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CNS Drug Action in Neurodegenerative Diseases
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CNS Drug Action in Neurodegenerative Diseases

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 (30 September 2020) | Viewed by 107986

Special Issue Editor

Prof. Dr. Stefanie Kürten

E-Mail Website
Guest Editor
Institute of Neuroanatomy, Faculty of Medicine, University of Bonn, 53115 Bonn, Germany
Interests: autoimmunity; autoantibodies; B cells; EAE; multiple sclerosis; neuroprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s, and Parkinson’s disease are neurodegenerative diseases of the central nervous system, which represent a major socioeconomic burden to society. All of these diseases are similar in that their etiology is still unclear and there are different theories on their pathogenesis. While most drugs that are approved to treat neurodegeneration are able to reduce clinical symptoms and slow down disease progression, they cannot cure the disease. In addition, the availability of suitable biomarkers that could predict treatment success is very limited, so that patient-oriented therapy has remained a future goal. Yet, intensive research is ongoing to eventually unravel the mechanisms underlying neurodegeneration and central nervous system repair. This open-access Special Issue will bring together original research and review articles on the mode of action of different drugs that were designed to limit neurodegeneration, support neuroprotection, and/or to promote neural repair, highlighting what has already been achieved and which new discoveries, approaches, and technical developments in central nervous system research are on their way.

Topics of this Special Issue include but are not limited to:

- Etiology and pathogenesis of neurodegenerative diseases;

- Mechanisms of neurodegeneration, neuroprotection, and neural repair in the central nervous system;

- Pharmaceutical and pharmacological central nervous system drug classification;

- Mode of action of central nervous system drugs;

- Past and ongoing clinical trials using CNS drugs in neurodegenerative diseases;

- Novel strategies for the prevention and treatment of CNS degeneration.

Prof. Dr. Stefanie Kürten
Guest Editor

Manuscript Submission Information

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

  • CNS drugs
  • neurodegenerative diseases
  • neuroprotection
  • neuroregeneration
  • pharmacology

Published Papers (20 papers)

