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

by Selleckchem | Jan 30 2024

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.

Comments:

Your research seems quite focused and detailed! It's fascinating that you're studying the blood-brain barrier (BBB) transport of peptide incretin receptor agonists (IRAs) and their potential for treating Alzheimer's and Parkinson's diseases. Identifying the kinetics of these IRAs in crossing the BBB is crucial for understanding their therapeutic potential.

The finding that albiglutide and dulaglutide exhibit rapid brain uptake rates within 1 hour is promising. It suggests their potential to act quickly within the brain, which could be advantageous for therapeutic interventions in Alzheimer's and Parkinson's diseases. Additionally, the observation that DA5-CH reaches equilibrium rapidly upon entering the brain indicates its potential as well.

The slower uptake of tirzepatide over 6 hours, resembling the extracellular pathways, provides interesting insights into its mode of transport. Although it doesn't penetrate the BBB within the initial hour, its eventual entry could still be relevant, especially considering the slow but continued access to the brain.

This distinction between fast and slow transport mechanisms for IRAs across the BBB is crucial in determining their suitability as therapeutics for AD and PD. Identifying candidates with rapid brain access could be advantageous for more immediate therapeutic effects.

Do you have plans to further investigate the specific mechanisms by which these IRAs traverse the BBB? Understanding these mechanisms could provide deeper insights into their potential as neurotherapeutics.