Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

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dc.creatorProkai-Tatrai, Katalin
dc.creatorDe La Cruz, Daniel L.
dc.creatorNguyen, Vien
dc.creatorRoss, Benjamin P.
dc.creatorToth, Istvan
dc.creatorProkai, Laszlo
dc.creator.orcid0000-0001-5595-1346 (Prokai-Tatrai, Katalin)
dc.creator.orcid0000-0002-4559-3458 (Prokai, Laszlo)
dc.date.accessioned2022-11-15T20:25:49Z
dc.date.available2022-11-15T20:25:49Z
dc.date.issued2019-07-18
dc.description.abstractUsing thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential.
dc.description.sponsorshipThis research was funded in part by a UNTHSC Intramural grant (to K.P.-T.) and by The Welch Foundation (endowment BK-0031 to L.P).
dc.identifier.citationProkai-Tatrai, K., De La Cruz, D. L., Nguyen, V., Ross, B. P., Toth, I., & Prokai, L. (2019). Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach. Pharmaceutics, 11(7), 349. https://doi.org/10.3390/pharmaceutics11070349
dc.identifier.issn1999-4923
dc.identifier.issue7
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31914
dc.identifier.volume11
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/pharmaceutics11070349
dc.rights.holder© 2019 by the authors.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePharmaceutics
dc.subjectCNS-drug delivery
dc.subjectTrh
dc.subjectbrain-targeting prodrug design
dc.subjectlipoamino acid
dc.subjectprolyl oligopeptides (POP)
dc.titleBrain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach
dc.typeArticle
dc.type.materialtext

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