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Neuroprotective Strategies 2018
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Neuroprotective Strategies 2018

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 112498

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,

We started the “Neuroprotective Strategies” collection, jointly with Molecules, in 2009. It was a great success; a large number of reviews and original research articles were published in the inaugural volume. Since then, the International Journal of Molecular Sciences has successfully continued this collection, covering neuroprotection broadly, including, but not limited to, preclinical/basic science assessments of various in vitro and animal models relevant to neurodegeneration and agents with potential or perceived translation value, as well as clinical case reports. We hope that the “Neuroprotective Strategies” Special Issue will also include thought-provoking comments, opinions and perspectives in addition to traditional reviews and research articles in this field. We especially encourage submissions that address critical issues that have prevented successful clinical translations of promising laboratory data, such as limitations of in vitro studies and preclinical animal models to mirror multiple pathologies underlying human neurodegenerative diseases, lack of drug-likeness of experimental agents, obstacles of drug delivery to the CNS, as well as the need to consider ADMET and pharmacokinetics even in the early stage of drug discovery. Critical reviews of relevant patent literature and clinical findings are also welcome. I appreciate past submissions and look forward to receiving future contributions on the promising and challenging aspects of neuroprotective strategies.

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.

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Keywords

  • Neurodegenerative diseases and CNS injury
  • Aging
  • CNS drug design and delivery
  • Inflammation and oxidative stress
  • In vitro and in vivo models of neurodegeneration
  • Clinical case reports
  • Peripheral nerve injury
  • Translational medicine

Related Special Issue

Published Papers (18 papers)

