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Special Issue "Neuroprotective Strategies 2019"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editor

Special Issue Information

Dear Colleagues,

It has been 10 years since we started the “Neuroprotective Strategies” collection, offering the latest information on neuroprotection through the preclinical/basic science assessments of the various in vitro and animal models relevant to neurodegeneration, drug discovery efforts, and clinical case reports. We hope that this Special Issue will continue to provide a forum for thought-provoking comments, opinions, and perspectives, in addition to traditional reviews and research articles on the latest developments of therapeutics in the field. We especially encourage submissions that address the critical issues that have prevented successful the clinical translations of otherwise promising laboratory data. These issues include the limitations of in vitro studies and preclinical animal models to mirror the multiple pathologies underlying human neurodegenerative diseases, the lack of drug-likeness of experimental agents, obstacles of drug delivery to the CNS, and the consideration of ADMET and pharmacokinetics, especially in early stage drug discovery. Critical reviews of relevant patent literature and clinical findings are also welcome. I wish to thank all of the authors for their exceptional contributions to this Special Issue over the years, and I look forward to receiving future contributions to the 10th anniversary issue on the promising and challenging aspects of neuroprotective strategies. I hope this topical collection has been, and will continue to be, a useful reference for everybody interested in the subject.

Prof. Dr. Katalin Prokai-Tatrai
Guest Editor

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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Clinical case report
  • CNS-targeting drug design and drug-likeness
  • Inflammation
  • Drug delivery
  • In-silico drug design and disease models
  • Ischemia and reperfusion
  • Ocular neurodegeneration
  • Oxidative stress
  • Peripheral nervous system
  • Proteomics
  • Spinal cord injury
  • Stroke
  • Structure–activity relationships
  • Translational medicine
  • Traumatic brain injury

Related Special Issue

Published Papers (9 papers)

