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Neuroprotective Strategies 2020
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Neuroprotective Strategies 2020

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 2020) | Viewed by 67341

Special Issue Editor

Prof. Dr. Katalin Prokai-Tatrai

E-Mail Website
Guest Editor
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
Interests: drug design of central nervous system agents; neuropeptides and peptidomimetics; prodrugs for CNS delivery; CNS-selective estrogen therapy; neuroprotection; proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It has been over 10 years since we started the “Neuroprotective Strategies” collection, offering the latest information on neuroprotection through 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 the successful clinical translations of otherwise promising laboratory data. These issues include the limitations of in vitro studies and preclinical animal models in mirroring the multiple pathologies underlying human neurodegenerative diseases, the lack of drug-likeness of experimental agents, the 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 this 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 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. 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

Published Papers (17 papers)

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11 pages, 2269 KiB  
Article
Dimethyl Fumarate Promotes the Survival of Retinal Ganglion Cells after Optic Nerve Injury, Possibly through the Nrf2/HO-1 Pathway
by Sotaro Mori, Takuji Kurimoto, Hidetaka Maeda and Makoto Nakamura
Int. J. Mol. Sci. 2021, 22(1), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010297 - 30 Dec 2020
Cited by 9 | Viewed by 2478
Abstract
This study aimed to verify whether dimethyl fumarate (DMF) promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush (ONC) accompanied by activation of the NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. We examined changes in the densities of tubulin β3 [...] Read more.
This study aimed to verify whether dimethyl fumarate (DMF) promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush (ONC) accompanied by activation of the NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. We examined changes in the densities of tubulin β3 (TUBB3)-positive RGCs and the amplitudes of the positive scotopic threshold response (pSTR), reflecting the functional activity of RGCs, recorded on an electroretinogram, with daily administration of DMF, on day 7 after ONC. Furthermore, immunohistochemical and immunoblotting analyses were performed to study the activation of the Nrf2/HO-1 pathway using retinas treated with daily administration of DMF. Daily administration of DMF increasedthe density of TUBB3-positive RGCs in a dose-dependent fashion and significantly increased the amplitude of the pSTR. Immunohistochemical analysis showed that DMF administration increased the immunoreactivity for Nrf2 and HO-1, a potent antioxidant enzyme, in RGCs immunolabeled with RNA-binding protein with multiple splicing (RBPMS). Immunoblotting analysis revealed an increase in the nuclear expression of Nrf2 and marked upregulation of HO-1 after DMF administration. These results suggest that DMF has survival-promoting effects in RGC after ONC, possibly via the Nrf2/HO-1 pathway. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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21 pages, 3516 KiB  
Article
N-Docosahexanoylethanolamine Reduces Microglial Activation and Improves Hippocampal Plasticity in a Murine Model of Neuroinflammation
by Anna Tyrtyshnaia, Anatoly Bondar, Sophia Konovalova, Ruslan Sultanov and Igor Manzhulo
Int. J. Mol. Sci. 2020, 21(24), 9703; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249703 - 19 Dec 2020
Cited by 16 | Viewed by 2302
Abstract
Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top [...] Read more.
Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi–Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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14 pages, 3857 KiB  
Article
2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson’s Disease
by Soo-Yeol Song, In-Su Kim, Sushruta Koppula, Ju-Young Park, Byung-Wook Kim, Sung-Hwa Yoon and Dong-Kug Choi
Int. J. Mol. Sci. 2020, 21(21), 8195; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218195 - 02 Nov 2020
Cited by 4 | Viewed by 2046
Abstract
Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in [...] Read more.
Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson’s disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 μM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson’s disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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20 pages, 3429 KiB  
Article
Homo-Tris-Nitrones Derived from α-Phenyl-N-tert-butylnitrone: Synthesis, Neuroprotection and Antioxidant Properties
by Daniel Diez-Iriepa, Beatriz Chamorro, Marta Talaván, Mourad Chioua, Isabel Iriepa, Dimitra Hadjipavlou-Litina, Francisco López-Muñoz, José Marco-Contelles and María Jesús Oset-Gasque
Int. J. Mol. Sci. 2020, 21(21), 7949; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217949 - 26 Oct 2020
Cited by 9 | Viewed by 2323
Abstract
Herein we report the synthesis, antioxidant and neuroprotective power of homo-tris-nitrones (HTN) 1-3, designed on the hypothesis that the incorporation of a third nitrone motif into our previously identified homo-bis-nitrone 6 (HBN6) would result in an improved and [...] Read more.
