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Polyamines in the Central Nervous System: Neurons, Glial Cells and...
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Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 18748

Special Issue Editors

Dr. Serguei Skatchkov

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Guest Editor
School of Medicine, Universidad Central del Caribe, Bayamon, PR, USA
Interests: polyamines and their accumulation in astrocytes; radial glial (Müller, Bergmann) cells; polyamine regulated channels; gap junctions and hemichannels; glia-neuron signaling; gliotransmitters; agmatine; synaptic plasticity; electrophysiology; biochemistry; polyamine function in the brain in health and polyamine-associated diseases and syndromes
Special Issues, Collections and Topics in MDPI journals
Dr. Rüdiger W. Veh

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Guest Editor
Institut für Zell- und Neurobiologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany
Interests: polyamines and their accumulation in astrocytes; radial glial (Müller, Bergmann) cells; polyamine regulated channels; gap junctions and hemichannels; glia-neuron signaling; gliotransmitters; agmatine; synaptic plasticity; electrophysiology; biochemistry; polyamine function in the brain in health and polyamine-associated diseases and syndromes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Polyamines contribute to the pathogenesis of Alzheimer’s, Parkinson’s, and other diseases of the central nervous system (CNS), while polyamine supplementation induces regeneration of neurons and increases longevity. In the normal adult CNS, the polyamines spermidine and spermine are accumulated preferentially in astrocytic cells, not in neurons, and are key molecules regulating many receptors and channels. Recent evidence emphasizes that the localization of polyamines; their metabolites, including agmatine; and their biosynthetic enzymes in CNS (brain and retina) vary with age and are altered in diseases. This Special Issue will highlight the uneven functional distribution of polyamines in the CNS, their effects on channels and transporters, as well as their roles in CNS disorders. We invite investigators to contribute high-quality original research and review articles focused on the roles of polyamines in health and disease, concerning the biological functions of neurons, gliotransmission, and the importance in the glial system.

Dr. Serguei Skatchkov
Dr. Rüdiger W. Veh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • astrocytes
  • polyamines
  • spermine
  • spermidine
  • agmatine
  • gliotransmitters, receptors
  • channels
  • diseases
  • syndromes

Related Special Issue

Published Papers (7 papers)

