一种新的呫诺美林衍生物EUK1001促进小鼠神经生成
摘要
中枢胆碱能系统参与认知功能的发挥和神经生成的调节,且与AD的病理过程密切相关。其中,M1受体主要在前脑和海马区表达,已有研究表明其激动剂咕诺美林(Xanomeline)能改善认知功能并缓解AD的病理症状,已进入临床试验,但由于严重的外周副反应而限制了其临床应用。在本实验室既往的研究中发现一种新的咕诺美林衍生物EUK1001可以改善老年小鼠的学习记忆功能并且能够增强海马的突触可塑性。而且值得注意的是,相比咕诺美林,EUK1001具有更小的毒副作用。
基于EUK1001能够改善小鼠学习记忆功能并且增强其大脑的突触可塑性,以及认知功能与神经生成之间的相互关系,EUK1001可能也会影响成年小鼠的神经生成。为验证这种可能性,对C57BL／6J小鼠给予15天的EUK1001处理,注射胸腺嘧啶的类似物BrdU标记新生的神经细胞,通过免疫组化实验,结合神经细胞分化成熟各阶段特有的生物标志分析,检测小鼠神经生成的变化。发现EUK1001处理促进小鼠海马的神经前体细胞增殖与新生神经细胞的存活,但对其分化无显著影响,对侧脑室室管膜下区的神经生成也没有明显效果。
为了初步探索EUK1001处理促进神经细胞增殖的机制,选择了6个文献报道与成年神经生成有关基因,对其在小鼠海马中的表达情况进行了实时荧光定量PCR分析。结果显示,EUK1001处理明显增加了BDNF在海马中的表达水平,但对其它相关基因的表达没有显著影响。这提示,EUK1001出来可能通过提高BDNF表达,进而促进海马神经细胞增殖。
研究表明,给予小鼠15天的EUK1001处理,能上调BDNF在海马区的mRNA表达,并促进海马神经细胞的增殖和生存,这可能是其改善小鼠认知能力的基础。由于与已知M1受体激动剂咕诺美林相比,EUK1001具有更明显的增强记忆的作用和较小的外周副作用,显示出在治疗AD或年龄相关的认知功能损害方面的药物开发潜力。
Cholinergic system of the brain systemically participated in the exertion of cognitive function and regulation of neurogenesis. It is also involved in the process of neurodegenerative diseases such as Alzheimer's disease (AD). The M1 receptor was highly expressed in forbrain and hippocampal area. Xanomeline, an agonist of M1 receptor, is in clinical trial for AD, which could alleviate pathological syndrome of AD and improve the cognitive function. The compound has a number of side effects, such as desudation, salivation and gastrointestinal discomforts. It was reported in previous studies in our lab that EUK1001, which is a novel derivative of xanomeline, could improve learning and memory in aged mice and enhance the synaptic plasticity in hippocampus. It is also noticeable that when compared with xanomeline, EUK1001 has less side effects.
Based on the impacts of EUK1001 on aged mice and the relationship between cognitive function and neurogenesis, we postulated that it might affect the neurogenesis of adult mice. In order to testify the hypothesis, C57BL/6J mice were administered with EUK1001 for 15 days and injected with BrdU, which is a thymine analog and used to label the newly generated neural cells. The change of newly generated neural cells was detected through immunohistochemistry by double-labeled BrdU and biological markers which were particularly expressed during the different stages of differentiation and maturation. We have found that EUK1001 could promote the proliferation of hippocampal neural progenitor cells and survival of newly generated neural cells, but had marginal effects on the differentiation of neural cells and neurogenesis of SVZ in lateral ventricles.
In order to reveal the mechanism underlying increased neurogenesis by EUK1001 treatment, the expression of six genes in hippocampus were analyzed by real-time fluorescence quantitative PCR (RT-PCR). These genes were reported in literatures that involved in regulation of adult neurogenesis, included cAMP responsive element binding protein 1 (Creb1), paired box gene 6 (Pax6), vascular endothelial growth factor A (VEGFa), neurogenic differentiation 1 (Neurodl), brain derived neurotrophic factor (BDNF) and wingless-related MMTV integration site 3A (Wnt3a). Our results demonstrated that the expression of BDNF was markedly increased after EUK1001 treatment.
