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Special Issue "Neuroprotective Agents"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 1 July 2018

Special Issue Editor

Guest Editor
Prof. Dr. Jia Zhou

Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
Website1 | Website2 | E-Mail
Interests: drug discovery; target-based drug design; fragment/structure-based drug design; pharmacological tools; CNS therapeutics; neuroprotective agents; anticancer agents; anti-inflammatory agents; antiviral agents; drug development; chemical biology

Special Issue Information

Dear Colleagues,

Neuroprotection represents one of the most appealing therapeutic strategies for preventing neurodegeneration and mitigating against neuronal damage.  The development of novel neuroprotective agents has attracted tremendous drug discovery efforts, with the aim of identifying effective neurotherapeutics for a variety of central nervous system (CNS) disorders, including neurodegenerative diseases such as Alzheimer's disease (AD),  Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia, stroke, traumatic brain injury (TBI), spinal cord injury, schizophrenia, drug abuse-induced neurotoxicity (i.e. methamphetamine overdoses), and even retinal diseases and glaucoma. This Special Issue aims to provide a forum for the dissemination of the latest information on new molecules including both synthetic compounds and natural products as well as novel drug targets associated with neuroprotective agents. As the Guest Editor, I would like to thank all the authors for their tremendous effort, dedication, and excellent contribution to this special issue of Neuroprotective Agents. I hope that this issue will serve as a key reference work for medicinal chemists, chemical biologists, neuropharmacologists, and other research investigators engaged in or interested in neuroprotection and neuroprotective agent drug discovery and development.

Prof. Dr. Jia Zhou
Guest Editor

Manuscript Submission Information

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

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

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuroprotection
  • neuroprotective agents
  • neuroprotective drugs
  • neurotherapeutics
  • neuroapoptosis
  • neuronal cell death
  • drug discovery and development
  • synthetic molecules
  • natural products
  • drug targets and mechanisms
  • central nervous system (CNS) disorders
  • neurodegenerative diseases
  • Alzheimer's disease (AD)
  • Parkinson's disease (PD)
  • amyotrophic lateral sclerosis (ALS)
  • dementia
  • stroke
  • traumatic brain injury (TBI)
  • spinal cord injury
  • schizophrenia
  • drug abuse-induced neurotoxicity (i.e. methamphetamine overdoses)
  • retinal diseases and glaucoma

Published Papers (10 papers)

