Transient Opening of the Blood-Brain Barrier by Vasoactive Peptides to Increase CNS Drug Delivery: Reality Versus Wishful Thinking?

Abstract

Background: The blood-brain barrier inhibits the central nervous system penetration of 98% of small molecule drugs and virtually all biologic agents, which has limited progress in the treatment of neurologic disease. Vasoactive peptides have been shown in animal studies to transiently disrupt the blood-brain barrier and regadenoson is currently being studied in humans to determine if it can improve drug delivery to the brain. However, there are many other vasoactive peptides that could potentially be used for this purpose. Methods: We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the blood-brain barrier, we devised a four-tier classification system to organize the evidence available. Results: We identified 33 vasoactive peptides with potential blood-brain barrier permeability-altering properties. To date, none of these are shown to open the blood-brain barrier in humans. 12 vasoactive peptides increased blood-brain barrier permeability in rodents. The remaining 23 had favorable physiologic effects on blood vessels but lacked specific information on permeability changes to the blood-brain barrier. Conclusion: Vasoactive peptides remain an understudied class of drugs with the potential to increase drug delivery and improve treatment in patients with brain tumors and other neurologic diseases. Dozens of vasoactive peptides have yet to be formally evaluated for this important clinical effect. This narrative review summarizes the available data on vasoactive peptides, highlighting agents that deserve further in vitro and in vivo investigations.

Evidence for interictal blood–brain barrier dysfunction in people with epilepsy

“…The inclusion criteria were the same as for the epilepsy group. Because medication can affect BBB permeability in two ways (disruptive and restorative) 20,32 and may cause memory deficits, 33 medication taken by individuals in this study were ascertained. The study was approved by the local institutional review board, and all people participating gave written informed consent.…”

Next‐generation agents for fluorescence‐guided glioblastoma surgery

“…Alternative mechanisms to BBB crossing can see both peptide‐mediated direct translocation, typical of cell‐penetrating peptides (CPPs), and transient disruption of the tight junctions between endothelial cells of the BBB. These BBB‐opening properties are shown in some peptide analogs of bradykinin, and can be exploited to improve the delivery of anticancer drugs to the brain 66,67 . Moreover, in general, the direct translocation of CPPs is typically triggered by the interaction between positively charged CPP residues and negatively charged membrane elements, causing either permanent or temporary membrane instability induced by the folding of the lipid membrane.…”

“…These BBB‐opening properties are shown in some peptide analogs of bradykinin, and can be exploited to improve the delivery of anticancer drugs to the brain. 66 , 67 Moreover, in general, the direct translocation of CPPs is typically triggered by the interaction between positively charged CPP residues and negatively charged membrane elements, causing either permanent or temporary membrane instability induced by the folding of the lipid membrane. Several mechanistic models for direct penetration have been proposed, as extensively reviewed elsewhere.…”

Nanoparticles loaded with natural medicines for the treatment of Alzheimer’s disease

“…While blocking toxins, the BBB can also prevent many drugs from reaching the nervous system. It has been reported that 98% of small-molecule drugs cannot cross the BBB and act on the nervous system ( Neumaier et al, 2021 ; Smith-Cohn et al, 2022 ). Moreover, the processing mechanisms for natural medicine make it difficult for the drug to pass through the BBB, and these drugs have low solubility in brain tissue ( Zhang J. et al, 2019 ).…”