Herein we report the synthesis, antioxidant and neuroprotective power of homo-tris-nitrones (HTN) 1-3, designed on the hypothesis that the incorporation of a third nitrone motif into our previously identified homo-bis-nitrone 6 (HBN6) would result in an improved and stronger neuroprotection. The neuroprotection of HTNs 1-3, measured against oligomycin A/rotenone, showed that HTN2 was the best neuroprotective agent at a lower dose (EC50 = 51.63 ± 4.32 μM), being similar in EC50 and maximal activity to α-phenyl-N-tert-butylnitrone (PBN) and less potent than any of HBNs 4-6. The results of neuroprotection in an in vitro oxygen glucose deprivation model showed that HTN2 was the most powerful (EC50 = 87.57 ± 3.87 μM), at lower dose, but 50-fold higher than its analogous HBN5, and ≈1.7-fold less potent than PBN. HTN3 had a very good antinecrotic (IC50 = 3.47 ± 0.57 μM), antiapoptotic, and antioxidant (EC50 = 6.77 ± 1.35 μM) profile, very similar to that of its analogous HBN6. In spite of these results, and still being attractive neuroprotective agents, HTNs 2 and 3 do not have better neuroprotective properties than HBN6, but clearly exceed that of PBN. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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22 pages, 3684 KiB  
Article
Inhaled H2 or CO2 Do Not Augment the Neuroprotective Effect of Therapeutic Hypothermia in a Severe Neonatal Hypoxic-Ischemic Encephalopathy Piglet Model
by Viktória Kovács, Gábor Remzső, Valéria Tóth-Szűki, Viktória Varga, János Németh and Ferenc Domoki
Int. J. Mol. Sci. 2020, 21(18), 6801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186801 - 16 Sep 2020
Cited by 3 | Viewed by 3172
Abstract
Hypoxic-ischemic encephalopathy (HIE) is still a major cause of neonatal death and disability as therapeutic hypothermia (TH) alone cannot afford sufficient neuroprotection. The present study investigated whether ventilation with molecular hydrogen (2.1% H2) or graded restoration of normocapnia with CO2 [...] Read more.
Hypoxic-ischemic encephalopathy (HIE) is still a major cause of neonatal death and disability as therapeutic hypothermia (TH) alone cannot afford sufficient neuroprotection. The present study investigated whether ventilation with molecular hydrogen (2.1% H2) or graded restoration of normocapnia with CO2 for 4 h after asphyxia would augment the neuroprotective effect of TH in a subacute (48 h) HIE piglet model. Piglets were randomized to untreated naïve, control-normothermia, asphyxia-normothermia (20-min 4%O2–20%CO2 ventilation; Tcore = 38.5 °C), asphyxia-hypothermia (A-HT, Tcore = 33.5 °C, 2–36 h post-asphyxia), A-HT + H2, or A-HT + CO2 treatment groups. Asphyxia elicited severe hypoxia (pO2 = 19 ± 5 mmHg) and mixed acidosis (pH = 6.79 ± 0.10). HIE development was confirmed by altered cerebral electrical activity and neuropathology. TH was significantly neuroprotective in the caudate nucleus but demonstrated virtually no such effect in the hippocampus. The mRNA levels of apoptosis-inducing factor and caspase-3 showed a ~10-fold increase in the A-HT group compared to naïve animals in the hippocampus but not in the caudate nucleus coinciding with the region-specific neuroprotective effect of TH. H2 or CO2 did not augment TH-induced neuroprotection in any brain areas; rather, CO2 even abolished the neuroprotective effect of TH in the caudate nucleus. In conclusion, the present findings do not support the use of these medical gases to supplement TH in HIE management. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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12 pages, 1992 KiB  
Communication
Functional Characterization of Muscarinic Receptors in Human Schwann Cells
by Roberta Piovesana, Alessandro Faroni, Ada Maria Tata and Adam J. Reid
Int. J. Mol. Sci. 2020, 21(18), 6666; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186666 - 11 Sep 2020
Cited by 10 | Viewed by 2042
Abstract
Functional characterization of muscarinic cholinergic receptors in myelinating glial cells has been well described both in central and peripheral nervous system. Rat Schwann cells (SCs) express different muscarinic receptor subtypes with the prevalence of the M2 subtype. The selective stimulation of this receptor [...] Read more.
