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.

Keywords: CNS; agmatine; astrocytes; glial cells; neurons; nutrition; polyamines; spermidine; spermine; transport.

Figure 1

Schematic representation of nutritional intake and regulated biosynthesis to maintain polyamine homeostasis in the body. Nutritional intake into the blood stream includes arginine and orhithine in addition to the polyamines (PAs) putrescine, spermidine, and spermine. PAs are taken up mostly in the small intestine and delivered to the blood stream, but they cannot pass the blood–brain barrier. However, arginine and ornithine can and will represent starting materials of the regulated biosynthesis of PAs in the central nervous system. Inside the neuron, PA concentrations are tightly controlled by at least six proteins, represented as boxes in the bottom row: antizyme inhibitor, ornithine decarboxylase, S-adenosylmethionine decarboxylase, Spd/Spm-synthase, antizyme, and Spm/Spd-N¹-acetyltransferase. Arrows or blocked arrows indicate which target proteins (green: increase PAs; red: decrease PAs) are modulated by a given PA. The colour of the (x) indicates which PA is involved.

Figure 2

Schematic representation of polyamine biosynthesis. The most important biosynthetic pathway begins with the action of arginase on arginine, forming ornithine, and its subsequent decarboxylation provides putrescine (PUT). PUT may also be obtained from arginine via decarboxylation to agmatine and subsequent action of agmatinase (left column). In addition, ornithine may be obtained from arginine and glycine via arginine-glycine-amidinotransferase. Glutamate and proline provide additional sources (middle columns). The additional carbon chains of spermidine and spermine are derived from methionine (right column).

Figure 3

Schematic representation of polyamine catabolism and conversions. In the first step, the classical degradation pathway for spermine and spermidine involves N-acetylation via the corresponding N-acetyl transferase. N-acetylated PAs are oxidized by peroxisomal polyamine oxidase, yielding spermidine or putrescine, respectively. Alternately, spermine may be directly oxidized by spermine oxidase to N⁸-3-propyl-spermidine (upper left side), which spontaneously splits off acrolein and thus is converted to spermidine. This molecule, instead of N-acetylation, may be oxidized by diamine oxidase to N¹-3-propyl-putrescine (lower left side), which again under loss of acrolein forms putrescine. There are two side pathways. Spermidine may be attached to a lysine side chain of a nascent protein, which subsequently is hydroxylated to the functional elF5A-hypusine transcription factor (right side). In a separate pathway, N¹-3-propyl-putrescine, the product of the oxidation of N-acetyl-spermidine by diamine oxidase, is reduced to putreanine.

Figure 4

Spermidine/spermine immunoreactivity is predominantly localized in astrocytes, not in neurons. Coronal sections of rat hippocampus after immunocytochemical visualization of SPD/SPM. The antibody (raised in the author’s lab [66]) does not differentiate between tissue-bound spermidine and spermine. Thus, these two polyamines cannot be visualized separately. (A) Spd/spm-immunoreactivity in the CA1 region of the hippocampus is largely restricted to astrocytes. Some of their processes extend to capillaries (left arrow), forming endfeet there. Note the strong staining of the capillary walls (right arrow). Whether this staining is due to labeled astrocyte endfeet or to an immunopositive endothelium cannot be decided here. (B) In the dentate gyrus spd/spm-immunoreactivity of astrocytes displays a very different appearance. Many cell bodies are found at the lower border of the granule cell layer (arrows), with rather straight processes extending to the molecular layer. Other astrocytes with a similar morphology are found in more superficial regions of the dentate gyrus. In contrast, the bottom of the photograph presents the hilar area, where astrocytes show their usual appearance. (C) Among immunoreactive astrocytes, the corpus callosum also displays spd/spm-positive oligodendrocytes (white arrow). Taken from Höhlig et al., this special issue. Bar in (A) indicates 50 µm in (A–C).

Figure 5

Immunocytochemical visualization of some components of polyamine metabolism. Coronal sections of rat cortex (A,C,E) and hippocampus (B,D,F) after immunocytochemical visualization of (1) N-acetylspermine, (2) acrolein, and (3) ornithine display staining predominantly in neurons. Antibodies had been raised in the author’s laboratory (1, 3) as described earlier [66] or were obtained from commercial sources (2, rabbit anti-acrolein; LS-C63521, MoBiTec, Göttingen, Germany). All control sections were negative. Surprisingly, immunoreactivity is more pronounced in interneurons (single arrows in all images) as compared to adjacent neurons in all sections. This indicates that there may be considerable differences between separate classes of neurons. Note the strong acrolein-immunoreactivity in capillary walls ((D), double arrow). Bar in (F) indicates 50 µm in all images. Taken from Höhlig et al., this special issue.

Figure 6

Distinct mechanisms promote circulation of polyamines and acetylated polyamines in the brain. (A) Suggested interaction between astrocytes (violet), neuronal dendrites (yellow), synapses (yellow), lymphocytes (green), and blood vessels (black) based on bi-directional polyamine (PA) fluxes (red arrows). PAs and aPAs are taken up and released from glia to neurons as well as propagated distantly through the syncytium. (B) Suggested PA and acetylated PAs (aPAs) pathways (uptake and release) in glia via (i) connexin 43 (Cx43) hemichannels (green) or gap-junctions (green), (ii) transporters such as organic cation transporters (OCTs) SLC22A1-3 (orange), and (iii) vesicular PA transporter (vPAT) SLC18B1 with subsequent vesicular uptake/release (brown). Minor pathways (iv) are present in some channels (Kir4.1, NMDAR, AMPAR, TRPV1, P2X7). The scheme represents data from Laube and Veh, 1997; Masuko et al., 2003; Cui et al., 2009; Benedikt et al., 2012; Sala-Rabanal et al., 2013; Merali et al., 2014; Skatchkov et al., 2014; 2015; 2016; Kucheryavykh et al., 2017; Malpica-Nieves et al., 2020; 2021. (C) Astrocytes extend their endfeet to small vessels, as shown here after staining of rat hippocampus for spermine-like immunoreactivity.