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Research

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14 pages, 2653 KiB  
Article
Antizyme Inhibitor 2-Deficient Mice Exhibit Altered Brain Polyamine Levels and Reduced Locomotor Activity
by Ana Lambertos, Maria Angeles Nuñez-Sanchez, Carlos López-García, Andrés Joaquín López-Contreras, Bruno Ramos-Molina and Rafael Peñafiel
Biomolecules 2023, 13(1), 14; https://doi.org/10.3390/biom13010014 - 21 Dec 2022
Cited by 2 | Viewed by 1203
Abstract
Background: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. [...] Read more.
Background: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations. Methods: The expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. β-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the βGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice. Results: Our results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills. Conclusions: Our study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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20 pages, 3360 KiB  
Article
The Polyamine Spermine Potentiates the Propagation of Negatively Charged Molecules through the Astrocytic Syncytium
by Jan Benedikt, Christian J. Malpica-Nieves, Yomarie Rivera, Miguel Méndez-González, Colin G. Nichols, Rüdiger W. Veh, Misty J. Eaton and Serguei N. Skatchkov
Biomolecules 2022, 12(12), 1812; https://doi.org/10.3390/biom12121812 - 05 Dec 2022
Cited by 1 | Viewed by 1479
Abstract
The interest in astrocytes, the silent brain cells that accumulate polyamines (PAs), is growing. PAs exert anti-inflammatory, antioxidant, antidepressant, neuroprotective, and other beneficial effects, including increasing longevity in vivo. Unlike neurons, astrocytes are extensively coupled to others via connexin (Cx) gap junctions (GJs). [...] Read more.
The interest in astrocytes, the silent brain cells that accumulate polyamines (PAs), is growing. PAs exert anti-inflammatory, antioxidant, antidepressant, neuroprotective, and other beneficial effects, including increasing longevity in vivo. Unlike neurons, astrocytes are extensively coupled to others via connexin (Cx) gap junctions (GJs). Although there are striking modulatory effects of PAs on neuronal receptors and channels, PA regulation of the astrocytic GJs is not well understood. We studied GJ-propagation using molecules of different (i) electrical charge, (ii) structure, and (iii) molecular weight. Loading single astrocytes with patch pipettes containing membrane-impermeable dyes, we observed that (i) even small molecules do not easily permeate astrocytic GJs, (ii) the ratio of the charge to weight of these molecules is the key determinant of GJ permeation, (iii) the PA spermine (SPM) induced the propagation of negatively charged molecules via GJs, (iv) while no effects were observed on propagation of macromolecules with net-zero charge. The GJ uncoupler carbenoxolone (CBX) blocked such propagation. Taken together, these findings indicate that SPM is essential for astrocytic GJ communication and selectively facilitates intracellular propagation via GJs for negatively charged molecules through glial syncytium. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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15 pages, 2786 KiB  
Article
Reactive Astrocytosis in a Mouse Model of Chronic Polyamine Catabolism Activation
by Chiara Cervetto, Monica Averna, Laura Vergani, Marco Pedrazzi, Sarah Amato, Simone Pelassa, Stefano Giuliani, Francesca Baldini, Guido Maura, Paolo Mariottini, Manuela Marcoli and Manuela Cervelli
Biomolecules 2021, 11(9), 1274; https://doi.org/10.3390/biom11091274 - 25 Aug 2021
Cited by 14 | Viewed by 2665
Abstract
Background: In the brain, polyamines are mainly synthesized in neurons, but preferentially accumulated in astrocytes, and are proposed to be involved in neurodegenerative/neuroinflammatory disorders and neuron injury. A transgenic mouse overexpressing spermine oxidase (SMOX, which specifically oxidizes spermine) in the neocortex neurons (Dach-SMOX [...] Read more.
Background: In the brain, polyamines are mainly synthesized in neurons, but preferentially accumulated in astrocytes, and are proposed to be involved in neurodegenerative/neuroinflammatory disorders and neuron injury. A transgenic mouse overexpressing spermine oxidase (SMOX, which specifically oxidizes spermine) in the neocortex neurons (Dach-SMOX mouse) was proved to be a model of increased susceptibility to excitotoxic injury. Methods: To investigate possible alterations in synapse functioning in Dach-SMOX mouse, both cerebrocortical nerve terminals (synaptosomes) and astrocytic processes (gliosomes) were analysed by assessing polyamine levels, ezrin and vimentin content, glutamate AMPA receptor activation, calcium influx, and catalase activity. Results: The main findings are as follows: (i) the presence of functional calcium-permeable AMPA receptors in synaptosomes from both control and Dach-SMOX mice, and in gliosomes from Dach-SMOX mice only; (ii) reduced content of spermine in gliosomes from Dach-SMOX mice; and (iii) down-regulation and up-regulation of catalase activity in synaptosomes and gliosomes, respectively, from Dach-SMOX mice. Conclusions: Chronic activation of SMOX in neurons leads to major changes in the astrocyte processes including reduced spermine levels, increased calcium influx through calcium-permeable AMPA receptors, and stimulation of catalase activity. Astrocytosis and the astrocyte process alterations, depending on chronic activation of polyamine catabolism, result in synapse dysregulation and neuronal suffering. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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16 pages, 3140 KiB  
Article
Uptake of Biotinylated Spermine in Astrocytes: Effect of Cx43 siRNA, HIV-Tat Protein and Polyamine Transport Inhibitor on Polyamine Uptake
by Christian J. Malpica-Nieves, Yomarie Rivera, David E. Rivera-Aponte, Otto Phanstiel, Rüdiger W. Veh, Misty J. Eaton and Serguei N. Skatchkov
Biomolecules 2021, 11(8), 1187; https://doi.org/10.3390/biom11081187 - 11 Aug 2021
Cited by 10 | Viewed by 2835