Functional characterization of muscarinic cholinergic receptors in myelinating glial cells has been well described both in central and peripheral nervous system. Rat Schwann cells (SCs) express different muscarinic receptor subtypes with the prevalence of the M2 subtype. The selective stimulation of this receptor subtype inhibits SC proliferation, improving their differentiation towards myelinating phenotype. In this work, we describe for the first time that human SCs are cholinoceptive as they express several muscarinic receptor subtypes and, as for rat SCs, M2 receptor is one of the most abundant. Human SCs, isolated from adult nerves, were cultured in vitro and stimulated with M2 muscarinic agonist arecaidine propargyl ester (APE). Similarly to that observed in rat, M2 receptor activation causes a decreased cell proliferation and promotes SC differentiation as suggested by increased Egr2 expression with an improved spindle-like shape cell morphology. Conversely, the non-selective stimulation of muscarinic receptors appears to promote cell proliferation with a reduction of SC average cell diameter. The data obtained demonstrate that human SCs are cholinoceptive and that human cultured SCs may represent an interesting tool to understand their physiology and increase the knowledge on how the cholinergic stimulation may contribute to address human SC development in normal and pathological conditions. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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18 pages, 6160 KiB  
Article
DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood–Brain Barrier Permeability
by Zhuo-Hao Liu, Nan-Yu Chen, Po-hsun Tu, Chen-Te Wu, Shao-Chieh Chiu, Ying-Cheng Huang, Siew-Na Lim and Ping K. Yip
Int. J. Mol. Sci. 2020, 21(17), 6291; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176291 - 31 Aug 2020
Cited by 16 | Viewed by 3403
Abstract
Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid [...] Read more.
Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood–brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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15 pages, 1861 KiB  
Article
Neuroprotection of Retinal Ganglion Cells with AAV2-BDNF Pretreatment Restoring Normal TrkB Receptor Protein Levels in Glaucoma
by Anna Wójcik-Gryciuk, Olga Gajewska-Woźniak, Katarzyna Kordecka, Paweł M. Boguszewski, Wioletta Waleszczyk and Małgorzata Skup
Int. J. Mol. Sci. 2020, 21(17), 6262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176262 - 29 Aug 2020
Cited by 29 | Viewed by 3279
Abstract
Intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury (ONI) or laser-induced ocular hypertension (OHT). In models of glaucoma, BDNF therapy can delay or halt [...] Read more.
Intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury (ONI) or laser-induced ocular hypertension (OHT). In models of glaucoma, BDNF therapy can delay or halt RGCs loss, but this protection is time-limited. The decreased efficacy of BDNF supplementation has been in part attributed to BDNF TrkB receptor downregulation. However, whether BDNF overexpression causes TrkB downregulation, impairing long-term BDNF signaling in the retina, has not been conclusively proven. After ONI or OHT, when increased retinal BDNF was detected, a concomitant increase, no change or a decrease in TrkB was reported. We examined quantitatively the retinal concentrations of the TrkB protein in relation to BDNF, in a course of adeno-associated viral vector gene therapy (AAV2-BDNF), using a microbead trabecular occlusion model of glaucoma. We show that unilateral glaucoma, with intraocular pressure ( IOP) increased for five weeks, leads to a bilateral decrease of BDNF in the retina at six weeks, accompanied by up to four-fold TrkB upregulation, while a moderate BDNF overexpression in a glaucomatous eye triggers changes that restore normal TrkB concentrations, driving signaling towards long-term RGCs neuroprotection. We conclude that for glaucoma therapy, the careful selection of the appropriate BDNF concentration is the main factor securing the long-term responsiveness of RGCs and the maintenance of normal TrkB levels. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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24 pages, 4372 KiB  
Article
Dual Leucine Zipper Kinase Is Constitutively Active in the Adult Mouse Brain and Has Both Stress-Induced and Homeostatic Functions
by Sunil Goodwani, Celia Fernandez, Paul J. Acton, Virginie Buggia-Prevot, Morgan L. McReynolds, Jiacheng Ma, Cheng Hui Hu, Mary E. Hamby, Yongying Jiang, Kang Le, Michael J. Soth, Philip Jones and William J. Ray
Int. J. Mol. Sci. 2020, 21(14), 4849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144849 - 09 Jul 2020
Cited by 7 | Viewed by 3479
Abstract
Dual leucine zipper kinase (DLK, Map3k12) is an axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). In peripheral nerves DLK is generally inactive until induced by injury, after which [...] Read more.
