Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier
One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amid...
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MDPI AG
2021-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/6/909 |
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| author | Yurii A. Zolotarev Vladimir A. Mitkevich Stanislav I. Shram Alexei A. Adzhubei Anna P. Tolstova Oleg B. Talibov Alexander K. Dadayan Nikolai F. Myasoyedov Alexander A. Makarov Sergey A. Kozin |
| author_facet | Yurii A. Zolotarev Vladimir A. Mitkevich Stanislav I. Shram Alexei A. Adzhubei Anna P. Tolstova Oleg B. Talibov Alexander K. Dadayan Nikolai F. Myasoyedov Alexander A. Makarov Sergey A. Kozin |
| author_sort | Yurii A. Zolotarev |
| collection | DOAJ |
| description | One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain. |
| first_indexed | 2024-03-10T10:17:11Z |
| format | Article |
| id | doaj.art-08035eaa9ffc4b28bcc34298430cb247 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T10:17:11Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-08035eaa9ffc4b28bcc34298430cb2472023-11-22T00:44:17ZengMDPI AGBiomolecules2218-273X2021-06-0111690910.3390/biom11060909Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain BarrierYurii A. Zolotarev0Vladimir A. Mitkevich1Stanislav I. Shram2Alexei A. Adzhubei3Anna P. Tolstova4Oleg B. Talibov5Alexander K. Dadayan6Nikolai F. Myasoyedov7Alexander A. Makarov8Sergey A. Kozin9Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaLaboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaDepartment of Physiologically Active Substances Chemistry, Institute of Molecular Genetics of National Research Center «Kurchatov Institute», 123182 Moscow, RussiaLaboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaLaboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaDepartment of Clinical Pharmacology, Faculty of Common Medicine, Evdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, RussiaDepartment of Physiologically Active Substances Chemistry, Institute of Molecular Genetics of National Research Center «Kurchatov Institute», 123182 Moscow, RussiaDepartment of Physiologically Active Substances Chemistry, Institute of Molecular Genetics of National Research Center «Kurchatov Institute», 123182 Moscow, RussiaLaboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaLaboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaOne of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.https://www.mdpi.com/2218-273X/11/6/909Alzheimer’s diseasebeta-amyloidα4β2 nicotinic acetylcholine receptorpeptide drugblood–brain barrierreceptor-mediated transcytosis |
| spellingShingle | Yurii A. Zolotarev Vladimir A. Mitkevich Stanislav I. Shram Alexei A. Adzhubei Anna P. Tolstova Oleg B. Talibov Alexander K. Dadayan Nikolai F. Myasoyedov Alexander A. Makarov Sergey A. Kozin Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier Biomolecules Alzheimer’s disease beta-amyloid α4β2 nicotinic acetylcholine receptor peptide drug blood–brain barrier receptor-mediated transcytosis |
| title | Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier |
| title_full | Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier |
| title_fullStr | Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier |
| title_full_unstemmed | Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier |
| title_short | Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier |
| title_sort | pharmacokinetics and molecular modeling indicate nachrα4 derived peptide haee goes through the blood brain barrier |
| topic | Alzheimer’s disease beta-amyloid α4β2 nicotinic acetylcholine receptor peptide drug blood–brain barrier receptor-mediated transcytosis |
| url | https://www.mdpi.com/2218-273X/11/6/909 |
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