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Neuroprotective Role and the Mechanism Induced by Rapid Estrogen Signaling

Author: YangLiCai
Tutor: WangRuiMin
School: North China Coal Medical
Course: Pathology and Pathophysiology
Keywords: Global cerebral ischemia Estrogen membrane receptor EDC E2-BSA AKT ERK JNK
CLC: R-332
Type: Master's thesis
Year: 2010
Downloads: 63
Quote: 0
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Abstract


Objective: Make a four-vessel ligation in rats with global cerebral ischemia model (a global cerebral ischemia in GCI), using a combination of estrogen the EDC (estrogen-dendrimer conjugates) and E2-BSA, the study of estrogen membrane receptor (membrane both estrogen receptor mER) rapid signaling pathway mediated neuroprotective effect of ischemic neuronal learning and memory function in rats, and to explore its possible molecular mechanism. Method: 1) SPF level of adult female SD rats (250 g), bilateral oophorectomy, a week after making four artery ligation model of global cerebral ischemia, ischemia for 10 min. 2) Animal groups: The animals were randomly divided into sham group, ischemia-reperfusion group, EDC or E2-BSA group inhibitor group (ICI 182780, LY294002, PD98059) and solvent control group. Before ischemia 1 h intraventricular injection of EDC and E2-BSA, inhibitors or solvent to give the EDC or E2-BSA 10 min before intraventricular injection. 3) laser confocal microscopy injury and survival of hippocampal CA1 neurons. 4) Morris water maze detect the rats spatial learning and memory function changes. 5) Western blot analysis, laser scanning confocal microscope to detect AKT kinase phosphorylation and protein expression levels. Results. Intraventricular injection of FITC-EDC and FITC-E2-BSA 1 h, laser confocal microscope found that EDC and E2-BSA is mainly located in the membrane of hippocampal CA1 neurons. 2. EDC and E2-BSA has a neuroprotective effect. 10 min of ischemia reperfusion 7 d, compared with Sham group, compared to The solvent control rats surviving neurons in hippocampal CA1 region significantly reduce the EDC and E2-BSA hippocampal CA1 region of surviving neurons with sham group did not significant difference, but significantly more than the solvent control group, and about 4 times of the solvent control group; given estrogen inhibitors ICI180, 782, ICI EDC and ICI E2-BSA group number of surviving neurons compared to the sham group, a significant reduction in the solvent, and The control group did not significantly different. 3. EDC and E2-BSA can significantly improve ischemic rat learning and memory and space exploration. Morris water maze test found that, after 10 min of ischemia reperfusion 7-9 d, compared with the sham group, the solvent control rats find a safe platform latency was prolonged, while EDC looking for safety, the latency of rats compared with the solvent control were significantly lower; removal of security platform, compared with sham group, solvent control group of rats within 90 s platform quadrant dwell time was significantly shorter, while EDC rats compared with the solvent control group significantly longer residence time in this quadrant. 4. EDC and E2-BSA rapid induction of promoting survival kinase AKT phosphorylation levels increased. Compared with sham group, reperfusion 10 min time point p-AKT levels began to increase, 3 h peaked 6 h began to decline, and continued until 1 d to the Sham same level. Give EDC and E2-BSA after treatment with ischemia-reperfusion group (I / R) compared to, 10min-3h time points, p-AKT levels significantly increased AKT and β-actin levels did not occur at all time points change, indicating that the protein content of all samples are equal. 5. EDC and E2-BSA rapid induction of promoting survival kinase of ERK1 / 2 phosphorylation levels. Compared with sham ischemia-reperfusion induced p-ERK1 / 2 levels of biphasic rise. The first peak in 10 min reperfusion time point continue until 3 h; the second peak reperfusion 1d. Give EDC and E2-BSA after reperfusion 10 min-6 h p-ERK1 / 2 was significantly higher than the I / R group, the most significant 10 min. Total ERK1 / 2 and β-actin levels were not changed at all time points. 6. EDC and E2-BSA inhibition promote apoptosis kinase p-JNK expression. Compared with the sham group, I / R each time point (3 h except) p-JNK water increased the average, and the the EDC set of p-JNK levels than the I / R group corresponds to significantly reduce the time points (3 h the exception). JNK in total protein levels did not change significantly. Blocking AKT and ERK1 / 2 pathway can eliminate the neuroprotective effect of EDC and E2-BSA. The results showed that the intraventricular injection of EDC and E2-BSA given 10 min prior PI3K inhibitor LY294002 eliminate AKT early rapid phosphorylation levels rise, the neuroprotective effect of estrogen disappeared. MEK inhibitor PD98059 can significantly reduce the EDC mediated p-ERK1 / 2 in the early rapidly rise, the same can be eliminated to the neuroprotective effects of the estrogen. In addition, given the estrogen receptor antagonist ICI182780 early rapid phosphorylation of AKT and ERK activation peaks disappear, but the levels of p-JNK, EDC and E2-BSA induced by estrogen membrane receptor pathway AKT and ERK1 / 2 phosphorylation The elevated level, while inhibiting the phosphorylation of JNK activation, and thus play a neuroprotective effect. 8. EDC and E2-BSA rapid induction of the transcription factor CREB phosphorylation level rise, which in turn raised the BDNF protein expression. Compared with the I / R group, EDC and E2-BSA can quickly within 10min reperfusion induced CREB phosphorylation levels increased, and 3 h, 6 h, 1 d time point maintained at a higher level of p-CREB . Compared with the I / R group, EDC and E2-BSA group BDNF protein levels began to increase at 6 h reperfusion, to maintain continued to rise to 1 d. Give PI3K inhibitor LY294002 and MEK inhibitor PD98059 were able to significantly weaken the 10-min time points EDC and E2-BSA-induced levels of p-CREB, BDNF protein expression has no effect, and 6 h reperfusion time point, EDC E2-BSA-induced elevated level of p-CREB and BDNF protein expression were inhibited. Conclusion EDC and E2-BSA combination with estrogen membrane receptors in hippocampal neurons membrane, rapid induction AKT/ERK1/2-CREB-BDNF promote survival signaling pathway, inhibition of JNK pro-apoptotic signaling pathways play an anti-ischemic The neuronal injury role, and the significant improvement in spatial learning and memory function in rats.

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