Dual leucine zipper kinase (DLK, Map3k12) is an axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). In peripheral nerves DLK is generally inactive until induced by injury, after which it transmits signals to the nucleus via retrograde transport. Here we report that in contrast to this mode of regulation, in the uninjured adult mouse cerebellum, DLK constitutively drives nuclear p-c-Jun in cerebellar granule neurons, whereas in the forebrain, DLK is similarly expressed and active, but nuclear p-c-Jun is undetectable. When neurodegeneration results from mutant human tau in the rTg4510 mouse model, p-c-Jun then accumulates in neuronal nuclei in a DLK-dependent manner, and the extent of p-c-Jun correlates with markers of synaptic loss and gliosis. This regional difference in DLK-dependent nuclear p-c-Jun accumulation could relate to differing levels of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1), whereas the forebrain contains more JIP-3 and plenty of SH3 (POSH). To characterize the functional differences between constitutive- versus injury-induced DLK signaling, RNA sequencing was performed after DLK inhibition in the cerebellum and in the non-transgenic and rTg4510 forebrain. In all contexts, DLK inhibition reduced a core set of transcripts that are associated with the JNK pathway. Non-transgenic forebrain showed almost no other transcriptional changes in response to DLK inhibition, whereas the rTg4510 forebrain and the cerebellum exhibited distinct differentially expressed gene signatures. In the cerebellum, but not the rTg4510 forebrain, pathway analysis indicated that DLK regulates insulin growth factor-1 (IGF1) signaling through the transcriptional induction of IGF1 binding protein-5 (IGFBP5), which was confirmed and found to be functionally relevant by measuring signaling through the IGF1 receptor. Together these data illuminate the complex multi-functional nature of DLK signaling in the central nervous system (CNS) and demonstrate its role in homeostasis as well as tau-mediated neurodegeneration. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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14 pages, 2543 KiB  
Article
E8002 Inhibits Peripheral Nerve Adhesion by Enhancing Fibrinolysis of l-Ascorbic Acid in a Rat Sciatic Nerve Model
by Kiyoshi Kikuchi, Kentaro Setoyama, Seiya Takada, Shotaro Otsuka, Kazuki Nakanishi, Kosuke Norimatsu, Akira Tani, Harutoshi Sakakima, Ko-ichi Kawahara, Kazuya Hosokawa, Ryoji Kiyama, Megumi Sumizono, Salunya Tancharoen, Ikuro Maruyama, Gohsuke Hattori, Motohiro Morioka, Eiichiro Tanaka and Hisaaki Uchikado
Int. J. Mol. Sci. 2020, 21(11), 3972; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113972 - 01 Jun 2020
Cited by 9 | Viewed by 2941
Abstract
Perineural adhesions leading to neuropathy are one of the most undesirable consequences of peripheral nerve surgery. However, there are currently no widely used compounds with anti-adhesive effects in the field of peripheral nerve surgery. E8002 is a novel, anti-adhesive, multi-layer membrane that contains [...] Read more.
