| 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 raloxifeneCalcium 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 diseaseMemantine 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 trialsRaloxifene 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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