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20 pages, 2547 KiB  
Article
Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6′-Dithiothalidomide on Traumatic Brain Injury
by Buyandelger Batsaikhan, Jing-Ya Wang, Michael T. Scerba, David Tweedie, Nigel H. Greig, Jonathan P. Miller, Barry J. Hoffer, Chih-Tung Lin and Jia-Yi Wang
Int. J. Mol. Sci. 2019, 20(3), 502; https://doi.org/10.3390/ijms20030502 - 24 Jan 2019
Cited by 20 | Viewed by 4409
Abstract
Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis [...] Read more.
Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis factor-α (TNF-α) is known to contribute to these processes. We have previously shown that 3,6′-dithiothalidomide (3,6′-DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF-α in cultured cells and reverses behavioral impairments induced by mild TBI in mice. In the present study, we further explored the therapeutic potential of 3,6′-DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6′-DT (28 mg/kg, i.p.) at 5 h after TBI significantly reduced contusion volume, neuronal degeneration, neuronal apoptosis and neurological deficits at 24 h post-injury. Expression of pro-inflammatory cytokines in the contusion regions were also suppressed at the transcription and translation level by 3,6′-DT. Notably, neuronal oxidative stress was also suppressed by 3,6′-DT. We conclude that 3,6′-DT may represent a potential therapy to ameliorate TBI-induced functional deficits. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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12 pages, 5007 KiB  
Article
Epitope Mapping Immunoassay Analysis of the Interaction between β-Amyloid and Fibrinogen
by Vo Van Giau and Seong Soo A. An
Int. J. Mol. Sci. 2019, 20(3), 496; https://doi.org/10.3390/ijms20030496 - 24 Jan 2019
Cited by 10 | Viewed by 3751
Abstract
The vast majority of patients with Alzheimer’s disease (AD) suffer from impaired cerebral circulation. Substantial evidence indicates that fibrinogen (Fbg) and fibrin clot formation play an important role in this circulatory dysfunction in AD. Fbg interacts with β-amyloid (1-42) (Aβ), forming plasmin-resistant abnormal [...] Read more.
The vast majority of patients with Alzheimer’s disease (AD) suffer from impaired cerebral circulation. Substantial evidence indicates that fibrinogen (Fbg) and fibrin clot formation play an important role in this circulatory dysfunction in AD. Fbg interacts with β-amyloid (1-42) (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition has been discovered in the brains of AD patients and mouse models. In this study, biochemical approaches and the epitope mapping immunoassay were employed to characterize binding epitopes within the Fbg and complementary epitopes in Aβ. We discovered the Aβ5–25 peptide as the most critical region for the interaction, which can be inhibited by specific monoclonal and polyclonal antibodies against the central region of Aβ. Aβ binding to Fbg may block plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of plasmin-resistant fibrin degradation fragments. Our study elucidates the Aβ–Fbg interaction that may involve the mechanism by which Aβ–Fbg binding delays fibrinolysis by plasmin, providing valuable information in the development of therapeutic approaches for AD. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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19 pages, 6777 KiB  
Article
Immunohistochemical Evaluation of Aquaporin-4 and its Correlation with CD68, IBA-1, HIF-1α, GFAP, and CD15 Expressions in Fatal Traumatic Brain Injury
by Margherita Neri, Alessandro Frati, Emanuela Turillazzi, Santina Cantatore, Luigi Cipolloni, Marco Di Paolo, Paola Frati, Raffaele La Russa, Aniello Maiese, Matteo Scopetti, Alessandro Santurro, Francesco Sessa, Rosanna Zamparese and Vittorio Fineschi
Int. J. Mol. Sci. 2018, 19(11), 3544; https://doi.org/10.3390/ijms19113544 - 10 Nov 2018
Cited by 53 | Viewed by 7437
Abstract
Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Our understanding of its pathobiology has substantially increased. Following TBI, the following occur, edema formation, brain swelling, increased intracranial pressure, changes in cerebral blood flow, hypoxia, neuroinflammation, oxidative [...] Read more.
Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Our understanding of its pathobiology has substantially increased. Following TBI, the following occur, edema formation, brain swelling, increased intracranial pressure, changes in cerebral blood flow, hypoxia, neuroinflammation, oxidative stress, excitotoxicity, and apoptosis. Experimental animal models have been developed. However, the difficulty in mimicking human TBI explains why few neuroprotective strategies, drawn up on the basis of experimental studies, have translated into improved therapeutic strategies for TBI patients. In this study, we retrospectively examined brain samples in 145 cases of death after different survival times following TBI, to investigate aquaporin-4 (AQP4) expression and correlation with hypoxia, and neuroinflammation in human TBI. Antibodies anti-glial