Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

Abstract

The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.

Contact System Activation in Plasma from Dengue Patients Might Harness Endothelial Virus Replication through the Signaling of Bradykinin Receptors

“…Efforts along these lines have yielded promising results in the first non-randomized trials conducted with icatibant in cohorts of COVID-19 patients [ 98 ]. However, as note of caution, one must be born in mind that BKR agonists are known to increase blood brain barrier permeability [ 99 ], therefore, it is conceivable that icatibant may have reduced the extent of inflammation inflicted by the surgical procedure. Disruption of the blood brain barrier may also facilitate the spread of DENV viruses in the subendothelial matrix, allowing for viral-induced degranulation of perivascular mast cells [ 100 ].…”

Increase in Blood–Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling

“…permeability of endothelial cells might be mediated by B2R under normal conditions, 36 whereas B2R is barely expressed in normal BMVECs. 37 TK was injected through the tail vein in the current study, and B2R was widely distributed in vascular endothelial cells of different organs.…”

Kinin B1 receptor deficiency protects mice fed by cafeteria diet from abnormal glucose homeostasis

“…Changes in the insulin sensitivity were also shown in similar models [ 6 ]. The injection of the B1 and B2 agonists corroborated those central influences of brain kinin receptor in the food intake regulation [ 42 , 43 ]. All the data require confirmation in future studies, in order to understand how the food composition can influence the eating behavior in different genetic models.…”