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Research

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Open AccessArticle
Parasympathetic Effect Induces Cell Cycle Activation in Upper Limbs of Paraplegic Patients with Spinal Cord Injury
Int. J. Mol. Sci. 2019, 20(23), 5982; https://doi.org/10.3390/ijms20235982 - 27 Nov 2019
Cited by 1
Abstract
The present study aimed to investigate gene expression changes related to cell cycle activation in patients with spinal cord injury (SCI) and to further evaluate the difference between the upper and lower limbs of SCI patients. Fibroblasts were obtained from the upper and [...] Read more.
The present study aimed to investigate gene expression changes related to cell cycle activation in patients with spinal cord injury (SCI) and to further evaluate the difference between the upper and lower limbs of SCI patients. Fibroblasts were obtained from the upper and lower limbs of SCI patients and healthy subjects. To investigate gene expression profiling in the fibroblasts from SCI patients compared to the healthy subjects, RNA-Seq transcriptome analysis was performed. To validate the parasympathetic effects on cell cycle activation, fibroblasts from upper or lower limbs of SCI patients were treated with the anticholinergic agents tiotropium or acetylcholine, and quantitative RT-PCR and Western blot were conducted. Cell proliferation was significantly increased in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. The pathway and genes involved in cell cycle were identified by RNA-Seq transcriptome analysis. Expression of cell-cycle-related genes CCNB1, CCNB2, PLK1, BUB1, and CDC20 were significantly higher in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. When the fibroblasts were treated with tiotropium the upper limbs and acetylcholine in the lower limbs, the expression of cell-cycle-related genes and cell proliferation were significantly modulated. This study provided the insight that cell proliferation and cell cycle activation were observed to be significantly increased in the upper limbs of SCI patients via the parasympathetic effect. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessArticle
SOCS1-Derived Peptide Administered by Eye Drops Prevents Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes
Int. J. Mol. Sci. 2019, 20(15), 3615; https://doi.org/10.3390/ijms20153615 - 24 Jul 2019
Cited by 3
Abstract
Current treatments for diabetic retinopathy (DR) target late stages when vision has already been significantly affected. Accumulating evidence suggests that neuroinflammation plays a major role in the pathogenesis of DR, resulting in the disruption of the blood-retinal barrier. Suppressors of cytokine signaling (SOCS) [...] Read more.
Current treatments for diabetic retinopathy (DR) target late stages when vision has already been significantly affected. Accumulating evidence suggests that neuroinflammation plays a major role in the pathogenesis of DR, resulting in the disruption of the blood-retinal barrier. Suppressors of cytokine signaling (SOCS) are cytokine-inducible proteins that function as a negative feedback loop regulating cytokine responses. On this basis, the aim of the present study was to evaluate the effect of a SOCS1-derived peptide administered by eye drops (2 weeks) on retinal neuroinflammation and early microvascular abnormalities in a db/db mouse model. In brief, we found that SOCS1-derived peptide significantly reduced glial activation and neural apoptosis induced by diabetes, as well as retinal levels of proinflammatory cytokines. Moreover, a significant improvement of electroretinogram parameters was observed, thus revealing a clear impact of the histological findings on global retinal function. Finally, SOCS1-derived peptide prevented the disruption of the blood-retinal barrier. Overall, our results suggest that topical administration of SOCS1-derived peptide is effective in preventing retinal neuroinflammation and early microvascular impairment. These findings could open up a new strategy for the treatment of early stages of DR. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessArticle
Sirtuin 1 Regulates Mitochondrial Biogenesis and Provides an Endogenous Neuroprotective Mechanism Against Seizure-Induced Neuronal Cell Death in the Hippocampus Following Status Epilepticus
Int. J. Mol. Sci. 2019, 20(14), 3588; https://doi.org/10.3390/ijms20143588 - 23 Jul 2019
Cited by 1
Abstract
Status epilepticus may decrease mitochondrial biogenesis, resulting in neuronal cell death occurring in the hippocampus. Sirtuin 1 (SIRT1) functionally interacts with peroxisome proliferator-activated receptors and γ coactivator 1α (PGC-1α), which play a crucial role in the regulation of mitochondrial biogenesis. In Sprague-Dawley rats, [...] Read more.
Status epilepticus may decrease mitochondrial biogenesis, resulting in neuronal cell death occurring in the hippocampus. Sirtuin 1 (SIRT1) functionally interacts with peroxisome proliferator-activated receptors and γ coactivator 1α (PGC-1α), which play a crucial role in the regulation of mitochondrial biogenesis. In Sprague-Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure activity. SIRT1, PGC-1α, and other key proteins involving mitochondrial biogenesis and the amount of mitochondrial DNA were investigated. SIRT1 antisense oligodeoxynucleotide was used to evaluate the relationship between SIRT1 and mitochondrial biogenesis, as well as the mitochondrial function, oxidative stress, and neuronal cell survival. Increased SIRT1, PGC-1α, and mitochondrial biogenesis machinery were found in the hippocampus following experimental status epilepticus. Downregulation of SIRT1 decreased PGC-1α expression and mitochondrial biogenesis machinery, increased Complex I dysfunction, augmented the level of oxidized proteins, raised activated caspase-3 expression, and promoted neuronal cell damage in the hippocampus. The results suggest that the SIRT1 signaling pathway may play a pivotal role in mitochondrial biogenesis, and could be considered an endogenous neuroprotective mechanism counteracting seizure-induced neuronal cell damage following status epilepticus. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessArticle
RTA 408 Inhibits Interleukin-1β-Induced MMP-9 Expression via Suppressing Protein Kinase-Dependent NF-κB and AP-1 Activation in Rat Brain Astrocytes
