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Biomedicines
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Advanced Research in Neuroprotection
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Advanced Research in Neuroprotection

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 4119

Special Issue Editors

Dr. Evangelia Kesidou

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Guest Editor
2nd Neurological University Department, Aristotle University of Thessaloniki, AHEPA General Hospital, 54634 Thessaloniki, Greece
Interests: neuroimmunology; experimental neurology; neurodegenerative diseases
Dr. Iliana Michailidou

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Guest Editor
2nd Neurological University Department, Aristotle University of Thessaloniki, AHEPA General Hospital, 54634 Thessaloniki, Greece
Interests: neuroimmunology; experimental neurology; neurodegenerative diseases; neuropathology
Dr. Christos Bakirtzis

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Guest Editor
University General Hospital of Thessaloniki "AHEPA", Thessaloniki, Greece
Interests: neuroimaging; cognition; multiple sclerosis; neuroimmunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite their privileged nature, the central and peripheral nervous systems may suffer injury and are vulnerable to immune attacks. Neuroinflammatory manifestations accompany alterations to the microenvironment, which may lead to neuronal dysregulation and the appearance of neurological disorders. Despite the distinct entity of each nervous system disease, they share common pathological traits, such as biochemical damage, oxidative stress, axonal loss, and neuronal death, thus revealing the essential role of neuroprotective pathways in ensuring neuronal homeostasis and longevity. Breakthroughs in the field of drug desig and neuropharmacology along with the latest progress in animal and human models have shown the utility of translational medicine, advocating for more appropriate strategies and pharmacologic agents that can mediate the task of neuroprotection.

This Special Issue, entitled “Advanced Research in Neuroprotection”, invites original research articles, short reports, and reviews that will expertly present recent advances in both experimental and clinical knowledge of neuroprotective mechanisms and strategies within various neurological disorders.

Dr. Evangelia Kesidou
Dr. Iliana Michailidou
Dr. Christos Bakirtzis
Guest Editors

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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. Biomedicines 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 2600 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

  • neuroprotection
  • neurodegeneration
  • neuroinflammation
  • axonal loss
  • neuropharmacology
  • traumatic brain injury
  • blood–brain barrier

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17 pages, 4098 KiB  
Article
Effects of Sildenafil on Cognitive Function Recovery and Neuronal Cell Death Protection after Transient Global Cerebral Ischemia in Gerbils
by Yeon Hee Yu, Gun Woo Kim, Yu Ran Lee, Dae-Kyoon Park, Beomjong Song and Duk-Soo Kim
Biomedicines 2024, 12(9), 2077; https://doi.org/10.3390/biomedicines12092077 - 12 Sep 2024
Cited by 1 | Viewed by 1555
Abstract
Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, [...] Read more.
Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a gerbil model of global brain ischemia. We investigated the effects of sildenafil on the expression of glial fibrillary acidic protein and aquaporin-4, which are markers related to astrocyte activation and water homeostasis, respectively. Immunofluorescence analysis showed that the number of cells co-expressing these markers, which was elevated in the ischemia-induced group, was significantly reduced in the sildenafil-treated groups. This suggests that sildenafil may have a potential mitigating effect on astrocyte activation induced by ischemia. Additionally, we performed various behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to evaluate sildenafil’s effect on cognitive function impaired by ischemia. Overall, the results suggest that sildenafil may serve as a neuroprotective agent, potentially alleviating delayed neuronal cell death and improving cognitive function impaired by ischemia. Full article
(This article belongs to the Special Issue Advanced Research in Neuroprotection)
►▼ Show Figures

