Reduction of Hippocampal Apoptosis by Intracerebroventricular Administration of Extracellular Signal-Regulated Protein Kinase and/or p38 Inhibitors in Amyloid Beta Rat Model of Alzheimer's Disease: Involvement of Nuclear-Related Factor-2 and Nuclear Factor-κB
Reduction of Hippocampal Apoptosis by Intracerebroventricular Administration of Extracellular Signal-Regulated Protein Kinase and/or p38 Inhibitors in Amyloid Beta Rat Model of Alzheimer's Disease: Involvement of Nuclear-Related Factor-2 and Nuclear Factor-κB
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DOI：
10.1111/bcpt.12000
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发表时间：
2013-03-01
影响因子：
3.1
通讯作者：
Khodagholi, Fariba
中科院分区：
文献类型：
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作者：
Ashabi, Ghorbangol;Alamdary, Shabnam Zeighamy;Khodagholi, Fariba
在本研究中，我们研究了侧脑室注射细胞外信号调节蛋白激酶（ERK）和p38特异性抑制剂U 0126和PD 169316对大鼠淀粉样β（A）诱导的细胞凋亡的影响。为了研究这些化合物的作用，我们评估了细胞凋亡的细胞内信号传导途径，以及炎症和抗氧化剂途径，注射后7和20天。我们发现，caspase-3和Bax/Bcl-2比值，两个细胞凋亡的标志，在预处理的大鼠中，在A注射后7 d，U 0126和PD 169316显著降低。这一观察结果与海马的免疫染色分析结果一致，海马的免疫染色分析结果显示，与A注射组相比，U 0126和PD 169316预处理大鼠海马中末端转移酶dUTP缺口末端标记阳性细胞的水平降低。我们还追踪了A注射组和治疗组中两种ER因子calpain-2和caspase-12水平的变化。U 0126和PD 169316预处理大鼠中钙蛋白酶-2和半胱天冬酶-12水平降低证实了这些抑制剂的保护作用。此外，我们研究了两种应激感应转录因子，核相关因子2（Nrf 2）和核因子-kB（NF-kB），在A注射的威尔斯和U 0126和PD 169316预处理的大鼠中的作用。U 0126和PD 169316在注射A后7 d激活Nrf 2并抑制NF-kB通路。这些抗氧化剂和炎症通路在20天内恢复到媒介物水平。总之，我们的研究结果加强和扩展了ERK和/或p38抑制剂对A.
In the present study, we examined the effects of intracerebroventricular administration of extracellular signal-regulated protein kinase- (ERK) and p38-specific inhibitors, U0126 and PD169316, respectively, on apoptosis induced by amyloid beta (A) in rats. To investigate the effects of these compounds, we evaluated intracellular signalling pathways of apoptosis, as well as inflammatory and antioxidant pathways, 7 and 20days after A injection. We found that caspase-3 and Bax/Bcl-2 ratio, two hallmarks of apoptosis, were significantly decreased in the rats pre-treated with U0126 and PD169316, 7days after A injection. This observation was in agreement with the results of immunostaining analysis of the hippocampus that showed decreased levels of terminal transferase dUTP nick end labelling positive cells in the hippocampus of U0126 and PD169316 pre-treated rats, compared with the A-injected group. We also chased the changes in the levels of calpain-2 and caspase-12, two ER factors, in the A-injected and treatment groups. Decreased levels of calpain-2 and caspase-12 in U0126 and PD169316 pre-treated rats confirmed the protective effects of these inhibitors. Furthermore, we studied the effect of two stress-sensing transcription factors, nuclear-related factor-2 (Nrf2) and nuclear factor-kB (NF-kB), in A-injected as wells as U0126 and PD169316 pre-treated rats. U0126 and PD169316 activated Nrf2 and suppressed NF-kB pathways, 7days after A injection. These antioxidant and inflammatory pathways restored to the vehicle level within 20days. Taken together, our findings reinforce and extend the notion of the potential neuroprotective role of ERK and/or p38 inhibitors against the neuronal toxicity induced by A.