The involvement of polyamine uptake and synthesis pathways in the proliferation of neonatal astrocytes
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ORIGINAL ARTICLE
The involvement of polyamine uptake and synthesis pathways in the proliferation of neonatal astrocytes Christian J. Malpica‑Nieves1 · David E. Rivera‑Aponte1 · Flavia A. Tejeda‑Bayron1 · Angel M. Mayor3 · Otto Phanstiel4 · Rüdiger W. Veh5 · Misty J. Eaton1 · Serguei N. Skatchkov1,2 Received: 24 March 2020 / Accepted: 10 August 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract Polyamines (PAs), such as spermidine (SPD) and spermine (SPM), are essential to promote cell growth, survival, proliferation, and longevity. In the adult central nervous system (CNS), SPD and SPM are accumulated predominantly in healthy adult glial cells where PA synthesis is not present. To date, the accumulation and biosynthesis of PAs in developing astrocytes are not well understood. The purpose of the present study was to determine the contribution of uptake and/or synthesis of PAs using proliferation of neonatal astrocytes as an endpoint. We inhibited synthesis of PAs using α-difluoromethylornithine (DFMO; an inhibitor of the PA biosynthetic enzyme ornithine decarboxylase (ODC)) and inhibited uptake of PAs using trimer44NMe (PTI; a novel polyamine transport inhibitor). DFMO, but not PTI alone, blocked proliferation, suggesting that PA biosynthesis was present. Furthermore, exogenous administration of SPD rescued cell proliferation when PA synthesis was blocked by DFMO. When both synthesis and uptake of PAs were inhibited (DFMO + PTI), exogenous SPD no longer supported proliferation. These data indicate that neonatal astrocytes synthesize sufficient quantities of PAs de novo to support cell proliferation, but are also able to import exogenous PAs. This suggests that the PA uptake mechanism is present in both neonates as well as in adults and can support cell proliferation in neonatal astrocytes when ODC is blocked. Keywords Astrocyte · Polyamines · α-Difluoromethylornithine · Ornithine decarboxylase · Novel polyamine transport inhibitor (trimer44NMe)
Introduction
Handling Editor: E. Agostinelli. * Serguei N. Skatchkov [email protected] 1
Department of Biochemistry, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR 00960‑6032, USA
2
Department of Physiology, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR 00960‑6032, USA
3
Department of Internal Medicine, Universidad Central del Caribe, Bayamón, PR 00956, USA
4
Department of Medical Education, University of Central Florida, Orlando, FL 32816, USA
5
Institut für Zell- Und Neurobiologie, Charité, 10117 Berlin, Germany
Polyamines (PAs) are essential to all living cells. They are low molecular weight, organic compounds containing two or more positively charged amine groups which can interact with negatively charged molecules such as RNA, DNA, phospholipids, ATP, and acidic proteins (Watanabe et al. 1991). PAs play multiple roles in cell proliferation, growth, and survival (Pegg 2016), as well as glial cell function (Skatchkov et al. 2014, 2016) and incre
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