Figure 1

Figure 1
<p>A representative diagram shows the overall surgical groups, behavior tests, and histology time schedules. Cresyl violet staining was performed on the fourth day after surgery. For the behavioral analysis, to prevent learning of the special cue, the Barnes maze and Y-maze tests were not performed on the same gerbils. Additionally, the behavioral analysis was conducted in two parts to minimize stress on the animals for each task. After completing the behavioral task, we collected tissue samples and performed immunofluorescence staining. SIL, sildenafil; IF, Immunofluorescence.</p> Full article ">Figure 2
<p>Sildenafil treatment increased cell populations in the cornu ammonis 1 (CA1) region compared to transient global cerebral ischemia. In the cresyl violet staining, the number of neurons in the stratum pyramidale (SP, asterisk) of the CA1 field was reduced in ischemic gerbils compared to control gerbils (<b>A1</b>–<b>B2</b>,<b>G</b>). S74IL-pre (10 mg/kg) gerbils showed slight recovery (<b>C1</b>,<b>C2</b>,<b>G</b>). The number of neurons in SIL-post (10 mg/kg) gerbils was significantly increased compared to ischemic gerbils (<b>D1</b>,<b>D2</b>,<b>G</b>, arrowhead). The number of neurons in the SP area in the SIL-treated (20 mg/kg) groups was significantly increased compared to the ischemic group (<b>E1</b>–<b>F2</b>,<b>G</b>, arrowhead). SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum. Scale bar = panels <b>A1</b>–<b>F1</b>, 200 μm; panels <b>A2</b>–<b>F2</b>, 50 μm. Data are presented as means ± standard errors of the mean. * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001 by one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparisons test, <span class="html-italic">n</span> = 11/group.</p> Full article ">Figure 3
<p>Sildenafil treatment decreased aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) co-expression in the CA1 region compared to transient global cerebral ischemia. The co-expression of AQP4 and GFAP was significantly increased in ischemic gerbils compared to control gerbils (<b>A1</b>–<b>B4</b>,<b>G</b>, arrow). Co-expression was significantly decreased in sildenafil-treated gerbils compared to ischemic gerbils (<b>C1</b>–<b>F4</b>,<b>G</b>, arrow). Scale bar = 20 μm. Diagram of the gerbil hippocampus and the red square indicates the area where IF imaging was performed (<b>H</b>). Data are presented as means ± standard errors of the mean. ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001 by one-way ANOVA followed by Dunnett’s multiple comparisons test, <span class="html-italic">n</span> = 11/group.</p> Full article ">Figure 4
<p>Sildenafil treatment restored generalized locomotor activity in transient global cerebral ischemia. Representative cumulative traces of navigation pathways in the control, ischemic, SIL-pre, and SIL-post groups during exploration in the open-field test (<b>A</b>). The total distance moved by ischemic gerbils was increased compared to control gerbils (<b>B</b>). The total distance moved by sildenafil-treated gerbils was significantly reduced compared with ischemic gerbils, except for SIL-pre (10 mg/kg) gerbils (<b>B</b>). Data are presented as means ± standard errors of the mean. *** <span class="html-italic">p</span> &lt; 0.001 by one-way ANOVA followed by Dunnett’s multiple comparisons test, <span class="html-italic">n</span> = 15/group.</p> Full article ">Figure 5
<p>Sildenafil treatment alleviated novel object recognition deficits induced by transient global cerebral ischemia. In the habituation phase, the frequency percentage of searching for the same two objects was similar in the control, ischemic, and sildenafil-treated groups (<b>A1</b>). The percentage of time spent on object exploration was similar in the control, ischemic, and sildenafil-treated groups (<b>A2</b>). In the test phase, the frequency and percentage of time spent exploring novel objects were decreased in ischemic gerbils compared with control gerbils (<b>B1</b>,<b>B2</b>). However, both the frequency and percentage of time spent exploring novel objects in sildenafil-treated gerbils were significantly increased as compared to ischemic gerbils (<b>B1</b>,<b>B2</b>). In particular, the discrimination index of the sildenafil-treated groups was notably different compared with the ischemic group (<b>B3</b>). Data are presented as means ± standard errors of the mean. *** <span class="html-italic">p</span> &lt; 0.001 by one-way ANOVA followed by Dunnett’s multiple comparisons test, control, and ischemia, <span class="html-italic">n</span> = 11; SIL-groups, <span class="html-italic">n</span> = 15.</p> Full article ">Figure 6
