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

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
School of Pharmacy, The University of Queensland, Brisbane, QLD 4072, Australia
School of Chemistry & Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(7), 349;
Received: 18 June 2019 / Revised: 14 July 2019 / Accepted: 16 July 2019 / Published: 18 July 2019
(This article belongs to the Special Issue Drug Delivery to the Brain)
PDF [1388 KB, uploaded 18 July 2019]


Using 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. View Full-Text
Keywords: TRH; brain-targeting prodrug design; prolyl oligopeptides (POP); lipoamino acid; CNS-drug delivery TRH; brain-targeting prodrug design; prolyl oligopeptides (POP); lipoamino acid; CNS-drug delivery

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Prokai-Tatrai, K.; De La Cruz, D.L.; Nguyen, V.; Ross, B.P.; Toth, I.; Prokai, L. Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach. Pharmaceutics 2019, 11, 349.

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