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

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Using thyrotropin-releasing hormone (TRH) as a model, paper explores 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.

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12 p.

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Prokai-Tatrai, Katalin; De La Cruz, Daniel L.; Nguyen, Vien; Ross, Benjamin P.; Toth, Istvan & Prókai, László, 1958- July 18, 2019.

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UNT Health Science Center is one of the nation's premier graduate academic medical centers, with five schools that specialize in patient-centered education, research, and health care: Texas College of Osteopathic Medicine, Graduate School of Biomedical Sciences, School of Public Health, School of Health Professions, and UNT System College of Pharmacy.

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Using thyrotropin-releasing hormone (TRH) as a model, paper explores 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.

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12 p.

Notes

Abstract: 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.

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  • Pharmaceutics, 11(7), Multidisciplinary Digital Publishing Institute, July 2019

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  • Volume: 11
  • Issue: 7
  • Pages: 12
  • Peer Reviewed: Yes
  • Publication Title: Pharmaceutics

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UNT Scholarly Works

Materials from the UNT community's research, creative, and scholarly activities and UNT's Open Access Repository. Access to some items in this collection may be restricted.

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  • July 18, 2019

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  • May 11, 2020, 3:41 p.m.

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  • Oct. 23, 2023, 1:35 p.m.

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Prokai-Tatrai, Katalin; De La Cruz, Daniel L.; Nguyen, Vien; Ross, Benjamin P.; Toth, Istvan & Prókai, László, 1958-. Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach, article, July 18, 2019; [Basel, Switzerland]. (https://digital.library.unt.edu/ark:/67531/metadc1638167/: accessed April 18, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Health Science Center.

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