有充足的证据证明雷洛昔芬对焦虑、睡眠、性功能、血管症状是否有效,但却显著地使绝经期症状恶化。
[结论]雷洛昔芬可能对认知有改善作用,但对焦虑、抑郁、睡眠、性功能、血管症状没有明显的影响,而且可使绝经期症状显著地恶化。它对绝经期女性骨质疏松的治疗以及乳腺癌的预防是安全的,但是不适合血管狭窄和有血栓形成倾向的患者。
Calcium is an important second messenger. It plays an important role in the process of cell differentiation, proliferation, fertilization, gene transcription and expression. The calcium dishomeostasis is one of the common pathological mechanism of many diseases. Lots of pathogenic products such as senile plaques, nerve fiber tangles and gene mutations of amyloid precursor protein (APP), apolipoprotein E (ApoE), presenilin (PS) induce neural calcium dishomeostasis in Alzheimer's patients, impair the exsit of the neurons and the process of learning and memory. The current interpretation is limited to the calcium overload caused by a variety of pathological changes on neuronal injury and the formation, consolidation of learning and memory, the detail machanisms are unclear and the study about the effect of low concentration calcium on learning and memory is not involved in. According to the preliminary work of this research, we report:calcium overload and low calcium are all influence the process of learning and memory, the mechanism is that the various pathological stimulus induce calcium dishomeostasis which inhibit the calcium oscillations, reducing the expression of memory related proteins and phosphorylation, affecting the formation and consolidation of memory. In order to confirm this conclusion, we treated neuron with NMD A receptor activator and calcium chelating agent respectively, simulated different calcium pathology and tested their effect on calcium oscillations and protein expression. We applied the raloxifene which was two-way adjustment on calcium pathology, it reversed the pathological process successfully. For further proving the correctness of this opinion, we chosed the memantine which is inhabitation of NMD A receptor and raloxifene to make a systematic review and Meta analysis. The results showed these two drugs improved memory significantly. So, calcium regulator is one of the effective treatment of AD. This research is divided into three parts:
PartⅠ The machnism of calcium dyshomeostasis influence the expression of calcium memory-related proteins and the reversal effect of raloxifene
Calcium dyshomeostasis is a important pathology of Alzheimer's disease, but the mechanism is not very clear. The aim of this study was to reveal the influence of calcium dyshomeostasis on expression of calcium memory-related proteins and it's relationship with calcium oscillations. We treated neuron with concentration gradient of glutamate and BAPTA-AM to simulate different calcium pathology and tested their influence on oscillations. Then, the total protein was exacted, the expression of calcium memory-related proteins was analysed by western blotting. MTT was used to test neuron activity after treating with glutamate and BAPTA-AM. We found1～100uM glutamate extended duration of calcium spikes and increased expression of Cav1.2, NR1, NR2B, PSD95, CaMKII, pCREB.300uM and luM glutamate inhibited calcium oscillations and decreased the expression of PSD93and pCREB. Raloxifene increased the expression of Cav1.2, NR2B, PKC, CREB after treating with300uM gulatamate. luM-50uM BAPTA-AM inhibited calcium oscillations depend on concentration and decreased the expression of NR1, PSD95, PSD93, CaMKⅡ, pCaMKⅡ, pCREB. Raloxifene would increased the expression of PSD95, PSD93, pCaMKⅡ, CREB after treating with20uM BAPTA-AM. High concentration glutamate and BAPTA-AM declined neuron activity, these was rescued by suitable concentration raloxifene. We would come to conclusion that the calcium dyshomeostasis decrease expression of calcium memory-related protein by inhibiting calcium oscillations, this may be a mechanism of cognition degeneration. Raloxifene would reverse this effect, so we recommend it as a selective treatment for Alzheimer's disease especially when the patients have high risk of osteoporosis or/and breast cancer.