<p>Sildenafil treatment improved long-term memory, spatial learning, and memory impairment caused by transient global cerebral ischemia. In the Barnes maze test conducted for 5 days, the number of errors in all groups decreased (<b>A</b>). On the probe day, the number of errors made by ischemic gerbils increased significantly compared to control gerbils (<b>B</b>). The number of errors was significantly reduced on the probe test day in all sildenafil-treated groups as compared to ischemic gerbils (<b>A</b>,<b>B</b>). The latency time to the escape hole decreased in all groups over 5 days (<b>C</b>). On the probe day, the latency time to the escape hole was significantly increased in ischemic gerbils compared to control gerbils (<b>D</b>). In all sildenafil-treated groups, the latency time to the escape hole was significantly reduced compared to the ischemic group (<b>C</b>,<b>D</b>). Data are presented as means ± standard errors of the mean. * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001 control group vs. ischemic group; <sup>##</sup> <span class="html-italic">p</span> &lt; 0.01, <sup>###</sup> <span class="html-italic">p</span> &lt; 0.001 ischemic group vs. SIL-pre (10 mg/kg); <sup><span>$</span></sup> <span class="html-italic">p</span> &lt; 0.05, <sup><span>$</span><span>$</span></sup> <span class="html-italic">p</span> &lt; 0.01, <sup><span>$</span><span>$</span><span>$</span></sup> <span class="html-italic">p</span> &lt; 0.001 ischemic group vs. SIL-post (10 mg/kg); <sup>+++</sup> <span class="html-italic">p</span> &lt; 0.001 ischemic group vs. SIL-pre (20 mg/kg); <sup>¶¶¶</sup> <span class="html-italic">p</span> &lt; 0.001 ischemic group vs. SIL-post (20 mg/kg) (<b>A</b>,<b>C</b>). ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001 (<b>B</b>,<b>D</b>) by one-way ANOVA followed by Dunnett’s multiple comparisons test, <span class="html-italic">n</span> = 10/group.</p> Full article ">Figure 7
<p>Sildenafil treatment alleviated the spatial and emotional memory deficits induced by transient global cerebral ischemia. A schematic diagram showing special cues in the working memory test (<b>A</b>). The average percentage of spontaneous alternations in ischemic gerbils was noticeably reduced compared with control gerbils (<b>B</b>). However, spontaneous alternations were significantly increased in the sildenafil-treated (20 mg/kg) groups compared to ischemic gerbils (<b>B</b>). A schematic diagram showing the passive avoidance test (<b>C</b>). The transfer time was significantly decreased in the ischemic group compared to the control group (<b>D</b>). In contrast, the latency time in all sildenafil-treated groups was increased compared to the ischemic group (<b>D</b>). Data are presented as means ± standard errors of the mean. ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001 ANOVA followed by Dunnett’s multiple comparisons test, Y-maze, <span class="html-italic">n</span> = 10/group; PA, <span class="html-italic">n</span> = 13/group.</p> Full article ">
28 pages, 6856 KiB  
Article
Regulatory Role and Cytoprotective Effects of Exogenous Recombinant SELENOM under Ischemia-like Conditions and Glutamate Excitotoxicity in Cortical Cells In Vitro
by Egor A. Turovsky, Egor Y. Plotnikov and Elena G. Varlamova
Biomedicines 2024, 12(8), 1756; https://doi.org/10.3390/biomedicines12081756 - 5 Aug 2024
Cited by 1 | Viewed by 1182
Abstract
Despite the successes in the prevention and treatment of strokes, it is still necessary to search for effective cytoprotectors that can suppress the damaging factors of cerebral ischemia. Among the known neuroprotectors, there are a number of drugs with a protein nature. In [...] Read more.
Despite the successes in the prevention and treatment of strokes, it is still necessary to search for effective cytoprotectors that can suppress the damaging factors of cerebral ischemia. Among the known neuroprotectors, there are a number of drugs with a protein nature. In the present study, we were able to obtain recombinant SELENOM, a resident of the endoplasmic reticulum that exhibits antioxidant properties in its structure and functions. The resulting SELENOM was tested in two brain injury (in vitro) models: under ischemia-like conditions (oxygen-glucose deprivation/reoxygenation, OGD/R) and glutamate excitotoxicity (GluTox). Using molecular biology methods, fluorescence microscopy, and immunocytochemistry, recombinant SELENOM was shown to dose-dependently suppress ROS production in cortical cells in toxic models, reduce the global increase in cytosolic calcium ([Ca2+]i), and suppress necrosis and late stages of apoptosis. Activation of SELENOM’s cytoprotective properties occurs due to its penetration into cortical cells through actin-dependent transport and activation of the Ca2+ signaling system. The use of SELENOM resulted in increased antioxidant protection of cortical cells and suppression of the proinflammatory factors and cytokines expression. Full article
(This article belongs to the Special Issue Advanced Research in Neuroprotection)
►▼ Show Figures