fibrillary acid protein (GFAP), aquaporin-4 (AQP4), hypoxia induced factor-1α (HIF-1α), macrophage/phagocytic activation (CD68), ionized calcium-binding adapter molecule-1 (IBA-1), and neutrophils (CD15) were used. AQP4 showed a significant, progressive increase between the control group and groups 2 (one-day survival) and 3 (three-day survival). There were further increases in AQP4 immunopositivity in groups 4 (seven-day survival), 5 (14-dayssurvival), and 6 (30-day survival), suggesting an upregulation of AQP4 at 7 to 30 days compared to group 1. GFAP showed its highest expression in non-acute cases at the astrocytic level compared with the acute TBI group. Data emerging from the HIF-1α reaction showed a progressive, significant increase. Immunohistochemistry with IBA-1 revealed activated microglia starting three days after trauma and progressively increasing in the next 15 to 20 days after the initial trauma. CD68 expression demonstrated basal macrophage and phagocytic activation mostly around blood vessels. Starting from one to three days of survival after TBI, an increase in the number of CD68 cells was progressively observed; at 15 and 30 days of survival, CD68 showed the most abundant immunopositivity inside or around the areas of necrosis. These findings need to be developed further to gain insight into the mechanisms through which brain AQP4 is upregulated. This could be of the utmost clinicopathological importance. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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16 pages, 4793 KiB  
Article
Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity
by Jeong Yeob Baek, Jae Yeong Jeong, Kyoung In Kim, So-Yoon Won, Young Cheul Chung, Jin Han Nam, Eun Ju Cho, Tae-Beom Ahn, Eugene Bok, Won-Ho Shin and Byung Kwan Jin
Int. J. Mol. Sci. 2018, 19(11), 3543; https://doi.org/10.3390/ijms19113543 - 10 Nov 2018
Cited by 31 | Viewed by 6595
Abstract
We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by [...] Read more.
We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRα) expression was evident on microglia in the MPP+-lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRα on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRα on microglia in the SN from human Parkinson’s disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson’s disease. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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16 pages, 7286 KiB  
Article
Sex-Dependent Effects of Bmal1-Deficiency on Mouse Cerebral Cortex Infarction in Response to Photothrombotic Stroke
by Anne Lembach, Anna Stahr, Amira A. H. Ali, Marc Ingenwerth and Charlotte Von Gall
Int. J. Mol. Sci. 2018, 19(10), 3124; https://doi.org/10.3390/ijms19103124 - 11 Oct 2018
Cited by 19 | Viewed by 4794
Abstract
Stroke is a leading cause of disability and death worldwide. There is increasing evidence that occurrence of ischemic stroke is affected by circadian system and sex. However, little is known about the effect of these factors on structural recovery after ischemic stroke. Therefore, [...] Read more.
Stroke is a leading cause of disability and death worldwide. There is increasing evidence that occurrence of ischemic stroke is affected by circadian system and sex. However, little is known about the effect of these factors on structural recovery after ischemic stroke. Therefore, we studied infarction in cerebral neocortex of male and female mice with deletion of the clock gene Bmal1 (Bmal1−/−) after focal ischemia induced by photothrombosis (PT). The infarct core size was significantly smaller 14 days (d) as compared to seven days after PT, consistent with structural recovery during the sub-acute phase. However, when sexes were analyzed separately 14 days after PT, infarct core was significantly larger in wild-type (Bmal1+/+) female as compared to male Bmal1+/+ mice, and in female Bmal1+/+, as compared to female Bmal1−/− mice. Volumes of reactive astrogliosis and densely packed microglia closely mirrored the size of infarct core in respective groups. Estradiol levels were significantly higher in female Bmal1−/− as compared to Bmal1+/+ mice. Our data suggests a sex-dependent effect and an interaction between sex and genotype on infarct size, the recruitment of astrocytes and microglia, and a relationship of these cells with structural recovery probably due to positive effects of estradiol during the subacute phase. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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16 pages, 2877 KiB  
Article
Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model
by Han-Fang Wu, Yi-Ju Chen, Ming-Chia Chu, Ya-Ting Hsu, Ting-Yi Lu, I-Tuan Chen, Po See Chen and Hui-Ching Lin
Int. J. Mol. Sci. 2018, 19(9), 2840; https://doi.org/10.3390/ijms19092840 - 19 Sep 2018
Cited by 21 | Viewed by 6350
Abstract
Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced [...] Read more.
Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT1A receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) and the β3 subunit of γ-aminobutyric acid type A receptors (GABAAR) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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16 pages, 3190 KiB  
