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Lubec J, Kalaba P, Hussein AM, et al. Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition. Mol Psychiatry. 2021;doi: 10.1038/s41380-021-01214-x.
Lubec, J., Kalaba, P., Hussein, A. M., Feyissa, D. D., Kotob, M. H., Mahmmoud, R. R., Wieder, O., Garon, A., Sagheddu, C., Ilic, M., Dragačević, V., Cybulska-Klosowicz, A., Zehl, M., Wackerlig, J., Sartori, S. B., Ebner, K., Kouhnavardi, S., Roller, A., Gajic, N., Pistis, M., Singewald, N., Leban, J. J., Korz, V., Malikovic, J., Plasenzotti, R., Sitte, H. H., Monje, F. J., Langer, T., Urban, E., Pifl, C., & Lubec, G. (2021). Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition. Molecular psychiatry, . https://doi.org/10.1038/s41380-021-01214-x
Lubec, Jana, et al. "Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition." Molecular psychiatry vol. (2021). doi: https://doi.org/10.1038/s41380-021-01214-x
Lubec J, Kalaba P, Hussein AM, Feyissa DD, Kotob MH, Mahmmoud RR, Wieder O, Garon A, Sagheddu C, Ilic M, Dragačević V, Cybulska-Klosowicz A, Zehl M, Wackerlig J, Sartori SB, Ebner K, Kouhnavardi S, Roller A, Gajic N, Pistis M, Singewald N, Leban JJ, Korz V, Malikovic J, Plasenzotti R, Sitte HH, Monje FJ, Langer T, Urban E, Pifl C, Lubec G. Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition. Mol Psychiatry. 2021 Jul 09; doi: 10.1038/s41380-021-01214-x. Epub 2021 Jul 09. PMID: 34244620.
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Mol Psychiatry. 2021 Jul 09; doi: 10.1038/s41380-021-01214-x. Epub 2021 Jul 09.

Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Molecular psychiatry

Jana Lubec, Predrag Kalaba, Ahmed M Hussein, Daniel Daba Feyissa, Mohamed H Kotob, Rasha R Mahmmoud, Oliver Wieder, Arthur Garon, Claudia Sagheddu, Marija Ilic, Vladimir Dragačević, Anita Cybulska-Klosowicz, Martin Zehl, Judith Wackerlig, Simone B Sartori, Karl Ebner, Shima Kouhnavardi, Alexander Roller, Natalie Gajic, Marco Pistis, Nicolas Singewald, Johann Jakob Leban, Volker Korz, Jovana Malikovic, Roberto Plasenzotti, Harald H Sitte, Francisco J Monje, Thierry Langer, Ernst Urban, Christian Pifl, Gert Lubec

Affiliations

  1. Programme for Proteomics, Paracelsus Medical University, Salzburg, Austria.
  2. Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
  3. Department of Zoology, Al-Azhar University, Assiut, Egypt.
  4. Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
  5. Department of Pediatrics, Faculty of Medicine, Assuit University, Assuit, Egypt.
  6. Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy.
  7. Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  8. Laboratory of Neuroplasticity, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
  9. Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  10. Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, Innsbruck, Austria.
  11. X-ray Structure Analysis Centre, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  12. Neuroscience Institute, National Research Council of Italy (CNR), Section of Cagliari, Cagliari, Italy.
  13. Division of Biomedical Research, Medical University of Vienna, Vienna, Austria.
  14. Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria.
  15. Center for Brain Research, Medical University of Vienna, Vienna, Austria.
  16. Programme for Proteomics, Paracelsus Medical University, Salzburg, Austria. [email protected].

PMID: 34244620 DOI: 10.1038/s41380-021-01214-x

Abstract

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

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