Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer's and Parkinson's diseases.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Elizabeth M Rhea, Alice Babin, Peter Thomas, Mohamed Omer, Riley Weaver, Kim Hansen, William A Banks, Konrad Talbot
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引用次数: 0

Abstract

Background: A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's disease (PD). Transport across the blood-brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics.

Methods: We quantitatively measure the ability of four IRAs to cross the BBB. We injected adult male CD-1 mice intravenously with 125I- or 14C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h).

Results: Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways.

Conclusions: We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole.

阿必鲁肽、度拉鲁肽、替唑帕肽和 DA5-CH 的脑摄取药代动力学,寻找阿尔茨海默氏症和帕金森氏症的新疗法。
背景:一些多肽增量素受体激动剂(IRA)有望成为治疗阿尔茨海默病(AD)和帕金森病(PD)的药物。通过血脑屏障(BBB)转运是IRAs直接作用于大脑的一种方式。为了确定哪些IRAs是治疗这些疾病的优先候选药物,我们研究了它们的脑摄取药代动力学:我们定量测量了四种IRA穿过BBB的能力。我们给成年雄性CD-1小鼠静脉注射了125I或14C标记的阿比鲁肽、度拉鲁肽、DA5-CH或替扎帕肽,并使用多元时间回归分析法测量了1小时内的脑动力学。对于静脉注射1小时后未能进入大脑的IRA,我们还研究了它们在更长时间(即6小时)内进入大脑的能力:结果:阿尔必鲁肽和度拉鲁肽在1小时内的脑吸收率最快。DA5-CH 似乎能迅速进入大脑,并很快达到平衡。替扎帕肽在静脉注射后1小时内似乎不能穿过BBB,但与白蛋白一样,在6小时内穿过BBB的速度很慢,可能是通过细胞外途径:我们发现,IRAs 可通过两个不同的过程穿过 BBB:一个是快速过程,另一个是缓慢过程。在本文研究的四种IRA中,有三种具有较快的运输速度,应考虑将其作为AD和PD的治疗药物进行测试,因为它们能够快速直接作用于整个大脑。
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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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