We have shown that fifteen days EUK1001 treatment upregulated the expression of BDNF and promoted the proliferation of neural progenitor cells and survival of newborn neural cells in hippocampus. It could be involved in the improvement of cognitive function in mice. Compared with xanomeline, EUK1001 exhibits higher efficiency for improving cognitive function and produces significantly less deleterious side effects, suggesting that it could be developed into a promising therapeutic agent for the treatment of AD and age-related memory disorders.
基于EUK1001能够改善小鼠学习记忆功能并且增强其大脑的突触可塑性,以及认知功能与神经生成之间的相互关系,EUK1001可能也会影响成年小鼠的神经生成。为验证这种可能性,对C57BL／6J小鼠给予15天的EUK1001处理,注射胸腺嘧啶的类似物BrdU标记新生的神经细胞,通过免疫组化实验,结合神经细胞分化成熟各阶段特有的生物标志分析,检测小鼠神经生成的变化。发现EUK1001处理促进小鼠海马的神经前体细胞增殖与新生神经细胞的存活,但对其分化无显著影响,对侧脑室室管膜下区的神经生成也没有明显效果。
为了初步探索EUK1001处理促进神经细胞增殖的机制,选择了6个文献报道与成年神经生成有关基因,对其在小鼠海马中的表达情况进行了实时荧光定量PCR分析。结果显示,EUK1001处理明显增加了BDNF在海马中的表达水平,但对其它相关基因的表达没有显著影响。这提示,EUK1001出来可能通过提高BDNF表达,进而促进海马神经细胞增殖。
研究表明,给予小鼠15天的EUK1001处理,能上调BDNF在海马区的mRNA表达,并促进海马神经细胞的增殖和生存,这可能是其改善小鼠认知能力的基础。由于与已知M1受体激动剂咕诺美林相比,EUK1001具有更明显的增强记忆的作用和较小的外周副作用,显示出在治疗AD或年龄相关的认知功能损害方面的药物开发潜力。
Cholinergic system of the brain systemically participated in the exertion of cognitive function and regulation of neurogenesis. It is also involved in the process of neurodegenerative diseases such as Alzheimer's disease (AD). The M1 receptor was highly expressed in forbrain and hippocampal area. Xanomeline, an agonist of M1 receptor, is in clinical trial for AD, which could alleviate pathological syndrome of AD and improve the cognitive function. The compound has a number of side effects, such as desudation, salivation and gastrointestinal discomforts. It was reported in previous studies in our lab that EUK1001, which is a novel derivative of xanomeline, could improve learning and memory in aged mice and enhance the synaptic plasticity in hippocampus. It is also noticeable that when compared with xanomeline, EUK1001 has less side effects.
Based on the impacts of EUK1001 on aged mice and the relationship between cognitive function and neurogenesis, we postulated that it might affect the neurogenesis of adult mice. In order to testify the hypothesis, C57BL/6J mice were administered with EUK1001 for 15 days and injected with BrdU, which is a thymine analog and used to label the newly generated neural cells. The change of newly generated neural cells was detected through immunohistochemistry by double-labeled BrdU and biological markers which were particularly expressed during the different stages of differentiation and maturation. We have found that EUK1001 could promote the proliferation of hippocampal neural progenitor cells and survival of newly generated neural cells, but had marginal effects on the differentiation of neural cells and neurogenesis of SVZ in lateral ventricles.
In order to reveal the mechanism underlying increased neurogenesis by EUK1001 treatment, the expression of six genes in hippocampus were analyzed by real-time fluorescence quantitative PCR (RT-PCR). These genes were reported in literatures that involved in regulation of adult neurogenesis, included cAMP responsive element binding protein 1 (Creb1), paired box gene 6 (Pax6), vascular endothelial growth factor A (VEGFa), neurogenic differentiation 1 (Neurodl), brain derived neurotrophic factor (BDNF) and wingless-related MMTV integration site 3A (Wnt3a). Our results demonstrated that the expression of BDNF was markedly increased after EUK1001 treatment.
We have shown that fifteen days EUK1001 treatment upregulated the expression of BDNF and promoted the proliferation of neural progenitor cells and survival of newborn neural cells in hippocampus. It could be involved in the improvement of cognitive function in mice. Compared with xanomeline, EUK1001 exhibits higher efficiency for improving cognitive function and produces significantly less deleterious side effects, suggesting that it could be developed into a promising therapeutic agent for the treatment of AD and age-related memory disorders.
引文
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