Noor Abdulhameed, Alice Babin, Kim Hansen, Riley Weaver, William A Banks, Konrad Talbot, Elizabeth M Rhea
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Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. 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引用次数: 0
摘要
针对脑胰岛素抵抗(BIR)的治疗已成为阿尔茨海默病(AD)传统疗法的一种有吸引力的替代疗法。事实证明,以胰高血糖素样肽 1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)受体中的一种或两种受体为靶点的胰岛素受体激动剂(IRAs)可以逆转胰岛素抵抗并改善 AD 小鼠模型的认知能力。我们以前的研究表明,静脉注射后,许多(但不是所有)IRA 可以穿过血脑屏障(BBB)。在这里,我们确定了是否可以通过鼻内给药绕过血脑屏障来实现脑部对 IRAs 的广泛吸收,鼻内给药的另一个优点是可以最大程度地减少全身给药对胃肠道的不良影响。在CD-1小鼠体内测试的5种放射性标记IRA(艾塞那肽、度拉鲁肽、赛马鲁肽、DA4-JC和DA5-CH)中,艾塞那肽、度拉鲁肽和DA4-JC在IN给药后成功分布于整个大脑。我们观察到 DA4-JC 的摄取存在明显的性别差异。杜拉鲁肽和 DA4-JC 在海马和多个新皮质区域表现出较高的摄取率。我们进一步测试发现,AD 相关 Aβ 病理学的存在对度拉鲁肽和 DA4-JC 的摄取影响很小。在测试的5种IRA中,杜拉鲁肽和DA4-JC在IN给药后最能进入AD最脆弱的脑区(新皮质和海马)。未来还需要进行研究,以确定 IN IRA 给药是否能减少注意力缺失症或该疾病动物模型的 BIR。
Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease.
Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.
期刊介绍:
Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.