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

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.

Central nervous system insulin signaling can influence the rate of insulin influx into brain.

BACKGROUND: Insulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer's disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD. METHODS: We investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice. RESULTS: We found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus. CONCLUSIONS: These results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.

Insulin blood-brain barrier transport and interactions are greater following exercise in mice.

Exercise has multiple beneficial effects including improving peripheral insulin sensitivity, improving central function such as memory, and restoring a dysregulated blood-brain barrier (BBB). Central nervous system (CNS) insulin resistance is a common feature of cognitive impairment, including Alzheimer's disease. Delivery of insulin to the brain can improve memory. Endogenous insulin must cross the BBB to directly act within the CNS and this transport system can be affected by various physiological states and serum factors. Therefore, the current study sought to investigate whether exercise could enhance insulin BBB transport as a mechanism for the underlying benefits of exercise on cognition. We investigated radioactive insulin BBB pharmacokinetics following an acute bout of exercise in young, male and female CD-1 mice. In addition, we investigated changes in serum levels of substrates that are known to affect insulin BBB transport. Finally, we measured the basal level of a downstream protein involved in insulin receptor signaling in various brain regions as well as muscle. We found insulin BBB transport in males was greater following exercise, and in males and females to both enhance the level of insulin vascular binding and alter CNS insulin receptor signaling, independent of changes in serum factors known to alter insulin BBB transport.NEW & NOTEWORTHY Central nervous system (CNS) insulin and exercise are beneficial for cognition. CNS insulin resistance is present in Alzheimer's disease. CNS insulin levels are regulated by transport across the blood-brain barrier (BBB). We show that exercise can enhance insulin BBB transport and binding of insulin to the brain's vasculature in mice. There were no changes in serum factors known to alter insulin BBB pharmacokinetics. We conclude exercise could impact cognition through regulation of insulin BBB transport.