Int. J. Mol. Sci. 2019, 20(11), 2826; https://doi.org/10.3390/ijms20112826 - 10 Jun 2019
Cited by 2
Abstract
Neuroinflammation is characterized by the elevated expression of various inflammatory proteins, including matrix metalloproteinases (MMPs), induced by various pro-inflammatory mediators, which play a critical role in neurodegenerative disorders. Interleukin-1β (IL-1β) has been shown to induce the upregulation of MMP-9 through nicotinamide adenine dinucleotide [...] Read more.
Neuroinflammation is characterized by the elevated expression of various inflammatory proteins, including matrix metalloproteinases (MMPs), induced by various pro-inflammatory mediators, which play a critical role in neurodegenerative disorders. Interleukin-1β (IL-1β) has been shown to induce the upregulation of MMP-9 through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-reactive oxygen species (ROS)-dependent signaling pathways. N-(2-cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2-2-difluoropropanamide (RTA 408), a novel synthetic triterpenoid, has been shown to possess anti-oxidant and anti-inflammatory properties in various types of cells. Here, we evaluated the effects of RTA 408 on IL-1β-induced inflammatory responses by suppressing MMP-9 expression in a rat brain astrocyte (RBA-1) line. IL-1β-induced MMP-9 protein and mRNA expression, and promoter activity were attenuated by RTA 408. The increased level of ROS generation in RBA-1 cells exposed to IL-1β was attenuated by RTA 408, as determined by using 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and CellROX. In addition, the inhibitory effects of RTA 408 on MMP-9 expression resulted from the suppression of the IL-1β-stimulated activation of Pyk2 (proline-rich tyrosine kinase), platelet-derived growth factor receptor β (PDGFRβ), Akt, ROS, and mitogen-activated protein kinases (MAPKs). Pretreatment with RTA 408 attenuated the IL-1β-induced c-Jun phosphorylation, mRNA expression, and promoter activity. IL-1β-stimulated nuclear factor-κB (NF-κB) p65 phosphorylation, translocation, and promoter activity were also attenuated by RTA 408. Furthermore, IL-1β-induced glial fibrillary acidic protein (GFAP) protein and mRNA expression, and cell migration were attenuated by pretreatment with RTA 408. These results provide new insights into the mechanisms by which RTA 408 attenuates IL-1β-mediated inflammatory responses and exerts beneficial effects for the management of brain diseases. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessArticle
Niemann-Pick Type A Disease: Behavior of Neutral Sphingomyelinase and Vitamin D Receptor
Int. J. Mol. Sci. 2019, 20(9), 2365; https://doi.org/10.3390/ijms20092365 - 13 May 2019
Cited by 4
Abstract
Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement [...] Read more.
Sphingomyelinase (SMase) is responsible for the breakdown of sphingomyelin (SM) with production of ceramide. The absence of acid sphingomyelinase (aSMase) causes abnormal synapse formation in Niemann-Pick type A (NPA) disease. Because high levels of ceramide in the NPA brain were demonstrated, the involvement of other SMases were supposed. In the present study we focused the attention on the neurogenic niches in the hippocampal gyrus dentatus (GD), a brain structure essential for forming cohesive memory. We demonstrated for the first time the increase of (Sex determining region Y)-box 2 (SOX2), and the down-regulation of glial fibrillary acidic protein (GFAP) NPA mice GD. Moreover, we found that the expression of Toll like receptors (TLRs), was increased in NPA mice, particularly TLR2, TLR7, TLR8 and TLR9 members. Although no significant change in neutral sphingomyelinase (nSMase) gene expression was detected in the NPA mice hippocampus of, protein levels were enhanced, probably because of the slower protein degradation rate in this area. Many studies demonstrated that vitamin D receptor (VDR) is expressed in the hippocampus GD. Unexpectedly, we showed that NPA mice exhibited VDR gene and protein expression up-regulation. In summary, our study suggests a relation between hippocampal cell differentiation defect, nSMase and VDR increase in NPA mice. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessArticle
Dose-Dependent Effect of Hyperbaric Oxygen Treatment on Burn-Induced Neuropathic Pain in Rats
Int. J. Mol. Sci. 2019, 20(8), 1951; https://doi.org/10.3390/ijms20081951 - 20 Apr 2019
Cited by 1
Abstract
Hyperbaric oxygen treatment (HBOT) has been used to reduce neuropathic pain. Melatonin and opioid receptors are involved in neuropathic pain, but it is not known if HBOT works through these pathways to achieve its antinociceptive effect. We divided anesthetized rats into two treatment [...] Read more.
Hyperbaric oxygen treatment (HBOT) has been used to reduce neuropathic pain. Melatonin and opioid receptors are involved in neuropathic pain, but it is not known if HBOT works through these pathways to achieve its antinociceptive effect. We divided anesthetized rats into two treatment and three sham groups. The two treatment groups received third-degree burns on their right hind paws, one treated in a hyperbaric chamber for a week and the other for two weeks. We evaluated the mechanical paw-withdrawal threshold (MWT) and expression of melatonin receptor 1 (MT1), melatonin receptor 2 (MT2), μ (MOR) and κ (KOR) opioid receptor, brain-derived neurotrophic factor (BDNF), Substance P, and calcitonin gene-related peptide (CGRP) in cuneate nucleus, dorsal horn, and hind paw skin by immunohistochemical, immunofluorescence assays and real-time quantitative polymerase chain reaction (RT-PCR). The group receiving one-week HBOT had increased expressions of MT1, MT2, MOR and KOR and decreased expressions of BDNF, Substance P, and CGRP. Their mechanically measured pain levels returned to normal within a week and lasted three weeks. This anti-allodynia effect lasted twice as long in those treated for two weeks. Our findings suggest that increasing the duration of HBOT can reduce burn-induced mechanical allodynia for an extended period of time in rats. The upregulation of melatonin and opioid receptors observed after one week of HBOT suggests they may be partly involved in attenuation of the mechanical allodynia. Downregulation of BDNF, substance P and CGRP may have also contributed to the overall beneficial effect of HBOT. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Review

