Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics.
Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics.
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DOI：
10.1016/j.bcp.2020.114187
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发表时间：
2020-10
影响因子：
5.8
通讯作者：
Banks WA
中科院分区：
文献类型：
--
作者：
Salameh TS;Rhea EM;Talbot K;Banks WA
针对阿尔茨海默病（AD）和帕金森病（PD）提出的更有前景的治疗方法是降低大脑胰岛素抵抗。肠促胰岛素受体激动剂 (IRAs) 类抗糖尿病药可减轻 AD 和 PD 动物模型的症状和脑部病理，以及全身给药后 AD 病例中的葡萄糖利用和 PD 病例中的临床症状。至少 9 种不同的 IRA 有望成为 AD 和 PD 治疗药物，但我们仍然缺乏它们穿过血脑屏障 (BBB) 到达脑实质的相对能力的定量数据。因此，我们比较了成年 CD-1 小鼠静脉注射 125I 标记 IRA 在 60 分钟内的脑摄取药代动力学。我们测试了单一 IRA（exendin-4、利拉鲁肽、利西拉肽和索马鲁肽），其结合一种肠促胰岛素（胰高血糖素样肽-1 [GLP-1]）的受体，以及双重 IRA，其结合两种肠促胰岛素（GLP-1 和葡萄糖依赖性促胰岛素多肽 [GIP]）的受体，包括无支链、酰化、聚乙二醇化或 C 末端修饰形式（Finan/Ma 肽 17、18 和 20 以及 Hölscher 肽 DA3-CH 和 DA-JC4）。非酰化和非聚乙二醇化 IRA（exendin-4、利西拉来、肽 17、DA3-CH 和 DA-JC4）具有显着的血脑流入率 (Ki)，但酰化 IRA（利拉鲁肽、索马鲁肽和肽 18）未显着穿过 BBB。非酰化、非聚乙二醇化 IRA 的脑流入量在这些药物达 1 μg 时不会饱和，并且最有可能是通过脑内皮细胞的吸附转胞吞作用介导的，如 exendin-4 所观察到的。在测试的非酰化、非聚乙二醇化 IRA 中，exendin-4 和 DA-JC4 根据其脑流入速率、到达大脑并在脑实质中积累的百分比以及每克脑组织吸收的全身剂量的百分比，最能穿过 BBB。因此，Exendin-4 和 DA-JC4 值得特别关注，因为 IRA 非常适合进入中枢神经系统 (CNS)，从而到达 AD 和 PD 的病理区域。
Among the more promising treatments proposed for Alzheimer’s disease (AD) and Parkinson’s disease (PD) are those reducing brain insulin resistance. The antidiabetics in the class of incretin receptor agonists (IRAs) reduce symptoms and brain pathology in animal models of AD and PD, as well as glucose utilization in AD cases and clinical symptoms in PD cases after their systemic administration. At least 9 different IRAs are showing promise as AD and PD therapeutics, but we still lack quantitative data on their relative ability to cross the blood-brain barrier (BBB) reaching the brain parenchyma. We consequently compared brain uptake pharmacokinetics of intravenous 125I-labeled IRAs in adult CD-1 mice over the course of 60 min. We tested single IRAs (exendin-4, liraglutide, lixisenatide, and semaglutide), which bind receptors for one incretin (glucagon-like peptide-1 [GLP-1]), and dual IRAs, which bind receptors for two incretins (GLP-1 and glucose-dependent insulinotropic polypeptide [GIP]), including unbranched, acylated, PEGylated, or C-terminally modified forms (Finan/Ma Peptides 17, 18, and 20 and Hölscher peptides DA3-CH and DA-JC4). The non-acylated and non-PEGylated IRAs (exendin-4, lixisenatide, Peptide 17, DA3-CH and DA-JC4) had significant rates of blood-to-brain influx (Ki), but the acylated IRAs (liraglutide, semaglutide, and Peptide 18) did not measurably cross the BBB. The brain influx of the non-acylated, non-PEGylated IRAs were not saturable up to 1 μg of these drugs and was most likely mediated by adsorptive transcytosis across brain endothelial cells, as observed for exendin-4. Of the non-acylated, non-PEGylated IRAs tested, exendin-4 and DA-JC4 were best able to cross the BBB based on their rate of brain influx, percentage reaching the brain that accumulated in brain parenchyma, and percentage of the systemic dose taken up per gram of brain tissue. Exendin-4 and DA-JC4 thus merit special attention as IRAs well-suited to enter the central nervous system (CNS), thus reaching areas pathologic in AD and PD.
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影响因子：
2.6
作者：
Banks WA
通讯作者：
Banks WA
影响因子：
3.7
作者：
Borlongan CV;Burns J;Tajiri N;Stahl CE;Weinbren NL;Shojo H;Sanberg PR;Emerich DF;Kaneko Y;van Loveren HR
通讯作者：
van Loveren HR
DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
通讯作者：
Foltynie T
影响因子：
6
作者：
Batista, Andre F.;Bodart-Santos, Victor;Ferreira, Sergio T.
通讯作者：
Ferreira, Sergio T.
影响因子：
4.1
作者：
Blanco-Silvente L;Capellà D;Garre-Olmo J;Vilalta-Franch J;Castells X
通讯作者：
Castells X