Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier
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
Affiliations
Yurii A. Zolotarev
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Vladimir A. Mitkevich
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Stanislav I. Shram
Department of Physiologically Active Substances Chemistry, Institute of Molecular Genetics of National Research Center «Kurchatov Institute», 123182 Moscow, Russia
Alexei A. Adzhubei
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Anna P. Tolstova
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Oleg B. Talibov
Department of Clinical Pharmacology, Faculty of Common Medicine, Evdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
Alexander K. Dadayan
Department of Physiologically Active Substances Chemistry, Institute of Molecular Genetics of National Research Center «Kurchatov Institute», 123182 Moscow, Russia
Nikolai F. Myasoyedov
Department of Physiologically Active Substances Chemistry, Institute of Molecular Genetics of National Research Center «Kurchatov Institute», 123182 Moscow, Russia
Alexander A. Makarov
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Sergey A. Kozin
Laboratory of Protein Conformational Polymorphism in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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.