Part Ⅱ Effectiveness and safety of memantine treatment for Alzheimer's disease
Memantine is approved as a treatment for moderate to severe Alzheimer's disease (AD). However, recent studies report that memantine is harmful for AD patients in several ways. This paper will systematically review all the available studies to provide an update regarding memantine as a treatment for AD. Two authors queried nine databases containing literature published prior to September15,2012and determined eligible studies based on the inclusion criteria. We used Review Manager to pool similar data. The Cochrane Handbook was used to assess the bias of the included studies. The chi-squared test, sensitivity analysis, Egger's test, and funnel plots were used to determine the heterogeneity and report bias, respectively. We obtained889studies and determined that12of those studies met the inclusion criteria. The pooled analysis showed that memantine had significant benefits for AD patients in terms of cognition and the clinician's global impression. There were no significant benefits for AD patients in terms of mental state or activities of daily life. The results on brain volume and metabolism were controversial in two of the studies. Memantine did not significantly affect discontinuation caused by serious adverse events but did increase the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling. Memantine is beneficial for AD patients with regards to cognition and clinician's global impression but increases the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling.
PartⅢ Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women:a systematic review of randomized controlled trials
Raloxifene has been used as therapy for osteoporosis and ER+breast cancer prevention in menopausal women. However, its effects on cognition and climacteric syndrome are controversial. This study reviews the relevant studies and reaches a comprehensive conclusion. We retrieved thirteen electronic databases, read the titles and abstracts to exclude ineligible articles, and then read the full text and references to form a basis for decisions using the inclusion criteria. If full text was not available, we asked the author for a copy of the article. After the data were extracted and recorded, the research quality was evaluated by two authors using the Jadad score and Cochrane handbook. We found seven eligible studies. The design, evaluated items, questionnaires and scales were heterogeneous. The design quality was fair as evaluated by the Cochrane Handbook. We found that60mg/day raloxifene could improve verbal memory, and120mg/day raloxifene produced a33%decrease in the risk of mild cognitive impairment and also lowered the risk of Alzheimer's disease. There was not enough evidence to state if raloxifene had any effect on depression, anxiety, sleep, sexual function, vasomotor symptoms, but significantly worsened menstrual symptoms. Raloxifene may have some benefit for cognition, but it's not significant effect on anxiety, depression, sleep, sexual function, vasomotor symptoms and worsens menstrual symptoms. This drug is safe for treating osteoporosis and preventing breast cancer in menopausal women, but it is not suitable for patients who have any arterial stenosis or thrombophilia.
第一部分钙稳态失衡对钙记忆相关蛋白表达的影响机制及雷洛昔芬的逆转效应
[背景/目的]钙稳态失衡是阿尔茨海默病重要的病理特征之一,其具体机制至今未明。本研究试图揭示钙稳态失衡对钙记忆相关蛋白的影响及与钙振荡的关联。
[方法]首先用各种浓度梯度的谷氨酸盐溶液和BAPTA-AM溶液刺激神经元来模拟细胞内钙超载和低钙状态,然后测试他们对钙振荡的影响。实验完毕,提取神经元总蛋白,用Western blotting分析钙-记忆相关蛋白的表达情况。用MTT法测试谷氨酸和BAPTA-AM刺激后神经元的活性。
[结果]研究发现1～100uM的谷氨酸盐延长了钙峰持续期并且增加Cav1.2,NR1, NR2B, PSD95, CaMKII, pCREB的表达。300uM和1uM谷氨酸盐抑制钙振荡并减少PSD93和pCREB表达。雷洛昔芬增加300uM谷氨酸盐刺激后Cav1.2,NR2B,PKC, CREB的表达。luM-50uM BAPTA-AM呈浓度依赖性的抑制钙振荡,减少NRl,PSD95, PSD93, CaMKII, pCaMKII, pCREB的表达。雷洛昔芬增加20uM BAPTA-AM刺激后PSD95, PSD93, pCaMKII, CREB的表达。高浓度的谷氨酸和BAPTA-AM降低神经元的活性,但是可以被适当浓度的雷洛昔芬所逆转。
[结论]钙稳态失调可以通过抑制钙振荡减少钙-记忆相关蛋白的表达,这可能是AD认知退变的机制之一。雷洛昔芬能够逆转钙振荡降低所致的钙-记忆相关蛋白表达下调。
第二部分：美金刚治疗阿尔茨海默病的有效性和安全性系统综述和Meta分析
[背景/目的]美金刚已经被美国食品药品监督管理局批准为治疗中重度阿尔茨海默病的治疗药物,然而,最近有几项临床研究却认为它对阿尔茨海默病并无明显的治疗益处,且存在一定的副作用。本研究将收集所有可以得到的临床研究以更新美金刚治疗阿尔茨海默病的结论。