Figure 1

Figure 1
<p>Effect of 24 h pre-incubation of neuroglial cortical cultures with 5 or 20 μg/mL exogenous SELENOM on GluTox-induced cell death. Double staining of cells with Hoechst 33342 (HO342) and propidium iodide (PI). GluTox—induction of the excitotoxic effect of glutamate (300 µM glutamate for 24 h) without prior incubation with SELENOM. SELENOM 5 µg and SELENOM 20 µg—24 h pre-incubation of cells with SELENOM and then 300 µM glutamate (GluTox) was added to the culture medium for 24 h.</p> Full article ">Figure 2
<p>Effect of 24 h pre-incubation of cortical cells with various concentrations of exogenous SELENOM on GluTox-induced cell death. (<b>A</b>) Cytogram demonstrating the viability of cortical cells after 24 h of exposure to GluTox depending on the concentration of SELENOM. <span class="html-italic">X</span>-axis—PI fluorescence intensity. The <span class="html-italic">Y</span>-axis is the fluorescence intensity of Hoechst 33342. Cells were stained with probes 24 h after GluTox. (<b>B</b>) Effect of 24 h pre-incubation with 5 or 20 μg of SELENOM on the induction of necrosis and apoptosis. Black asterisks indicate the differences between the experimental groups comparable to the Control group. Differences between experimental groups are marked with asterisks of different colors. n/s—data not significant (<span class="html-italic">p</span> &gt; 0.05), *** <span class="html-italic">p</span> &lt; 0.001, ** <span class="html-italic">p</span> &lt; 0.01, and * <span class="html-italic">p</span> &lt; 0.05. Cell images are presented in <a href="#biomedicines-12-01756-f001" class="html-fig">Figure 1</a>.</p> Full article ">Figure 3
<p>Effect of 24 h pre-incubation of neuroglial cortical cultures with 5, 20, or 50 μg/mL exogenous SELENOM on OGD/R-induced cell death. Double staining of cells with Hoechst 33342 (HO342) and propidium iodide (PI). OGD/R—induction of ischemia-like conditions (2 h) and reoxygenation for 24 h without pre-incubation with SELENOM. SELENOM 5 µg + OGD/R, SELENOM 20 µg + OGD/R, and SELENOM 50 µg + OGD/R—24 h pre-incubation of cells with SELENOM followed by creation of OGD/R.</p> Full article ">Figure 4
<p>Effect of 24 h pre-incubation of cortical cells with various concentrations of exogenous SELENOM on OGD/R-induced cell death. (<b>A</b>) Cytogram demonstrating the viability of cortical cells after 24 h of exposure to OGD/R depending on the concentration of SELENOM. <span class="html-italic">X</span>-axis—PI fluorescence intensity. The <span class="html-italic">Y</span>-axis is the fluorescence intensity of Hoechst 33342. Cells were stained with probes 24 h after OGD/R. (<b>B</b>) Effect of 24 h pre-incubation with 5, 20, or 50 μg/mL SELENOM on the induction of necrosis and apoptosis in OGD/R. Designations: OGD/R—induction of ischemia-like conditions (2 h of oxygen-glucose deprivation) and reoxygenation for 24 h without prior incubation with SELENOM. SELENOM 5 µg + OGD/R, SELENOM 20 µg + OGD/R, and SELENOM 50 µg + OGD/R—24 h pre-incubation of cells with SELENOM followed by creation of OGD/R. Results are presented as mean ± SEM. Black asterisks indicate the differences between the experimental groups comparable to the OGD group. Differences between experimental groups are marked with asterisks of different colors. n/s—data not significant (<span class="html-italic">p</span> &gt; 0.05), *** <span class="html-italic">p</span> &lt; 0.001, ** <span class="html-italic">p</span> &lt; 0.01, and * <span class="html-italic">p</span> &lt; 0.05. Cell images are presented in <a href="#biomedicines-12-01756-f003" class="html-fig">Figure 3</a>.</p> Full article ">Figure 5
<p>Effect of 24 hours’ pre-incubation of neuroglial cortical cultures with 5, 20, or 50 μg/mL exogenous SELENOM on OGD/R-induced cell death. Double staining of cells with Hoechst 33342 (HO342) and propidium iodide (PI). OGD/R—induction of ischemia-like conditions (2 h) and reoxygenation for 24 h without pre-incubation with SELENOM. SELENOM 5 µg + OGD/R, SELENOM 20 µg + OGD/R, and SELENOM 50 µg + OGD/R—24 h pre-incubation of cells with SELENOM followed by creation of OGD/R. Effect of 24 h pre-incubation of cortical neuroglial cultures with 50 μg/mL exogenous SELENOM on basal (<b>A</b>), GluTox-induced (<b>B</b>), and OGD/R-induced (<b>C</b>) expression of genes encoding proteins involved in redox status regulation. The dotted line indicates protein expression in cortical cells treated with solvent buffer for panel (<b>A</b>), in cells after 24 h of GluTox exposure without pre-incubation with SELENOM for panel (<b>B</b>), and ischemia-like conditions (OGD/R) without pre-incubation with SELENOM for panel (<b>C</b>). Results are presented as mean ± SEM. Black asterisks indicate the differences between the experimental groups comparable to the Buffer-treated group (<b>A</b>), GluTox-treated group (<b>B</b>), and OGD/R-treated group (<b>C</b>) without pre-incubation with SELENOM. n/s—data not significant (<span class="html-italic">p</span> &gt; 0.05), *** <span class="html-italic">p</span> &lt; 0.001, * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 6
