Novel GLP-1 Mimetics Developed To Treat Type 2 Diabetes Promote Progenitor Cell Proliferation in the Brain
Novel GLP-1 Mimetics Developed To Treat Type 2 Diabetes Promote Progenitor Cell Proliferation in the Brain
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DOI：
10.1002/jnr.22565
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Holscher, C.
中科院分区：
文献类型：
--
作者：
Hamilton, A.;Patterson, S.;Holscher, C.
糖尿病的症状之一是神经病变的进行性发展。替代CNS中神经元的一种机制是通过激活干细胞和神经元祖细胞。我们已经测试了新型GLP-1模拟物艾塞那肽（exendin-4; Byetta）和利拉鲁肽（NN 2211; Victoza）对糖尿病小鼠模型脑齿状回中祖细胞增殖速率和分化为神经元的影响，这两种药物已经上市作为2型糖尿病的治疗药物。在三种糖尿病小鼠模型（ob/ob小鼠、db/db小鼠或高脂饲料喂养小鼠）中，每天一次皮下注射GLP-1类似物4、6或10周。在灌注前24小时，给动物注射5 ′-溴-2 ′-脱氧尿苷（BrdU）以标记分裂的祖细胞。应用免疫组织化学和体视学方法，观察海马齿状回内祖细胞和doublecortin阳性神经元的数量。我们发现，在所有三种小鼠模型中，与非糖尿病对照组相比，长期腹腔注射利拉鲁肽或exendin-4后，祖细胞分裂增强了100-150%（P < 0.001）。我们还发现药物治疗后高脂饮食小鼠DG中的年轻神经元增加（P < 0.001）。GLP-1受体拮抗剂exendin（9-36）降低了这些小鼠中的祖细胞增殖。结果表明，GLP-1模拟物显示出治疗神经退行性疾病如阿尔茨海默病的前景，因为这些新药穿过血脑屏障并增加神经元生成。(C)2011 Wiley-Liss，Inc.
One of the symptoms of diabetes is the progressive development of neuropathies. One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells. We have tested the effects of the novel GLP-1 mimetics exenatide (exendin-4; Byetta) and liraglutide (NN2211; Victoza), which are already on the market as treatments for type 2 diabetes, on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes. GLP-1 analogues were injected subcutaneously for 4, 6, or 10 weeks once daily in three mouse models of diabetes: ob/ob mice, db/db mice, or high-fat-diet-fed mice. Twenty-four hours before perfusion, animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) to mark dividing progenitor cells. By using immunohistochemistry and stereological methods, the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated. We found that, in all three mouse models, progenitor cell division was enhanced compared with nondiabetic controls after chronic i.p. injection of either liraglutide or exendin-4 by 100-150% (P < 0.001). We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment (P < 0.001). The GLP-1 receptor antagonist exendin(9-36) reduced progenitor cell proliferation in these mice. The results demonstrate that GLP-1 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer's disease, because these novel drugs cross the blood-brain barrier and increase neuroneogenesis. (C) 2011 Wiley-Liss, Inc.