[方法]我们检索了九个数据库,时间截止2012年9月25日。用Review Manager version5.1合并同样的研究项目,检测异质性和敏感性,用森林图表示合并效应。Cochrane Handbook (version5.0.1)用于评价纳入研究的总体偏倚。Egger's检验和漏斗图用于评价报告偏倚。同时,我们也评价了美金刚治疗AD的有效性和安全性。
[结果]一共检索到889篇文章,12篇入选。合并分析发现美金刚对阿尔茨海默病认知和临床医师总体印象有利；对精神状态,日常生活行动能力,没有明显的益处。对脑容量和代谢的结果存在争议。美金刚对失访率,不良事件导致的失访没有明显的影响,但对肥胖,思维混沌感,高血压,神经系统障碍和跌倒有更高的风险。漏斗图显示报告偏倚存在,但Egger's检验发现偏倚不显著。
[结论]美金刚对AD患者认知和临床医师总体印象有益,但是对思维混沌,肥胖,高血压,神经系统障碍和跌倒存在较高的诱发风险。
第三部分雷洛昔芬对更年期妇女认知和生活质量的影响：一个临床随机对照研究的系统综述
[背景/目的]雷洛昔芬在临床上用作绝经后妇女骨质疏松的治疗和乳腺癌的预防。然而,他对老年女性认知和更年期症状的影响存在争议。本研究将用循证医学的方法尽可能收集所有的相关研究得出一个综合性的结论,给病人一些有意义的建议。
[方法]我们检索了13个电子数据库,阅读标题和摘要以排除明显不合要求的文章,然后根据准入标准阅读全文和参考文献。如果没有全文,我们将会写信向作者索要PDF文本。将提取的数据记录在EXCEL表格中,两个作者将会根据Jadad分数和循证医学手册评价该研究的质量。
[结果]我们获得了7项合格的研究,设计、评价指标和问卷有相当大的异质性。根据Jadad分数,其中有四项研究得到5分,三项研究得3分,仅仅两项研究使用了分配掩藏方法。有两项研究(n=5599)发现60mg/ml雷洛昔芬能够改善动词记忆,120mg/ml雷洛昔芬能减少轻度认知障碍的发病风险达33%,在一定程度上降低AD的发病率,其他两项研究则没有发现显著差异。有三项研究发现雷洛昔芬并不能减轻抑郁,其他研究则发现能够减轻抑郁。从现有的研究来看,没有充足的证据证明雷洛昔芬对焦虑、睡眠、性功能、血管症状是否有效,但却显著地使绝经期症状恶化。
[结论]雷洛昔芬可能对认知有改善作用,但对焦虑、抑郁、睡眠、性功能、血管症状没有明显的影响,而且可使绝经期症状显著地恶化。它对绝经期女性骨质疏松的治疗以及乳腺癌的预防是安全的,但是不适合血管狭窄和有血栓形成倾向的患者。
Calcium is an important second messenger. It plays an important role in the process of cell differentiation, proliferation, fertilization, gene transcription and expression. The calcium dishomeostasis is one of the common pathological mechanism of many diseases. Lots of pathogenic products such as senile plaques, nerve fiber tangles and gene mutations of amyloid precursor protein (APP), apolipoprotein E (ApoE), presenilin (PS) induce neural calcium dishomeostasis in Alzheimer's patients, impair the exsit of the neurons and the process of learning and memory. The current interpretation is limited to the calcium overload caused by a variety of pathological changes on neuronal injury and the formation, consolidation of learning and memory, the detail machanisms are unclear and the study about the effect of low concentration calcium on learning and memory is not involved in. According to the preliminary work of this research, we report:calcium overload and low calcium are all influence the process of learning and memory, the mechanism is that the various pathological stimulus induce calcium dishomeostasis which inhibit the calcium oscillations, reducing the expression of memory related proteins and phosphorylation, affecting the formation and consolidation of memory. In order to confirm this conclusion, we treated neuron with NMD A receptor activator and calcium chelating agent respectively, simulated different calcium pathology and tested their effect on calcium oscillations and protein expression. We applied the raloxifene which was two-way adjustment on calcium pathology, it reversed the pathological process successfully. For further proving the correctness of this opinion, we chosed the memantine which is inhabitation of NMD A receptor and raloxifene to make a systematic review and Meta analysis. The results showed these two drugs improved memory significantly. So, calcium regulator is one of the effective treatment of AD. This research is divided into three parts:
PartⅠ The machnism of calcium dyshomeostasis influence the expression of calcium memory-related proteins and the reversal effect of raloxifene
Calcium dyshomeostasis is a important pathology of Alzheimer's disease, but the mechanism is not very clear. The aim of this study was to reveal the influence of calcium dyshomeostasis on expression of calcium memory-related proteins and it's relationship with calcium oscillations. We treated neuron with concentration gradient of glutamate and BAPTA-AM to simulate different calcium pathology and tested their influence on oscillations. Then, the total protein was exacted, the expression of calcium memory-related proteins was analysed by western blotting. MTT was used to test neuron activity after treating with glutamate and BAPTA-AM. We found1～100uM glutamate extended duration of calcium spikes and increased expression of Cav1.2, NR1, NR2B, PSD95, CaMKII, pCREB.300uM and luM glutamate inhibited calcium oscillations and decreased the expression of PSD93and pCREB. Raloxifene increased the expression of Cav1.2, NR2B, PKC, CREB after treating