Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/11/7/349 |
| _version_ | 1798040466382389248 |
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| author | Katalin Prokai-Tatrai Daniel L. De La Cruz Vien Nguyen Benjamin P. Ross Istvan Toth Laszlo Prokai |
| author_facet | Katalin Prokai-Tatrai Daniel L. De La Cruz Vien Nguyen Benjamin P. Ross Istvan Toth Laszlo Prokai |
| author_sort | Katalin Prokai-Tatrai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T22:07:59Z |
| format | Article |
| id | doaj.art-686d567471794e75b134ed3a90d7fa5e |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T22:07:59Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-686d567471794e75b134ed3a90d7fa5e2022-12-22T04:00:38ZengMDPI AGPharmaceutics1999-49232019-07-0111734910.3390/pharmaceutics11070349pharmaceutics11070349Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug ApproachKatalin Prokai-Tatrai0Daniel L. De La Cruz1Vien Nguyen2Benjamin P. Ross3Istvan Toth4Laszlo Prokai5Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USASchool of Pharmacy, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Chemistry & Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, AustraliaDepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USAUsing 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.https://www.mdpi.com/1999-4923/11/7/349TRHbrain-targeting prodrug designprolyl oligopeptides (POP)lipoamino acidCNS-drug delivery |
| spellingShingle | Katalin Prokai-Tatrai Daniel L. De La Cruz Vien Nguyen Benjamin P. Ross Istvan Toth Laszlo Prokai Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach Pharmaceutics TRH brain-targeting prodrug design prolyl oligopeptides (POP) lipoamino acid CNS-drug delivery |
| title | Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach |
| title_full | Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach |
| title_fullStr | Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach |
| title_full_unstemmed | Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach |
| title_short | Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach |
| title_sort | brain delivery of thyrotropin releasing hormone via a novel prodrug approach |
| topic | TRH brain-targeting prodrug design prolyl oligopeptides (POP) lipoamino acid CNS-drug delivery |
| url | https://www.mdpi.com/1999-4923/11/7/349 |
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