Perineural adhesions leading to neuropathy are one of the most undesirable consequences of peripheral nerve surgery. However, there are currently no widely used compounds with anti-adhesive effects in the field of peripheral nerve surgery. E8002 is a novel, anti-adhesive, multi-layer membrane that contains L-ascorbic acid (AA). Here, we investigated the effect and mechanism of E8002 in a rat sciatic nerve adhesion model. A total of 21 rats were used. Six weeks after surgery, macroscopic adhesion scores were significantly lower in the E8002 group (adhesion procedure followed by nerve wrapping with E8002) compared to the E8002 AA(−) group (adhesion procedure followed by nerve wrapping with the E8002 membrane excluding AA) and adhesion group (adhesion procedure but no treatment). Correspondingly, a microscopic examination revealed prominent scar tissue in the E8002 AA(−) and adhesion groups. Furthermore, an in vitro study using human blood samples showed that AA enhanced tissue-type, plasminogen activator-mediated fibrinolysis. Altogether, these results suggest that E8002 may exert an anti-adhesive action via AA and the regulation of fibrinolysis. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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18 pages, 4093 KiB  
Article
Targeted Delivery of Iron Oxide Nanoparticle-Loaded Human Embryonic Stem Cell-Derived Spherical Neural Masses for Treating Intracerebral Hemorrhage
by Min Kyoung Kang, Tae Jung Kim, Young-Ju Kim, Lamie Kang, Jonghoon Kim, Nohyun Lee, Taeghwan Hyeon, Mi-sun Lim, Hee Jung Mo, Jung Hwan Shin, Sang-Bae Ko and Byung-Woo Yoon
Int. J. Mol. Sci. 2020, 21(10), 3658; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103658 - 22 May 2020
Cited by 20 | Viewed by 3109
Abstract
This study evaluated the potential of iron oxide nanoparticle-loaded human embryonic stem cell (ESC)-derived spherical neural masses (SNMs) to improve the transportation of stem cells to the brain, ameliorate brain damage from intracerebral hemorrhage (ICH), and recover the functional status after ICH under [...] Read more.
This study evaluated the potential of iron oxide nanoparticle-loaded human embryonic stem cell (ESC)-derived spherical neural masses (SNMs) to improve the transportation of stem cells to the brain, ameliorate brain damage from intracerebral hemorrhage (ICH), and recover the functional status after ICH under an external magnetic field of a magnet attached to a helmet. At 24 h after induction of ICH, rats were randomly separated into three experimental groups: ICH with injection of phosphate-buffered saline (PBS group), ICH with intravenous injection of magnetosome-like ferrimagnetic iron oxide nanocubes (FION)-labeled SNMs (SNMs* group), and ICH with intravenous injection of FION-labeled SNMs followed by three days of external magnetic field exposure for targeted delivery by a magnet-embedded helmet (SNMs*+Helmet group). On day 3 after ICH induction, an increased Prussian blue-stained area and decreased swelling volume were observed in the SNMs*+Helmet group compared with that of the other groups. A significantly decreased recruitment of macrophages and neutrophils and a downregulation of pro-inflammatory cytokines followed by improved neurological function three days after ICH were observed in the SNMs*+Helmet group. Hemispheric atrophy at six weeks after ICH was significantly decreased in the SNMs*+Helmet group compared with that of the PBS group. In conclusion, we have developed a targeted delivery system using FION tagged to stem cells and a magnet-embedded helmet. The targeted delivery of SNMs might have the potential for developing novel therapeutic strategies for ICH. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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16 pages, 16115 KiB  
Article
PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis
by Agata Grazia D’Amico, Grazia Maugeri, Salvatore Saccone, Concetta Federico, Sebastiano Cavallaro, Dora Reglodi and Velia D’Agata
Int. J. Mol. Sci. 2020, 21(8), 2943; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082943 - 22 Apr 2020
Cited by 30 | Viewed by 3504
