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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The Bradykinin B2 Receptor Agonist (NG291) Causes Rapid Onset of Transient Blood-Brain Barrier Disruption Without Evidence of Early Brain Injury

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Rodriguez-Masso, Sergio R. [1] ; Erickson, Michelle A. [2, 3] ; Banks, William A. [2, 3] ; Ulrich, Henning [4] ; Martins, Antonio Henrique [1]
Total Authors: 5
[1] Univ Puerto Rico Med Sciences Campus, Dept Pharmacol & Toxicol, San Juan, PR - USA
[2] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA - USA
[3] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA - USA
[4] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: FRONTIERS IN NEUROSCIENCE; v. 15, DEC 15 2021.
Web of Science Citations: 0

Background: The blood-brain barrier (BBB) describes the brain's highly specialized capillaries, which form a dynamic interface that maintains central nervous system (CNS) homeostasis. The BBB supports the CNS, in part, by preventing the entry of potentially harmful circulating molecules into the brain. However, this specialized function is challenging for the development of CNS therapeutics. Several strategies to facilitate drug delivery into the brain parenchyma via disruption of the BBB have been proposed. Bradykinin has proven effective in disrupting mechanisms across the blood-tumor barrier. Unfortunately, bradykinin has limited therapeutic value because of its short half-life and the undesirable biological activity elicited by its active metabolites.Objective: To evaluate NG291, a stable bradykinin analog, with selective agonist activity on the bradykinin-B2 receptor and its ability to disrupt the BBB transiently.Methods: Sprague Dawley rats and CD-1 mice were subjected to NG291 treatment (either 50 or 100 mu g/kg, intravenously). Time and dose-dependent BBB disruption were evaluated by histological analysis of Evans blue (EB) extravasation. Transcellular and paracellular BBB leakage were assessed by infiltration of Tc-99m-albumin (66.5 KDa) and C-14-sucrose (340 Da) radiolabeled probes into the brains of CD-1 mice treated with NG291. NG291 influence on P-glycoprotein (P-gp) efflux pump activity was evaluated by quantifying the brain accumulation of H-3-verapamil, a known P-gp substrate, in CD-1 mice.Results: NG291-mediated BBB disruption was localized, dose-dependent, and reversible as measured by EB extravasation. Tc-99m-albumin leakage was significantly increased by 50 mu g/kg of NG291, whereas 100 mu g/kg of NG291 significantly augmented both C-14-sucrose and Tc-99m-albumin leakage. NG291 enhanced P-gp efflux transporter activity and was unable to increase brain uptake of the P-gp substrate pralidoxime. NG291 did not evoke significant short-term neurotoxicity, as it did not increase brain water content, the number of Fluoro-Jade C positive cells, or astrocyte activation.Conclusion: Our findings strongly suggest that NG291 increases BBB permeability by two different mechanisms in a dose-dependent manner and increases P-gp efflux transport. This increased permeability may facilitate the penetration into the brain of therapeutic candidates that are not P-gp substrates. (AU)

FAPESP's process: 18/08426-0 - Indole alkaloid sub products of Maqui (Aristotelia chilensis) processing as food additives to Alzheimer's Disease treatment
Grantee:Alexander Henning Ulrich
Support Opportunities: Regular Research Grants