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Research

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Open AccessArticle Suramin-Induced Neurotoxicity: Preclinical Models and Neuroprotective Strategies
Molecules 2018, 23(2), 346; https://doi.org/10.3390/molecules23020346
Received: 15 December 2017 / Revised: 23 January 2018 / Accepted: 3 February 2018 / Published: 7 February 2018
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Abstract
Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed
[...] Read more.
Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin-induced neuropathy with a focus on calcium (Ca2+) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal-demyelinating polyneuropathy. In a next step, we used cultured dorsal root ganglia neurons (DRGN) as an in vitro cell model to further investigate underlying pathomechanisms. Cell viability of DRGN was significantly decreased after 24-hour suramin treatment with a calculated IC50 of 283 µM. We detected a suramin-induced Ca2+ influx into DRGN from the extracellular space, which could be reduced with the voltage-gated calcium channel (VGCC) inhibitor nimodipine. Co-incubation of suramin and nimodipine partially improved cell viability of DRGN after suramin exposure. In summary, we describe suramin-induced neurotoxic effects on DRGN as well as potentially neuroprotective agents targeting intracellular Ca2+ dyshomeostasis. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessArticle Synthesis and Biological Evaluations of NO-Donating Oxa- and Aza-Pentacycloundecane Derivatives as Potential Neuroprotective Candidates
Molecules 2018, 23(2), 308; https://doi.org/10.3390/molecules23020308
Received: 1 December 2017 / Revised: 26 January 2018 / Accepted: 28 January 2018 / Published: 31 January 2018
PDF Full-text (2488 KB) | HTML Full-text | XML Full-text
Abstract
In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds
[...] Read more.
In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-d-aspartate (NMDA)-mediated Ca2+ influx, the inhibition of voltage-mediated Ca2+ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20–39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessArticle α-Synuclein Regulates Neuronal Cholesterol Efflux
Molecules 2017, 22(10), 1769; https://doi.org/10.3390/molecules22101769
Received: 26 September 2017 / Revised: 18 October 2017 / Accepted: 19 October 2017 / Published: 19 October 2017
Cited by 3 | PDF Full-text (1140 KB) | HTML Full-text | XML Full-text
Abstract
α-Synuclein is a neuronal protein that is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies, which includes Parkinson’s disease (PD). Despite much research, the exact physiological function of α-synuclein is still unclear. α-Synuclein has
[...] Read more.
α-Synuclein is a neuronal protein that is at the center of focus in understanding the etiology of a group of neurodegenerative diseases called α-synucleinopathies, which includes Parkinson’s disease (PD). Despite much research, the exact physiological function of α-synuclein is still unclear. α-Synuclein has similar biophysical properties as apolipoproteins and other lipid-binding proteins and has a high affinity for cholesterol. These properties suggest a possible role for α-synuclein as a lipid acceptor mediating cholesterol efflux (the process of removing cholesterol out of cells). To test this concept, we “loaded” SK-N-SH neuronal cells with fluorescently-labelled cholesterol, applied exogenous α-synuclein, and measured the amount of cholesterol removed from the cells using a classic cholesterol efflux assay. We found that α-synuclein potently stimulated cholesterol efflux. We found that the process was dose and time dependent, and was saturable at 1.0 µg/mL of α-synuclein. It was also dependent on the transporter protein ABCA1 located on the plasma membrane. We reveal for the first time a novel role of α-synuclein that underscores its importance in neuronal cholesterol regulation, and identify novel therapeutic targets for controlling cellular cholesterol levels. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessArticle Ginsenoside Rg3 Prevents Oxidative Stress-Induced Astrocytic Senescence and Ameliorates Senescence Paracrine Effects on Glioblastoma
Molecules 2017, 22(9), 1516; https://doi.org/10.3390/molecules22091516
Received: 1 August 2017 / Revised: 22 August 2017 / Accepted: 8 September 2017 / Published: 10 September 2017
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Abstract