<p>Effect of 24 h pre-incubation of cortical neuroglial cultures with 50 μg/mL exogenous SELENOM on basal (<b>A</b>), GluTox-induced (<b>B</b>), and OGD/R-induced (<b>C</b>) expression of genes encoding proteins involved in cell death. The dotted line indicates protein expression in cortical cells treated with solvent buffer for panel (<b>A</b>), in cells after 24 h of GluTox exposure without pre-incubation with SELENOM for panel (<b>B</b>), and ischemia-like conditions (OGD/R) without pre-incubation with SELENOM for panel (<b>C</b>). Results are presented as mean ± SEM. Black asterisks indicate the differences between the experimental groups comparable to the Buffer-treated group (<b>A</b>), GluTox-treated group (<b>B</b>), and OGD/R-treated group (<b>C</b>) without pre-incubation with SELENOM. n/s—data not significant (<span class="html-italic">p</span> &gt; 0.05), *** <span class="html-italic">p</span> &lt; 0.001, ** <span class="html-italic">p</span> &lt; 0.01, and * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 7
<p>Dose-dependent effect of acute (<b>A</b>,<b>C</b>,<b>D</b>) recombinant SELENOM action and 24 h pre-incubation (<b>B</b>) of cortical astrocytes with different concentrations of SELENOM on ROS production. (<b>A</b>) ROS production in cortical astrocytes on the application of various SELENOM concentrations in an acute experiment after 3 h of recording DCF fluorescence. (<b>B</b>) ROS production in cortical astrocytes after 24 h pre-incubation with various SELENOM concentrations. Data obtained with an automated multiplate reader (Spark™ 10M multimode microplate reader) are presented. Data are shown as the mean of fluorescence intensity, arb.units ± S.E.M. Statistical analysis of experimental groups versus Control (dashed line) was performed with a paired <span class="html-italic">t</span>-test. *** <span class="html-italic">p</span> &lt; 0.001, and n/s—insignificant differences (<span class="html-italic">p</span> &gt; 0.05). (<b>C</b>,<b>D</b>) Predominantly cytosolic ROS production (<b>C</b>) and mitochondrial ROS production (<b>D</b>) in cortical astrocytes in response to different concentrations of SELENOM and 100 μM H<sub>2</sub>O<sub>2</sub>. The curves of ROS production averaged over several dozens of cells are presented.</p> Full article ">Figure 8
<p>The effect of 24 h pre-incubation of astrocytes from a pure cortical culture with 50 μg/mL recombinant SELENOM on the level of gene expression encoding redox status proteins. The dotted line indicates expression in cortical astrocytes treated with protein solvent buffer. The results are presented as mean ± SEM. Black asterisks indicate the differences between the experimental groups comparable to the Buffer-treated group. n/s—data not significant (<span class="html-italic">p</span> &gt; 0.05), *** <span class="html-italic">p</span> &lt; 0.001, ** <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 9
<p>Effect of exogenous SELENOM on Ca<sup>2+</sup> signals of neurons (<b>A</b>) and astrocytes (<b>B</b>) and their death in a mixed cortical neuroglial culture when exposed to glutamate excitotoxicity (GluTox) for ~40 min. (<b>A</b>,<b>B</b>) Ca<sup>2+</sup> signals of neurons (<b>A</b>) and astrocytes (<b>B</b>) under GluTox, depending on pre-incubation for 24 h with 50 µg/mL SELENOM. The Ca<sup>2+</sup> signals of neurons and astrocytes averaged over several dozen cells in one experiment are presented. Neurons were distinguished from astrocytes using a short-term (30 s) application of 35 mM KCl, to which only neurons responded by generating Ca<sup>2+</sup> signals. Conversely, astrocytes responded with Ca<sup>2+</sup> signals to the addition of 10 µM ATP. (<b>C</b>,<b>D</b>) Propidium iodide (PI) staining of cell cultures after ~40 min of GluTox without pre-incubation with SELENOM (<b>C</b>) and after 24 h of pre-incubation with SELENOM (50 µg/mL). The appearance of PI fluorescence (red cell nuclei) reflects necrotic cell death.</p> Full article ">Figure 10