Abstract
Polyamines (PAs) are polycationic biomolecules containing multiple amino groups. Patients with HIV-associated neurocognitive disorder (HAND) have high concentrations of the polyamine N-acetylated spermine in their brain and cerebral spinal fluid (CSF) and have increased PA release from astrocytes. These effects are due to [...] Read more.
Polyamines (PAs) are polycationic biomolecules containing multiple amino groups. Patients with HIV-associated neurocognitive disorder (HAND) have high concentrations of the polyamine N-acetylated spermine in their brain and cerebral spinal fluid (CSF) and have increased PA release from astrocytes. These effects are due to the exposure to HIV-Tat. In healthy adult brain, PAs are accumulated but not synthesized in astrocytes, suggesting that PAs must enter astrocytes to be N-acetylated and released. Therefore, we tested if Cx43 hemichannels (Cx43-HCs) are pathways for PA flux in control and HIV-Tat-treated astrocytes. We used biotinylated spermine (b-SPM) to examine polyamine uptake. We found that control astrocytes and those treated with siRNA-Cx43 took up b-SPM, similarly suggesting that PA uptake is via a transporter/channel other than Cx43-HCs. Surprisingly, astrocytes pretreated with both HIV-Tat and siRNA-Cx43 showed increased accumulation of b-SPM. Using a novel polyamine transport inhibitor (PTI), trimer 44NMe, we blocked b-SPM uptake, showing that PA uptake is via a PTI-sensitive transport mechanism such as organic cation transporter. Our data suggest that Cx43 HCs are not a major pathway for b-SPM uptake in the condition of normal extracellular calcium concentration but may be involved in the release of PAs to the extracellular space during viral infection. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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12 pages, 2873 KiB  
Article
Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity
by Zsolt Szabó, Márton Péter, László Héja and Julianna Kardos
Biomolecules 2021, 11(4), 604; https://doi.org/10.3390/biom11040604 - 19 Apr 2021
Cited by 7 | Viewed by 2704
Abstract
Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by [...] Read more.
Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by reverse operation of the astroglial GABA transporter, induced by Glu-Na+ symport. GABA, released from astrocytes, is synthesized from the polyamine (PA) putrescine and this process involves copper amino oxidase. Through this pathway, putrescine can be considered as an important source of inhibitory signaling that counterbalances epileptic discharges. Putrescine, however, is also a precursor for spermine that is known to enhance gap junction channel communication and, consequently, supports long-range Ca2+ signaling and contributes to spreading of excitatory activity through the astrocytic syncytium. Recently, we presented the possibility of neuron-glia redox coupling through copper (Cu+/Cu2+) signaling and oxidative putrescine catabolism. In the current work, we explore whether the Cu+/Cu2+ homeostasis is involved in astrocytic control on neuronal excitability by regulating PA catabolism. We provide supporting experimental data underlying this hypothesis. We show that the blockade of copper transporter (CTR1) by AgNO3 (3.6 µM) prevents GABA transporter-mediated tonic inhibitory currents, indicating causal relationship between copper (Cu+/Cu2+) uptake and the catabolism of putrescine to GABA in astrocytes. In addition, we show that MnCl2 (20 μM), an inhibitor of the divalent metal transporter DMT1, also prevents the astrocytic Glu-GABA exchange. Furthermore, we observed that facilitation of copper uptake by added CuCl2 (2 µM) boosts tonic inhibitory currents. These findings corroborate the hypothesis that modulation of neuron-glia coupling by copper uptake drives putrescine → GABA transformation, which leads to subsequent Glu-GABA exchange and tonic inhibition. Findings may in turn highlight the potential role of copper signaling in fine-tuning the activity of the tripartite synapse. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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24 pages, 5132 KiB  
Article
High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BKCa-Channel Activity and Inhibits IK(M) or Ih
by Te-Ling Lu, Zi-Han Gao, Shih-Wei Li and Sheng-Nan Wu
Biomolecules 2020, 10(2), 188; https://doi.org/10.3390/biom10020188 - 25 Jan 2020
Cited by 5 | Viewed by 2823
Abstract
GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca2+-activated K+ (BKCa) channels has been reported. [...] Read more.
GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca2+-activated K+ (BKCa) channels has been reported. In pituitary tumor (GH3) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an effective IC50 of 2.33 μM. GAL-021-mediated reduction of IK(Ca) was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BKCa channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BKCa channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BKCa channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K+ current with an effective IC50 of 3.75 μM; however, its presence did not alter the amplitude of erg-mediated K+ current, or mildly suppressed delayed-rectifier K+ current. GAL-021 at a concentration of 30 μM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing α-hSlo, the addition of GAL-021 was also able to suppress the BKCa-channel open probabilities, and GAL-021-mediated suppression of BKCa-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BKCa channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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Review

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20 pages, 5047 KiB  
Review
Unique Chemistry, Intake, and Metabolism of Polyamines in the Central Nervous System (CNS) and Its Body
by Julian Rieck, Serguei N. Skatchkov, Christian Derst, Misty J. Eaton and Rüdiger W. Veh
Biomolecules 2022, 12(4), 501; https://doi.org/10.3390/biom12040501 - 25 Mar 2022
Cited by 8 | Viewed by 2898
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)
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