针对脑胰岛素抵抗(BIR)已成为阿尔茨海默病(AD)传统治疗方法的一种有吸引力的替代方法。肠促胰岛素受体激动剂(IRAs),靶向胰高血糖素样肽1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)受体之一或两者,已被证明可以逆转BIR并改善AD小鼠模型的认知。我们之前展示了很多,但不是全部,IRA可在静脉内(IV)递送后穿过血脑屏障(BBB)。在这里,我们确定是否可以通过使用鼻内(IN)递送绕过BBB来实现IRA的广泛脑摄取,其具有最小化全身递送的IRA的不良胃肠道作用的额外优点。在测试的5个放射性标记的IRA中(艾塞那肽,杜拉鲁肽,塞马鲁肽,DA4-JC,和DA5-CH)在CD-1小鼠中,艾塞那肽,杜拉鲁肽,和DA4-JC在IN递送后成功分布在整个大脑中。我们观察到DA4-JC摄取的显著性别差异。Dulaglutide和DA4-JC表现出海马和多个新皮质区域的高摄取。我们进一步测试并发现与AD相关的Aβ病理的存在对杜拉鲁肽和DA4-JC的摄取影响最小。在5个测试的IRA中,杜拉鲁肽和DA4-JC最有能力在给药后进入AD中最脆弱的大脑区域(新皮质和海马)。需要进行未来的研究以确定在AD或该疾病的动物模型中INIRA递送是否可以减少BIR。
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.