<p>Effect of exogenous SELENOM on Ca<sup>2+</sup> signals of neurons (<b>A</b>) and astrocytes (<b>B</b>) and their death after ischemia-like conditions (OGD, oxygen-glucose deprivation) for ~40 min. (<b>A</b>,<b>B</b>) Ca<sup>2+</sup> signals of neurons (<b>A</b>) and astrocytes (<b>B</b>) under the OGD, depending on pre-incubation for 24 h with 50 µg/mL SELENOM. The Ca<sup>2+</sup> signals of neurons and astrocytes averaged over several dozen cells in one experiment are presented. Neurons were distinguished from astrocytes using a short-term (30 s) application of 35 mM KCl, to which only neurons responded by generating Ca<sup>2+</sup> signals. Conversely, astrocytes responded with Ca<sup>2+</sup> signals to the application of 10 µM ATP. (<b>C</b>,<b>D</b>) Propidium iodide (PI) staining of cell cultures after ~40 min OGD without pre-incubation with SELENOM (<b>C</b>) and after 24 h pre-incubation with SELENOM (50 µg/mL). The appearance of PI fluorescence (red cell nuclei) reflects necrotic cell death.</p> Full article ">Figure 11
<p>Putative signaling pathways of recombinant SELENOM-induced [Ca<sup>2+</sup>]<sub>i</sub> increase in cortical neurons and astrocytes. (<b>A</b>) Application of 100 μL solvent buffer for SELENOM did not cause Ca<sup>2+</sup> signal generation in neurons (black curve) and astrocytes (red curve). (<b>B</b>,<b>C</b>) Application of various exogenous SELENOM concentrations to neurons (<b>B</b>) and astrocytes (<b>C</b>) in a cortical neuroglial culture. (<b>D</b>) Application of 50 μg exogenous SELENOM to a cortical neuroglial culture after 1 h pre-incubation with 10 μM of the actin-dependent endocytosis blocker Cytochalasin D (Cyto D). (<b>E</b>) Application of 50 μg exogenous SELENOM to a neuroglial culture in a nominally calcium-free medium (Ca<sup>2+</sup>-free) with the addition of 0.5 mM of the calcium chelator EGTA. (<b>F</b>) Application of 50 μg exogenous SELENOM to a neuroglial culture after depletion of the Ca<sup>2+</sup> store of the endoplasmic reticulum using the SERCA blocker thapsigargin (TG, 10 μM).</p> Full article ">Figure 12
<p>Western blot analysis of cortical cell lysate samples after incubation with 50 μg of exogenous SELENOM or buffer. (<b>A</b>) Immunoblotting results obtained using antibodies against hexahistidine-labeled SELENOM at 30 min, 2 h, and 24 h after application of SELENOM to the culture medium. (<b>B</b>) Quantification of the studied proteins in the samples obtained using ImageJ software, presented as mean ± standard deviation of three independent experiments. GAPDH was used as a control for normalization. The expression level in the control (without treatment) was taken as 1 (dotted line). Statistical comparisons were made relative to the control group using the <span class="html-italic">t</span>-test. *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 13
<p>Immunocytochemical staining of cortical cells after pre-incubation with 50 μg/mL recombinant SELENOM for 30 min and 2 h. (<b>A</b>) Images of astrocytes (GFAP<sup>+</sup> cells) and non-astrocytes (GFAP<sup>–</sup> cells) stained with antibodies against histidine (His), reflecting the presence of recombinant SELENOM in the cells. HO342—cell nuclei stained with Hoechst 33342. GFAP + His—merged images of GFAP<sup>+</sup> cells and histidine<sup>+</sup> (His) cells, reflecting the presence of recombinant SELENOM in cortical astrocytes. (<b>B</b>) Intensity levels of histidine were determined by confocal imaging. We analyzed individual cells that had fluorescence of secondary antibodies. The quantitative data reflecting the level of histidine expression in GFAP<sup>+</sup>-cells and GFAP<sup>—</sup>-cells are presented as fluorescence intensity values in summary bar charts (mean ± SEM). The values were averaged by 100 cells for each column. The results obtained after immunostaining agree with the data of fluorescence presented in (<b>A</b>). Statistical significance was assessed using a paired <span class="html-italic">t</span>-test. Comparison with Buffer is marked by black asterisk. Comparisons between experimental groups are marked in red. n/s—data not significant (<span class="html-italic">p</span> &gt; 0.05), *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">