Article
Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice
by Julia Relat, Julio Come, Belen Perez, Pelayo Camps, Diego Muñoz-Torrero, Albert Badia, Lydia Gimenez-Llort and M. Victòria Clos
Int. J. Mol. Sci. 2018, 19(9), 2615; https://doi.org/10.3390/ijms19092615 - 04 Sep 2018
Cited by 3 | Viewed by 3885
Abstract
Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ [...] Read more.
Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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14 pages, 4472 KiB  
Article
Thyroxin Protects White Matter from Hypoxic-Ischemic Insult in the Immature Sprague–Dawley Rat Brain by Regulating Periventricular White Matter and Cortex BDNF and CREB Pathways
by Pi-Lien Hung, Mei-Hsin Hsu, Hong-Ren Yu, Kay L. H. Wu and Feng-Sheng Wang
Int. J. Mol. Sci. 2018, 19(9), 2573; https://doi.org/10.3390/ijms19092573 - 29 Aug 2018
Cited by 16 | Viewed by 3542
Abstract
Background: Periventricular white-matter (WM) injury is a prominent feature of brain injury in preterm infants. Thyroxin (T4) treatment reduces the severity of hypoxic-ischemic (HI)-mediated WM injury in the immature brain. This study aimed to delineate molecular events underlying T4 protection following periventricular WM [...] Read more.
Background: Periventricular white-matter (WM) injury is a prominent feature of brain injury in preterm infants. Thyroxin (T4) treatment reduces the severity of hypoxic-ischemic (HI)-mediated WM injury in the immature brain. This study aimed to delineate molecular events underlying T4 protection following periventricular WM injury in HI rats. Methods: Right common-carotid-artery ligation, followed by hypoxia, was performed on seven-day-old rat pups. The HI pups were injected with saline, or 0.2 or 1 mg/kg of T4 at 48–96 h postoperatively. Cortex and periventricular WM were dissected for real-time (RT)-quantitative polymerase chain reactions (PCRs), immunoblotting, and for immunofluorescence analysis of neurotrophins, myelin, oligodendrocyte precursors, and neointimal. Results: T4 significantly mitigated hypomyelination and oligodendrocyte death in HI pups, whereas angiogenesis of periventricular WM, observed using antiendothelium cell antibody (RECA-1) immunofluorescence and vascular endothelium growth factor (VEGF) immunoblotting, was not affected. T4 also increased the brain-derived neurotrophic factors (BDNFs), but not the nerve growth factor (NGF) expression of injured periventricular WM. However, phosphorylated extracellular signal regulated kinase (p-ERK) and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) concentrations, but not the BDNF downstream pathway kinases, p38, c-Jun amino-terminal kinase (c-JNK), or Akt, were reduced in periventricular WM with T4 treatment. Notably, T4 administration significantly increased BDNF and phosphorylated CREB in the overlying cortex of the HI-induced injured cortex. Conclusion: Our findings reveal that T4 reversed BNDF signaling to attenuate HI-induced WM injury by activating ERK and CREB pathways in the cortex, but not directly in periventricular WM. This study offers molecular insight into the neuroprotective actions of T4 in HI-mediated WM injury in the immature brain. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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13 pages, 1498 KiB  
Article
GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
by Ching-Chi Chang, Tzu-Chin Lin, Hsiao-Li Ho, Chien-Yin Kuo, Hsin-Hua Li, Tatiana A. Korolenko, Wei-Jen Chen, Te-Jen Lai, Ying-Jui Ho and Chih-Li Lin
Int. J. Mol. Sci. 2018, 19(9), 2505; https://doi.org/10.3390/ijms19092505 - 24 Aug 2018
Cited by 23 | Viewed by 5681
Abstract
Huntington’s disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to [...] Read more.
Huntington’s disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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16 pages, 3671 KiB  
Article
Diosgenin Glucoside Protects against Spinal Cord Injury by Regulating Autophagy and Alleviating Apoptosis
by Xian-Bing Chen, Zi-Li Wang, Qing-Yu Yang, Fang-Yu Zhao, Xiao-Li Qin, Xian-E Tang, Jun-Long Du, Zong-Hai Chen, Kui Zhang and Fei-Jun Huang
Int. J. Mol. Sci. 2018, 19(8), 2274; https://doi.org/10.3390/ijms19082274 - 02 Aug 2018
Cited by 36 | Viewed by 4465
Abstract
Spinal cord injury (SCI) is a severe traumatic lesion of central nervous system (CNS) with only a limited number of restorative therapeutic options. Diosgenin glucoside (DG), a major bioactive ingredient of Trillium tschonoskii Max., possesses neuroprotective effects through its antioxidant and anti-apoptotic functions. [...] Read more.