with300uM gulatamate. luM-50uM BAPTA-AM inhibited calcium oscillations depend on concentration and decreased the expression of NR1, PSD95, PSD93, CaMKⅡ, pCaMKⅡ, pCREB. Raloxifene would increased the expression of PSD95, PSD93, pCaMKⅡ, CREB after treating with20uM BAPTA-AM. High concentration glutamate and BAPTA-AM declined neuron activity, these was rescued by suitable concentration raloxifene. We would come to conclusion that the calcium dyshomeostasis decrease expression of calcium memory-related protein by inhibiting calcium oscillations, this may be a mechanism of cognition degeneration. Raloxifene would reverse this effect, so we recommend it as a selective treatment for Alzheimer's disease especially when the patients have high risk of osteoporosis or/and breast cancer.
Part Ⅱ Effectiveness and safety of memantine treatment for Alzheimer's disease
Memantine is approved as a treatment for moderate to severe Alzheimer's disease (AD). However, recent studies report that memantine is harmful for AD patients in several ways. This paper will systematically review all the available studies to provide an update regarding memantine as a treatment for AD. Two authors queried nine databases containing literature published prior to September15,2012and determined eligible studies based on the inclusion criteria. We used Review Manager to pool similar data. The Cochrane Handbook was used to assess the bias of the included studies. The chi-squared test, sensitivity analysis, Egger's test, and funnel plots were used to determine the heterogeneity and report bias, respectively. We obtained889studies and determined that12of those studies met the inclusion criteria. The pooled analysis showed that memantine had significant benefits for AD patients in terms of cognition and the clinician's global impression. There were no significant benefits for AD patients in terms of mental state or activities of daily life. The results on brain volume and metabolism were controversial in two of the studies. Memantine did not significantly affect discontinuation caused by serious adverse events but did increase the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling. Memantine is beneficial for AD patients with regards to cognition and clinician's global impression but increases the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling.
PartⅢ Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women:a systematic review of randomized controlled trials
Raloxifene has been used as therapy for osteoporosis and ER+breast cancer prevention in menopausal women. However, its effects on cognition and climacteric syndrome are controversial. This study reviews the relevant studies and reaches a comprehensive conclusion. We retrieved thirteen electronic databases, read the titles and abstracts to exclude ineligible articles, and then read the full text and references to form a basis for decisions using the inclusion criteria. If full text was not available, we asked the author for a copy of the article. After the data were extracted and recorded, the research quality was evaluated by two authors using the Jadad score and Cochrane handbook. We found seven eligible studies. The design, evaluated items, questionnaires and scales were heterogeneous. The design quality was fair as evaluated by the Cochrane Handbook. We found that60mg/day raloxifene could improve verbal memory, and120mg/day raloxifene produced a33%decrease in the risk of mild cognitive impairment and also lowered the risk of Alzheimer's disease. There was not enough evidence to state if raloxifene had any effect on depression, anxiety, sleep, sexual function, vasomotor symptoms, but significantly worsened menstrual symptoms. Raloxifene may have some benefit for cognition, but it's not significant effect on anxiety, depression, sleep, sexual function, vasomotor symptoms and worsens menstrual symptoms. This drug is safe for treating osteoporosis and preventing breast cancer in menopausal women, but it is not suitable for patients who have any arterial stenosis or thrombophilia.
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