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Review
Identifying Biomarkers for Remyelination and Recovery in Multiple Sclerosis: A Measure of Progress
by Vito A. G. Ricigliano, Silvia Marenna, Serena Borrelli, Valentina Camera, Edgar Carnero Contentti, Natalia Szejko, Christos Bakirtzis, Sanja Gluscevic, Sara Samadzadeh, Hans-Peter Hartung, Krzysztof Selmaj, Bruno Stankoff, Giancarlo Comi and ECF Young Investigators/Fellows Initiative
Biomedicines 2025, 13(2), 357; https://doi.org/10.3390/biomedicines13020357 - 4 Feb 2025
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Abstract
Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the [...] Read more.
Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the remyelination process, where researchers are studying the effects of pharmacotherapy on myelin repair mechanisms. Multiple compounds are being tested for their potential to foster remyelination in different clinical settings through the application of less or more complex techniques to assess their efficacy. Objective: To review current methods and biomarkers to track myelin regeneration and recovery over time in people with MS (PwMS), with potential implications for promyelinating drug testing. Methods: Narrative review, based on a selection of PubMed articles discussing techniques to measure in vivo myelin repair and functional recovery in PwMS. Results: Non-invasive tools, such as structural Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), are being implemented to track myelin repair, while other techniques like evoked potentials, functional MRI, and digital markers allow the assessment of functional recovery. These methods, alone or in combination, have been employed to obtain precise biomarkers of remyelination and recovery in various clinical trials on MS. Conclusions: Combining different techniques to identify myelin restoration in MS could yield novel biomarkers, enhancing the accuracy of clinical trial outcomes for remyelinating therapies in PwMS. Full article
(This article belongs to the Special Issue Advanced Research in Neuroprotection)
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Figure 1

Figure 1
<p>Tools to track remyelination and recovery in MS. Examples of techniques to assess myelin repair and functional recovery in vivo. (<b>a</b>) PET-derived map of remyelinated voxels (labeled in green) within MS lesions (white) overlayed on a brain 3DT1 MRI (axial plane) of a PwMS. (<b>b</b>) Brain magnetization transfer ratio image of a PwMS (axial plane). (<b>c</b>) Quantitative susceptibility mapping brain scan (axial plan) (<b>d</b>). Illustration of a functional MRI brain scan. (<b>e</b>) Schematic illustration of CSF sample analysis to measure biomarkers related to myelin dynamics. (<b>f</b>) Illustration of motor evoked potentials testing (left) and the membrane potential (right). (<b>g</b>) T2-weighted image of the spinal cord of a PwMS (sagittal plane). (<b>h</b>) Optical coherence tomography scan (left) and zoom on the optic disc at the ocular fundus assessment (right). (<b>i</b>) Visual stimuli on a video screen for visual evoked potentials recording (left) and illustration of the membrane potential (right). Created in BioRender. Camera, V. (2025) <a href="https://BioRender.com/b39y141" target="_blank">https://BioRender.com/b39y141</a>, accessed on 29 January 2025.</p> Full article ">
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