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of complex etiology leading to motor neuron degeneration. Many gene alterations cause this pathology, including mutation in Cu, Zn superoxide dismutase (SOD1), which leads to its gain of function. Mutant SOD1 proteins are prone [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of complex etiology leading to motor neuron degeneration. Many gene alterations cause this pathology, including mutation in Cu, Zn superoxide dismutase (SOD1), which leads to its gain of function. Mutant SOD1 proteins are prone to aberrant misfolding and create aggregates that impair autophagy. The hypoxic stress is strictly linked to the disease progression since it induces uncontrolled autophagy activation and the consequent high rates of cell death. Previously, we showed that pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activity in cultured mSOD1 motor neurons exposed to serum deprivation. To date, no studies have examined whether the protective effect of PACAP on mSOD1 cells exposed to hypoxic insult is mediated through the regulation of the autophagy process. In the present study, we used the neuroblastoma-spinal cord-34 (NSC-34) cell line, stably expressing human wild type or mutant SOD1 G93A, to represent a well characterized in vitro model of a familial form of ALS. These cells were exposed to 100-µM desferrioxamine mesylate salt for 24h, to mimic the hypoxic stress affecting motor neurons during the disease progression. Our results showed that PACAP treatment significantly reduced cell death and hypoxia-induced mSOD1 accumulation by modulating the autophagy process in G93A motor neurons, as revealed by the decreased LC3II and the increased p62 levels, two autophagy indicators. These results were also confirmed by evaluating the vacuole formation detected through light chain 3 (LC3) immunofluorescence. Furthermore, the PACAP effects on autophagy seem to be mediated through the activation of the MAPK/ERK signaling pathway. Overall, our data demonstrated that PACAP exerts an ameliorative effect on the mSOD1 motor neuron viability by modulating a hypoxia-induced autophagy process through activation of MAPK/ERK signaling cascade. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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15 pages, 3491 KiB  
Article
Neurochemical Plasticity of nNOS-, VIP- and CART-Immunoreactive Neurons Following Prolonged Acetylsalicylic Acid Supplementation in the Porcine Jejunum
by Dominika Rząp, Marta Czajkowska and Jarosław Całka
Int. J. Mol. Sci. 2020, 21(6), 2157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062157 - 20 Mar 2020
Cited by 10 | Viewed by 2336
Abstract
Aspirin, also known as acetylsalicylic acid (ASA), is a commonly used anti-inflammatory drug that has analgesic and antipyretic properties. The side effects are well known, however, knowledge concerning its influence on gastric and intestinal innervation is limited. The enteric nervous system (ENS) innervates [...] Read more.
Aspirin, also known as acetylsalicylic acid (ASA), is a commonly used anti-inflammatory drug that has analgesic and antipyretic properties. The side effects are well known, however, knowledge concerning its influence on gastric and intestinal innervation is limited. The enteric nervous system (ENS) innervates the whole gastrointestinal tract (GIT) and is comprised of more than one hundred million neurons. The capacity of neurons to adapt to microenvironmental influences, termed as an enteric neuronal plasticity, is an essential adaptive response to various pathological stimuli. Therefore, the goal of the present study was to determine the influence of prolonged ASA supplementation on the immunolocalization of neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP) and cocaine- and amphetamine- regulated transcript peptide (CART) in the porcine jejunum. The experiment was performed on 8 Pietrain × Duroc immature gilts. Using routine double-labelling immunofluorescence, we revealed that the ENS nerve cells underwent adaptive changes in response to the induced inflammation, which was manifested by upregulated or downregulated expression of the studied neurotransmitters. Our results suggest the participation of nNOS, VIP and CART in the development of inflammation and may form the basis for further neuro-gastroenterological research. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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Review

Jump to: Research

26 pages, 1025 KiB  
Review
Antioxidant Supplementation in the Treatment of Neurotoxicity Induced by Platinum-Based Chemotherapeutics—A Review
by Jelena S. Katanic Stankovic, Dragica Selakovic, Vladimir Mihailovic and Gvozden Rosic
Int. J. Mol. Sci. 2020, 21(20), 7753; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207753 - 20 Oct 2020
Cited by 48 | Viewed by 4318
Abstract
Cancer represents one of the most pernicious public health problems with a high mortality rate among patients worldwide. Chemotherapy is one of the major therapeutic approaches for the treatment of various malignancies. Platinum-based drugs (cisplatin, oxaliplatin, carboplatin, etc.) are highly effective chemotherapeutic drugs [...] Read more.