Spinal cord injury (SCI) is a severe traumatic lesion of central nervous system (CNS) with only a limited number of restorative therapeutic options. Diosgenin glucoside (DG), a major bioactive ingredient of Trillium tschonoskii Max., possesses neuroprotective effects through its antioxidant and anti-apoptotic functions. In this study, we investigated the therapeutic benefit and underlying mechanisms of DG treatment in SCI. We found that in Sprague-Dawley rats with traumatic SCI, the expressions of autophagy marker Light Chain 3 (LC3) and Beclin1 were decreased with concomitant accumulation of autophagy substrate protein p62 and ubiquitinated proteins, indicating an impaired autophagic activity. DG treatment, however, significantly attenuated p62 expression and upregulated the Rheb/mTOR signaling pathway (evidenced as Ras homolog enriched in brain) due to the downregulation of miR-155-3p. We also observed significantly less tissue injury and edema in the DG-treated group, leading to appreciable functional recovery compared to that of the control group. Overall, the observed neuroprotection afforded by DG treatment warrants further investigation on its therapeutic potential in SCI. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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19 pages, 2409 KiB  
Article
Protective Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate on Aβ1-42-Induced Cognitive Deficit, Oxidative Stress, Inflammation, and Apoptosis in Mice
by Fabiana Morroni, Giulia Sita, Agnese Graziosi, Eleonora Turrini, Carmela Fimognari, Andrea Tarozzi and Patrizia Hrelia
Int. J. Mol. Sci. 2018, 19(7), 2083; https://doi.org/10.3390/ijms19072083 - 18 Jul 2018
Cited by 24 | Viewed by 4542
Abstract
Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of β-amyloid oligomers (Aβ1-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated Aβ1-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following Aβ1-42O injection were reduced by 6-MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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23 pages, 3550 KiB  
Article
Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures
by Joanna Ślusarczyk, Ewa Trojan, Katarzyna Głombik, Anna Piotrowska, Bogusława Budziszewska, Marta Kubera, Katarzyna Popiołek-Barczyk, Władysław Lasoń, Joanna Mika and Agnieszka Basta-Kaim
Int. J. Mol. Sci. 2018, 19(7), 1965; https://doi.org/10.3390/ijms19071965 - 05 Jul 2018
Cited by 89 | Viewed by 7079
Abstract
An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment [...] Read more.
An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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20 pages, 2624 KiB  
Article
Role for Cystathionine γ Lyase (CSE) in an Ethanol (E)-Induced Lesion in Fetal Brain GSH Homeostasis
by Dhyanesh Patel, Marylatha Rathinam, Courtney Jarvis, Lenin Mahimainathan, George Henderson and Madhusudhanan Narasimhan
Int. J. Mol. Sci. 2018, 19(5), 1537; https://doi.org/10.3390/ijms19051537 - 22 May 2018
Cited by 7 | Viewed by 5421
Abstract
Earlier, we reported that gestational ethanol (E) can dysregulate neuron glutathione (GSH) homeostasis partially via impairing the EAAC1-mediated inward transport of Cysteine (Cys) and this can affect fetal brain development. In this study, we investigated if there is a role for the transulfuration [...] Read more.
Earlier, we reported that gestational ethanol (E) can dysregulate neuron glutathione (GSH) homeostasis partially via impairing the EAAC1-mediated inward transport of Cysteine (Cys) and this can affect fetal brain development. In this study, we investigated if there is a role for the transulfuration pathway (TSP), a critical bio-synthetic point to supply Cys in E-induced dysregulation of GSH homeostasis. These studies utilized an in utero E binge model where the pregnant Sprague–Dawley (SD) rat dams received five doses of E at 3.5 g/kg by gastric intubation beginning embryonic day (ED) 17 until ED19 separated by 12 h. The postnatal day 7 (PN7) alcohol model employed an oral dosing of 4 g/kg body weight split into 2 feedings at 2 h interval and an iso-caloric and iso-volumic equivalent maltose-dextrin milk solution served as controls. The in vitro model consisted of cerebral cortical neuron cultures from embryonic day (ED) 16–17 fetus from SD rats and differentiated neurons from ED18 rat cerebral cortical neuroblasts. E concentrations were 4 mg/mL. E induced an accumulation of cystathionine in primary cortical neurons (PCNs), 2nd trimester equivalent in utero binge, and 3rd trimester equivalent PN7 model suggesting that breakdown of cystathionine, a required process for Cys supply is impaired. This was associated with a significant reduction in cystathionine γ-lyase (CSE) protein expression in PCN (p < 0.05) and in fetal cerebral cortex in utero (53%, p < 0.05) without a change in the expression of cystathionine β-synthase (CBS). Concomitantly, E decreased Cse mRNA expression in PCNs (by 32% within 6 h of exposure, p < 0.05) and in fetal brain (33%, p < 0.05). In parallel, knock down of CSE in differentiated rat cortical neuroblasts exaggerated the E-induced ROS, GSH loss with a pronounced caspase-3 activation and cell death. These studies illustrate the importance of TSP in CSE-related maintenance of GSH and the downstream events via Cys synthesis in neurons and fetal brain. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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Review