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Open AccessReview
Vascular and Neuronal Protection in the Developing Retina: Potential Therapeutic Targets for Retinopathy of Prematurity
Int. J. Mol. Sci. 2019, 20(17), 4321; https://doi.org/10.3390/ijms20174321 - 03 Sep 2019
Cited by 4
Abstract
Retinopathy of prematurity (ROP) is a common retinal disease in preterm babies. To prolong the lives of preterm babies, high oxygen is provided to mimic the oxygen level in the intrauterine environment for postnatal organ development. However, hyperoxia-hypoxia induced pathological events occur when [...] Read more.
Retinopathy of prematurity (ROP) is a common retinal disease in preterm babies. To prolong the lives of preterm babies, high oxygen is provided to mimic the oxygen level in the intrauterine environment for postnatal organ development. However, hyperoxia-hypoxia induced pathological events occur when babies return to room air, leading to ROP with neuronal degeneration and vascular abnormality that affects retinal functions. With advances in neonatal intensive care, it is no longer uncommon for increased survival of very-low-birth-weight preterm infants, which, therefore, increased the incidence of ROP. ROP is now a major cause of preventable childhood blindness worldwide. Current proven treatment for ROP is limited to invasive retinal ablation, inherently destructive to the retina. The lack of pharmacological treatment for ROP creates a great need for effective and safe therapies in these developing infants. Therefore, it is essential to identify potential therapeutic agents that may have positive ROP outcomes, especially in preserving retinal functions. This review gives an overview of various agents in their efficacy in reducing retinal damages in cell culture tests, animal experiments and clinical studies. New perspectives along the neuroprotective pathways in the developing retina are also reviewed. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessReview
Polyethylene Glycol: The Future of Posttraumatic Nerve Repair? Systemic Review
Int. J. Mol. Sci. 2019, 20(6), 1478; https://doi.org/10.3390/ijms20061478 - 24 Mar 2019
Cited by 2
Abstract
Peripheral nerve injury is a common posttraumatic complication. The precise surgical repair of nerve lesion does not always guarantee satisfactory motor and sensory function recovery. Therefore, enhancement of the regeneration process is a subject of many research strategies. It is believed that polyethylene [...] Read more.
Peripheral nerve injury is a common posttraumatic complication. The precise surgical repair of nerve lesion does not always guarantee satisfactory motor and sensory function recovery. Therefore, enhancement of the regeneration process is a subject of many research strategies. It is believed that polyethylene glycol (PEG) mediates axolemmal fusion, thus enabling the direct restoration of axon continuity. It also inhibits Wallerian degeneration and recovers nerve conduction. This systemic review, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, describes and summarizes published studies on PEG treatment efficiency in various nerve injury types and repair techniques. Sixteen original experimental studies in animal models and one in humans were analyzed. PEG treatment superiority was reported in almost all experiments (based on favorable electrophysiological, histological, or behavioral results). To date, only one study attempted to transfer the procedure into the clinical phase. However, some technical aspects, e.g., the maximal delay between trauma and successful treatment, await determination. PEG therapy is a promising prospect that may improve the surgical treatment of peripheral nerve injuries in the clinical practice. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Other

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Open AccessOpinion
Neuroprotective Potential of GDF11: Myth or Reality?
Int. J. Mol. Sci. 2019, 20(14), 3563; https://doi.org/10.3390/ijms20143563 - 21 Jul 2019
Abstract
In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been [...] Read more.
In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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