Senescent astrocytes in aging brain express senescence-associated secretory phenotype (SASP) and link with increased brain aging and its related diseases. In order to determine whether ginsenosides ameliorate the astrocytic senescence in vitro, human astrocytic CRT cells and primary rat astrocytes were used in
[...] Read more.
Senescent astrocytes in aging brain express senescence-associated secretory phenotype (SASP) and link with increased brain aging and its related diseases. In order to determine whether ginsenosides ameliorate the astrocytic senescence in vitro, human astrocytic CRT cells and primary rat astrocytes were used in the present study. Ginsenosides Rg1, Re, Rb1 and Rg3 (5 μg/mL) could effectively prevent the astrocytic senescence induced by H2O2 exposure. However, these ginsenosides did not reverse the astrocytic senescence. Importantly, senescent astrocytes herein produce SASP. The expression of major components of SASP, IL-6 and IL-8, are greatly increased in senescent astrocytes. Ginsenoside Rg3 (10 μg/mL) effectively suppressed the expressions of IL-6 and IL-8, which is associated with regulations of NF-κB and p38MAPK activation. In addition, after incubation with Rg3, conditioned medium from senescent astrocytic CRT cells significantly decreased the ability to promote the proliferation of astrocytoma U373-MG, U87-MG and U251-MG cells compared with non-treated senescent samples. Similar patterns were confirmed in chemotherapy-induced glioblastoma senescent cells. The present study explored a potential candidate for amelioration of astrocytic senescence and SASP in brain aging, which provided a basis for developing strategies to reduce the dark side of senescence in normal or pathological aging process. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessArticle Trehalose Inhibits A53T Mutant α-Synuclein Overexpression and Neurotoxicity in Transduced PC12 Cells
Molecules 2017, 22(8), 1293; https://doi.org/10.3390/molecules22081293
Received: 6 July 2017 / Accepted: 1 August 2017 / Published: 8 August 2017
Cited by 1 | PDF Full-text (2670 KB) | HTML Full-text | XML Full-text
Abstract
Fibrillar accumulation of A53T mutant α-synuclein (A53T-AS) in Lewy bodies is a symptom of Parkinsonism. Inhibitions of the overexpression and fibrillar aggregation of α-synuclein (AS) in vivo could be a promising strategy for treating Parkinson’s disease (PD). In this study, at concentrations lower
[...] Read more.
Fibrillar accumulation of A53T mutant α-synuclein (A53T-AS) in Lewy bodies is a symptom of Parkinsonism. Inhibitions of the overexpression and fibrillar aggregation of α-synuclein (AS) in vivo could be a promising strategy for treating Parkinson’s disease (PD). In this study, at concentrations lower than 1 mM, trehalose decreased the A53T-AS expression level in transduced PC12 cells. Although H2O2 and aluminum ions increased the expression level and neurotoxicity of A53T-AS in cells, proper trehalose concentrations inhibited the event. These studies adequately prove that trehalose at an appropriate dose would be potentially useful for PD treatment. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessArticle Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent
Molecules 2017, 22(8), 1246; https://doi.org/10.3390/molecules22081246
Received: 5 July 2017 / Revised: 17 July 2017 / Accepted: 23 July 2017 / Published: 25 July 2017
Cited by 1 | PDF Full-text (5630 KB) | HTML Full-text | XML Full-text
Abstract
In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer’s disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells
[...] Read more.
In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer’s disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells were utilized for transport studies, and homology modelling of human P-gp was built for further docking study to uncover the binding mode of DL0410. The results showed that the apparent permeability (Papp) value of DL0410 was approximately 1 × 10−6 cm/s, indicating the low permeability of DL0410. With the presence of verapamil, the directional transport of DL0410 disappeared in Caco-2 and MDCK-MDR1 cells, suggesting that DL0410 should be a substrate of P-gp, which was also confirmed by P-gp ATPase assay. In addition, DL0410 could competitively inhibit the transport of Rho123, a P-gp known substrate. According to molecular docking, we also found that DL0410 could bind to the drug binding pocket (DBP), but not the nucleotide binding domain (NBD). In conclusion, DL0410 was a substrate as well as a competitive inhibitor of P-gp, and P-gp had a remarkable impact on the intestine and brain permeability of DL0410, which is of significance for drug research and development. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Review

