Unique Chemistry, Intake, and Metabolism of Polyamines in the Central Nervous System (CNS) and Its Body

Abstract

Polyamines (PAs) are small, versatile molecules with two or more nitrogen-containing positively charged groups and provide widespread biological functions. Most of these aspects are well known and covered by quite a number of excellent surveys. Here, the present review includes novel aspects and questions: (1) It summarizes the role of most natural and some important synthetic PAs. (2) It depicts PA uptake from nutrition and bacterial production in the intestinal system following loss of PAs via defecation. (3) It highlights the discrepancy between the high concentrations of PAs in the gut lumen and their low concentration in the blood plasma and cerebrospinal fluid, while concentrations in cellular cytoplasm are much higher. (4) The present review provides a novel and complete scheme for the biosynthesis of Pas, including glycine, glutamate, proline and others as PA precursors, and provides a hypothesis that the agmatine pathway may rescue putrescine production when ODC knockout seems to be lethal (solving the apparent contradiction in the literature). (5) It summarizes novel data on PA transport in brain glial cells explaining why these cells but not neurons preferentially accumulate PAs. (6) Finally, it provides a novel and complete scheme for PA interconversion, including hypusine, putreanine, and GABA (unique gliotransmitter) as end-products. Altogether, this review can serve as an updated contribution to understanding the PA mystery.

Putrescine Intensifies Glu/GABA Exchange Mechanism and Promotes Early Termination of Seizures

“…We are confident that the realm of the astroglial Glu-GABA exchange mechanism enhanced the possibility of understanding the role of disinhibition in seizure development and recognizing novel targets along with the potential of furthering antiepileptics [ 13 , 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Therefore, in this study, we investigated whether the intensification of the astroglial Glu-GABA exchange mechanism by exogenous application of the GABA precursor PUT [ 24 ] may be relevant in seizure dynamics.…”

The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration

“…Polyamines present a unique biochemistry in the brain, being primarily synthetized in neurons, while glial and microglial cells are mainly involved in their uptake and release. Furthermore, glial and microglial cells convert and oxidize PAs and release, besides hydrogen peroxide (H 2 O 2 ), 3-aminopropanal (3-AP) and 3-acetoamidopropanal, hypusine, putreanine and gamma-aminobutyric acid (GABA) as end-products as well [ 4 , 11 ]. The major pathway of PAs to enter the brain was found through transporters on the astrocyte endfeet enwrapping blood vessels at the glial–blood interface [ 12 ], turning the focus on the mechanisms of uptake and replenishment in the case of an age-dependent decrease in PA synthesis.…”

“…The major pathway of PAs to enter the brain was found through transporters on the astrocyte endfeet enwrapping blood vessels at the glial–blood interface [ 12 ], turning the focus on the mechanisms of uptake and replenishment in the case of an age-dependent decrease in PA synthesis. The most relevant PA transport system includes large pores such as connexins and pannexin hemichannels and transporters such as polyspecific organic cation transporters (OCTs), including solute carrier (SLC) 22A1-3 [ 4 ]. Such systems also transport monoamines such as dopamine or levodopa ( l -dopa) [ 13 ] and may function in reverse mode releasing PAs, therefore regulating the extracellular PA levels and neuronal activity [ 12 ].…”

“…Recently, the P-type ATPase transporter ATP13A3 has also been demonstrated to be involved in PA mammalian import [ 17 , 18 ]. In the adult brain, neurons are capable of synthetizing PAs [ 4 , 19 , 20 ], and glial cells but not neurons accumulate PAs [ 4 , 21 , 22 , 23 , 24 ]. However, the work of Masuko et al [ 25 ] reported that PAs, especially Spm, are accumulated in synaptic vesicles and released by depolarization.…”

“…In mammalian cells, PAs are involved in cell proliferation, differentiation, apoptosis, the synthesis of proteins and nucleic acids, the regulation of ion channel activity and the protection from oxidative injury [ 1 , 2 , 3 ]. Animals devoid of PA biosynthesis do not survive the early stages of embryonic development; notably, the supplementation of agmatine, a compound that belongs to the PA family and may serve as a precursor for Put (although exerting largely separate functions in mammal tissues), may be sufficient to rescue PA biosynthesis when the biosynthesis of Put is blocked (suggesting that the agmatine pathway is fully developed only later in life; for a discussion, see [ 4 ]). In fact, agmatine is a promising candidate for the treatment of several disorders, including neurodegenerative diseases, and highlights key roles for PAs in central nervous system (CNS) disorders [ 5 ].The cellular content of PAs is tightly regulated [ 1 , 2 , 3 ]; their biosynthesis is catalyzed by different enzymes including S-adenosylmethionine decarboxylase (AdoMetDC), ornithine decarboxylase (ODC), spermine synthase (SMS) and spermidine synthase (SRM) [ 6 ], while the enzymes N1-acetylpolyamine oxidase (PAOX), spermidine/spermine N1-acetyltransferase (SAT1) and spermine oxidase (SMOX) are involved in the PA catabolism ( Figure 1 ) [ 7 , 8 , 9 , 10 ].…”