Jump to: Research

33 pages, 2308 KiB  
Review
Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity
by Stefano Thellung, Alessandro Corsaro, Mario Nizzari, Federica Barbieri and Tullio Florio
Int. J. Mol. Sci. 2019, 20(4), 901; https://doi.org/10.3390/ijms20040901 - 19 Feb 2019
Cited by 78 | Viewed by 8388
Abstract
The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the “self-defense” equipment of neurons, such as autophagy. Through the degradation and [...] Read more.
The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the “self-defense” equipment of neurons, such as autophagy. Through the degradation and recycling of the intracellular content, autophagy promotes neuron survival in conditions of trophic factor deprivation, oxidative stress, mitochondrial and lysosomal damage, or accumulation of misfolded proteins. Autophagy involves the activation of self-digestive pathways, which is different for dynamics (macro, micro and chaperone-mediated autophagy), or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which causes the inability to remove the neurotoxic oligomers of misfolded proteins. Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1), removing its autophagy suppressor activity observed under physiological conditions; acting in this way, rapamycin provided the first proof of principle that pharmacological autophagy enhancement can induce neuroprotection through the facilitation of oligomers’ clearance. The demand for effective disease-modifying strategies against neurodegenerative disorders is currently stimulating the development of a wide number of novel molecules, as well as the re-evaluation of old drugs for their pro-autophagic potential. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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11 pages, 700 KiB  
Review
Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System
by Ken-ichiro Hayashida and Hideaki Obata
Int. J. Mol. Sci. 2019, 20(4), 822; https://doi.org/10.3390/ijms20040822 - 14 Feb 2019
Cited by 46 | Viewed by 11308
Abstract
Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in [...] Read more.
Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in the analgesic mechanisms of these drugs. Gabapentinoids activate the LC by inhibiting the release of γ-aminobutyric acid (GABA) and inducing the release of glutamate, thereby increasing noradrenaline levels in the spinal cord. Antidepressants increase noradrenaline levels in the spinal cord by inhibiting reuptake, and accumulating noradrenaline inhibits chronic pain through α2-adrenergic receptors in the spinal cord. Recent animal studies, however, revealed that the function of the descending noradrenergic inhibitory system is impaired in chronic pain states. Other recent studies found that histone deacetylase inhibitors and antidepressants restore the impaired noradrenergic descending inhibitory system acting on noradrenergic neurons in the LC. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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36 pages, 3020 KiB  
Review
Novel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease
by Michiel Van Bulck, Ana Sierra-Magro, Jesus Alarcon-Gil, Ana Perez-Castillo and Jose A. Morales-Garcia
Int. J. Mol. Sci. 2019, 20(3), 719; https://doi.org/10.3390/ijms20030719 - 08 Feb 2019
Cited by 128 | Viewed by 13923
Abstract
Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer’s and Parkinson’s diseases. A progressive neurodegenerative process [...] Read more.
Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer’s and Parkinson’s diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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31 pages, 871 KiB  
Review
A Systematic Review of Neuroprotective Strategies in the Management of Hypoglycemia
by Marius Nistor, Martin Schmidt, Isabel Graul, Florian Rakers and René Schiffner
Int. J. Mol. Sci. 2019, 20(3), 550; https://doi.org/10.3390/ijms20030550 - 28 Jan 2019
Cited by 2 | Viewed by 4353
Abstract
Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies [...] Read more.
Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies during hypoglycemia in the form of a systematic review in adherence to the PRISMA statement. A review protocol was registered in the PROSPERO database. A systematic literature search of PubMed, Web of Science, and CENTRAL was performed in September 2018. Based on a predefined inclusion protocol, results were screened and evaluated by two researchers. Both animal experiments and human studies were included, and their risk of bias was assessed with SYRCLE’s and the Cochrane risk of bias tools, respectively. Of a total of 16,230 results, 145 were assessed in full-text form: 27 articles adhered to the inclusion criteria and were qualitatively analyzed. The retrieved neuroprotective strategies could be categorized into three subsets: (1) Energy substitution, (2) hypoglycemia unawareness, and (3) other neuroprotective strategies. While on a study level, the individual results appeared promising, more research is required to investigate not only specific neuroprotective strategies against hypoglycemic cerebral damage, but also its underlying pathophysiological mechanisms. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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12 pages, 830 KiB  
Review
Modulation of the Endocannabinoid System Following Central Nervous System Injury
by Juan Zhou, Haneen Noori, Ian Burkovskiy, J. Daniel Lafreniere, Melanie E. M. Kelly and Christian Lehmann
Int. J. Mol. Sci. 2019, 20(2), 388; https://doi.org/10.3390/ijms20020388 - 17 Jan 2019
Cited by 13 | Viewed by 5427
Abstract
Central nervous system (CNS) injury, such as stroke or trauma, is known to increase susceptibility to various infections that adversely affect patient outcomes (CNS injury-induced immunodepression—CIDS). The endocannabinoid system (ECS) has been shown to have immunoregulatory properties. Therefore, the ECS might represent a [...] Read more.
Central nervous system (CNS) injury, such as stroke or trauma, is known to increase susceptibility to various infections that adversely affect patient outcomes (CNS injury-induced immunodepression—CIDS). The endocannabinoid system (ECS) has been shown to have immunoregulatory properties. Therefore, the ECS might represent a druggable target to overcome CIDS. Evidence suggests that cannabinoid type 2 receptor (CB2R) activation can be protective during the early pro-inflammatory phase after CNS injury, as it limits neuro-inflammation and, therefore, attenuates CIDS severity. In the later phase post CNS injury, CB2R inhibition is suggested as a promising pharmacologic strategy to restore immune function in order to prevent infection. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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