Cancer represents one of the most pernicious public health problems with a high mortality rate among patients worldwide. Chemotherapy is one of the major therapeutic approaches for the treatment of various malignancies. Platinum-based drugs (cisplatin, oxaliplatin, carboplatin, etc.) are highly effective chemotherapeutic drugs used for the treatment of several types of malignancies, but their application and dosage are limited by their toxic effects on various systems, including neurotoxicity. Simultaneously, researchers have tried to improve the survival rate and quality of life of cancer patients and decrease the toxicity of platinum-containing drugs by combining them with non-chemotherapy-based drugs, dietary supplements and/or antioxidants. Additionally, recent studies have shown that the root cause for the many side effects of platinum chemotherapeutics involves the production of reactive oxygen species (ROS) in naive cells. Therefore, suppression of ROS generation and their inactivation with antioxidants represents an appropriate approach for platinum drug-induced toxicities. The aim of this paper is to present an updated review of the protective effects of different antioxidant agents (vitamins, dietary antioxidants and supplements, medicaments, medicinal plants and their bioactive compounds) against the neurotoxicity induced by platinum-based chemotherapeutics. This review highlights the high potential of plant antioxidants as adjuvant strategies in chemotherapy with platinum drugs. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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19 pages, 1566 KiB  
Review
Metformin as a Potential Agent in the Treatment of Multiple Sclerosis
by Angela Dziedzic, Joanna Saluk-Bijak, Elzbieta Miller and Michal Bijak
Int. J. Mol. Sci. 2020, 21(17), 5957; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21175957 - 19 Aug 2020
Cited by 30 | Viewed by 5104
Abstract
Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis [...] Read more.
Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses. Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood–brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels. Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions. The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function. Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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17 pages, 1263 KiB  
Review
Possible Neuroprotective Mechanisms of Physical Exercise in Neurodegeneration
by B. Mahalakshmi, Nancy Maurya, Shin-Da Lee and V. Bharath Kumar
Int. J. Mol. Sci. 2020, 21(16), 5895; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165895 - 16 Aug 2020
Cited by 124 | Viewed by 13419
Abstract
Physical exercise (PE) improves physical performance, mental status, general health, and well-being. It does so by affecting many mechanisms at the cellular and molecular level. PE is beneficial for people suffering from neuro-degenerative diseases because it improves the production of neurotrophic factors, neurotransmitters, [...] Read more.
Physical exercise (PE) improves physical performance, mental status, general health, and well-being. It does so by affecting many mechanisms at the cellular and molecular level. PE is beneficial for people suffering from neuro-degenerative diseases because it improves the production of neurotrophic factors, neurotransmitters, and hormones. PE promotes neuronal survival and neuroplasticity and also optimizes neuroendocrine and physiological responses to psychosocial and physical stress. PE sensitizes the parasympathetic nervous system (PNS), Autonomic Nervous System (ANS) and central nervous system (CNS) by promoting many processes such as synaptic plasticity, neurogenesis, angiogenesis, and autophagy. Overall, it carries out many protective and preventive activities such as improvements in memory, cognition, sleep and mood; growth of new blood vessels in nervous system; and the reduction of stress, anxiety, neuro-inflammation, and insulin resistance. In the present work, the protective effects of PE were overviewed. Suitable examples from the current research work in this context are also given in the article. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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29 pages, 1098 KiB  
Review
HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential Mechanisms and Therapeutic Opportunities
by Yam Nath Paudel, Efthalia Angelopoulou, Christina Piperi, Iekhsan Othman and Mohd. Farooq Shaikh
Int. J. Mol. Sci. 2020, 21(13), 4609; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134609 - 29 Jun 2020
Cited by 57 | Viewed by 7017
Abstract
Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like [...] Read more.
Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like cytokine with an initiator role in neuroinflammation that has been implicated in Traumatic brain injury (TBI) as well as in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Herein, we discuss the implication of HMGB1-induced neuroinflammatory responses in these brain injuries, mediated through binding to the receptor for advanced glycation end products (RAGE), toll-like receptor4 (TLR4) and other inflammatory mediators. Moreover, we provide evidence on the biomarker potential of HMGB1 and the significance of its nucleocytoplasmic translocation during brain injuries along with the promising neuroprotective effects observed upon HMGB1 inhibition/neutralization in TBI and EBI induced by SAH. Overall, this review addresses the current advances on neuroinflammation driven by HMGB1 in brain injuries indicating a future treatment opportunity that may overcome current therapeutic gaps. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2020)
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