Jump to: Research

Open AccessReview Therapeutic Potential of Oridonin and Its Analogs: From Anticancer and Antiinflammation to Neuroprotection
Molecules 2018, 23(2), 474; https://doi.org/10.3390/molecules23020474
Received: 10 January 2018 / Revised: 13 February 2018 / Accepted: 21 February 2018 / Published: 22 February 2018
Cited by 1 | PDF Full-text (2519 KB) | HTML Full-text | XML Full-text
Abstract
Oridonin, a diterpenoid natural product commonly used in East Asian herbal medicine, is garnering increased attention in the biomedical community due to its extensive biological activities that include antitumor, anti-inflammatory, antimicrobial, hepatic fibrosis prevention, and neurological effects. Over the past decade, significant progress
[...] Read more.
Oridonin, a diterpenoid natural product commonly used in East Asian herbal medicine, is garnering increased attention in the biomedical community due to its extensive biological activities that include antitumor, anti-inflammatory, antimicrobial, hepatic fibrosis prevention, and neurological effects. Over the past decade, significant progress has been made in structure activity relationship and mechanism of action studies of oridonin for the treatment of cancer and other diseases. This review provides a brief summary on oridonin and its analogs in cancer drug discovery and antiinflammation and highlights its emerging therapeutic potential in neuroprotection applications. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessReview Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection
Molecules 2018, 23(2), 259; https://doi.org/10.3390/molecules23020259
Received: 24 December 2017 / Revised: 25 January 2018 / Accepted: 26 January 2018 / Published: 28 January 2018
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Abstract
Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some
[...] Read more.
Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER) stress, glucose metabolism, and synaptic function. The interleukin (IL)-1β and tumor necrosis factor (TNF)-α signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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Open AccessFeature PaperReview Impact & Blast Traumatic Brain Injury: Implications for Therapy
Molecules 2018, 23(2), 245; https://doi.org/10.3390/molecules23020245
Received: 26 December 2017 / Revised: 22 January 2018 / Accepted: 24 January 2018 / Published: 26 January 2018
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Abstract
Traumatic brain injury (TBI) is one of the most frequent causes of combat casualties in Operations Iraqi Freedom (OIF), Enduring Freedom (OEF), and New Dawn (OND). Although less common than combat-related blast exposure, there have been significant numbers of blast injuries in civilian
[...] Read more.
Traumatic brain injury (TBI) is one of the most frequent causes of combat casualties in Operations Iraqi Freedom (OIF), Enduring Freedom (OEF), and New Dawn (OND). Although less common than combat-related blast exposure, there have been significant numbers of blast injuries in civilian populations in the United States. Current United States Department of Defense (DoD) ICD-9 derived diagnoses of TBI in the DoD Health Care System show that, for 2016, severe and moderate TBIs accounted for just 0.7% and 12.9%, respectively, of the total of 13,634 brain injuries, while mild TBIs (mTBIs) accounted for 86% of the total. Although there is a report that there are differences in the frequency of long-term complications in mTBI between blast and non-blast TBIs, clinical presentation is classified by severity score rather than mechanism because severity scoring is associated with prognosis in clinical practice. Blast TBI (bTBI) is unique in its pathology and mechanism, but there is no treatment specific for bTBIs—these patients are treated similarly to TBIs in general and therapy is tailored on an individual basis. Currently there is no neuroprotective drug recommended by the clinical guidelines based on evidence. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
Open AccessReview Mitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection
Molecules 2018, 23(1), 191; https://doi.org/10.3390/molecules23010191
Received: 8 December 2017 / Revised: 14 January 2018 / Accepted: 15 January 2018 / Published: 17 January 2018
PDF Full-text (3974 KB) | HTML Full-text | XML Full-text
Abstract
In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude
[...] Read more.
In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude by presenting the potential modulating role of the kynurenine pathway in the ageing processes. Mitochondrial dynamics are supposed to have important physiological roles in maintaining cell homeostasis. During ageing, a decrease in mitochondrial dynamics was reported, potentially compromising the function of mitochondria. Mitochondrial biogenesis not only encompasses mitochondrial dynamics, but also the regulation of transcription and translation of genes, and mitochondria are supposed to play a prominent role in cell death during senescence. Defects in the mtDNA replication machinery and failure in the repair of mtDNA might result in the accumulation of mutations, leading to mitochondrial dysfunction and bioenergetic failure of the cell. The role of reactive oxygen species (ROS) in the ageing processes is widely acknowledged. Exaggerated oxidative damage to mDNA is supposed to take place during senescence, including single-nucleotide base alterations, nucleotide base pair alterations, chain breaks and cross linkage. A broad repertoire for the repair of DNA faults has evolved, but they do not function efficiently during senescence. Poly (ADP-ribose) polymerase (PARP) is an enzyme that assists in DNA repair, i.e., it participates in the repair of single-stranded DNA nicks, initiating base excision repair (BER). In the case of extensive DNA damage, PARP-1 becomes overactivated and rapidly depletes the intracellular NAD+ and ATP pools. This results in a profound energy loss of the cell and leads to cell dysfunction, or even cell death. Alterations in the kynurenine system have been linked with ageing processes and several age-related disorders. The kynurenine pathway degrades tryptophan (TRP) to several metabolites, among others kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN). The end product of the route is NAD+. The first metabolic reaction is mediated by TRP-2,3-dioxygenase (TDO) or indolamine-2,3-dioxygenases (IDO), the latter being induced by inflammation, and it is thought to have a significant role in several disorders and in ageing. Research is currently focusing on the KYN pathway, since several intermediates possess neuro- and immunoactive properties, and hence are capable of modulating the activity of certain brain cells and inflammatory responses. During ageing, and in many age-associated disorders like obesity, dyslipidaemia, hypertension, insulin resistance and neurodegenerative diseases, low-grade, sustained inflammation and upregulation of IDO have been reported. However, TRP downstream catabolites create a negative feedback loop by weakening the activated immune system through several actions, including a decline in the Th1 response and an enhancement of Th2-type processes. The broad actions of the KYN-intermediates in brain excitation/inhibition and their role in regulating immune responses may provide the possibility of modifying the pathological processes in an array of age-associated diseases in the future. Full article
(This article belongs to the Special Issue Neuroprotective Agents)
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