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Research

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19 pages, 4588 KiB  
Article
Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage
by Silvia Gazzin, Matteo Dal Ben, Michele Montrone, Sri Jayanti, Andrea Lorenzon, Alessandra Bramante, Cristina Bottin, Rita Moretti and Claudio Tiribelli
Int. J. Mol. Sci. 2021, 22(1), 299; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010299 - 30 Dec 2020
Cited by 11 | Viewed by 3002
Abstract
Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological [...] Read more.
Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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17 pages, 1960 KiB  
Article
Obinutuzumab-Induced B Cell Depletion Reduces Spinal Cord Pathology in a CD20 Double Transgenic Mouse Model of Multiple Sclerosis
by Thomas Breakell, Sabine Tacke, Verena Schropp, Henrik Zetterberg, Kaj Blennow, Eduard Urich and Stefanie Kuerten
Int. J. Mol. Sci. 2020, 21(18), 6864; https://doi.org/10.3390/ijms21186864 - 18 Sep 2020
Cited by 6 | Viewed by 2883
Abstract
B cell-depleting therapies have recently proven to be clinically highly successful in the treatment of multiple sclerosis (MS). This study aimed to determine the effects of the novel type II anti-human CD20 (huCD20) monoclonal antibody (mAb) obinutuzumab (OBZ) on spinal cord degeneration in [...] Read more.
B cell-depleting therapies have recently proven to be clinically highly successful in the treatment of multiple sclerosis (MS). This study aimed to determine the effects of the novel type II anti-human CD20 (huCD20) monoclonal antibody (mAb) obinutuzumab (OBZ) on spinal cord degeneration in a B cell-dependent mouse model of MS. Double transgenic huCD20xHIGR3 (CD20dbtg) mice, which express human CD20, were immunised with the myelin fusion protein MP4 to induce experimental autoimmune encephalomyelitis (EAE). Both light and electron microscopy were used to assess myelination and axonal pathology in mice treated with OBZ during chronic EAE. Furthermore, the effects of the already established murine anti-CD20 antibody 18B12 were assessed in C57BL/6 wild-type (wt) mice. In both models (18B12/wt and OBZ/CD20dbtg) anti-CD20 treatment significantly diminished the extent of spinal cord pathology. While 18B12 treatment mainly reduced the extent of axonal pathology, a significant decrease in demyelination and increase in remyelination were additionally observed in OBZ-treated mice. Hence, the data suggest that OBZ could have neuroprotective effects on the CNS, setting the drug apart from the currently available type I anti-CD20 antibodies. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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20 pages, 7251 KiB  
Article
Photobiomodulation Mediates Neuroprotection against Blue Light Induced Retinal Photoreceptor Degeneration
by Nora Heinig, Ulrike Schumann, Daniela Calzia, Isabella Panfoli, Marius Ader, Mirko H. H. Schmidt, Richard H. W. Funk and Cora Roehlecke
Int. J. Mol. Sci. 2020, 21(7), 2370; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072370 - 30 Mar 2020
Cited by 25 | Viewed by 5751
Abstract
Potent neuroprotective effects of photobiomodulation with 670 nm red light (RL) have been demonstrated in several models of retinal disease. RL improves mitochondrial metabolism, reduces retinal inflammation and oxidative cell stress, showing its ability to enhance visual function. However, the current knowledge is [...] Read more.
Potent neuroprotective effects of photobiomodulation with 670 nm red light (RL) have been demonstrated in several models of retinal disease. RL improves mitochondrial metabolism, reduces retinal inflammation and oxidative cell stress, showing its ability to enhance visual function. However, the current knowledge is limited to the main hypothesis that the respiratory chain complex IV, cytochrome c oxidase, serves as the primary target of RL. Here, we demonstrate a comprehensive cellular, molecular, and functional characterization of neuroprotective effects of 670 nm RL and 810 nm near-infrared light (NIRL) on blue light damaged murine primary photoreceptors. We show that respiratory chain complexes I and II are additional PBM targets, besides complex IV, leading to enhanced mitochondrial energy metabolism. Accordingly, our study identified mitochondria related RL- and NIRL-triggered defense mechanisms promoting photoreceptor neuroprotection. The observed improvement of mitochondrial and extramitochondrial respiration in both inner and outer segments is linked with reduced oxidative stress including its cellular consequences and reduced mitochondria-induced apoptosis. Analysis of regulatory mechanisms using gene expression analysis identified upregulation α-crystallins that indicate enhanced production of proteins with protective functions that point to the rescued mitochondrial function. The results support the hypothesis that energy metabolism is a major target for retinal light therapy. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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17 pages, 3273 KiB  
Article
Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions
by Catharina C. Gross, Marc Pawlitzki, Andreas Schulte-Mecklenbeck, Leoni Rolfes, Tobias Ruck, Petra Hundehege, Heinz Wiendl, Michael Herty and Sven G. Meuth
Int. J. Mol. Sci. 2020, 21(6), 2046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062046 - 17 Mar 2020
Cited by 5 | Viewed by 2367
Abstract
The central nervous system (CNS) is an immune-privileged compartment that is separated from the circulating blood and the peripheral organs by the blood–brain and the blood–cerebrospinal fluid (CSF) barriers. Transmigration of lymphocyte subsets across these barriers and their activation/differentiation within the periphery and [...] Read more.
The central nervous system (CNS) is an immune-privileged compartment that is separated from the circulating blood and the peripheral organs by the blood–brain and the blood–cerebrospinal fluid (CSF) barriers. Transmigration of lymphocyte subsets across these barriers and their activation/differentiation within the periphery and intrathecal compartments in health and autoinflammatory CNS disease are complex. Mathematical models are warranted that qualitatively and quantitatively predict the distribution and differentiation stages of lymphocyte subsets in the blood and CSF. Here, we propose a probabilistic mathematical model that (i) correctly reproduces acquired data on location and differentiation states of distinct lymphocyte subsets under homeostatic and neuroinflammatory conditions, (ii) provides a quantitative assessment of differentiation and transmigration rates under these conditions, (iii) correctly predicts the qualitative behavior of immune-modulating therapies, (iv) and enables simulation-based prediction of distribution and differentiation stages of lymphocyte subsets in the case of limited access to biomaterial. Taken together, this model might reduce future measurements in the CSF compartment and allows for the assessment of the effectiveness of different immune-modulating therapies. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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24 pages, 3524 KiB  
Article
Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice
by Baruh Polis, Kolluru D. Srikanth, Vyacheslav Gurevich, Naamah Bloch, Hava Gil-Henn and Abraham O. Samson
Int. J. Mol. Sci. 2020, 21(3), 1133; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031133 - 08 Feb 2020
Cited by 13 | Viewed by 3385
Abstract
Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay [...] Read more.
Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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10 pages, 854 KiB  
Article
Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen
by Andreas Totzeck, Benjamin Stolte, Kathrin Kizina, Saskia Bolz, Melina Schlag, Andreas Thimm, Christoph Kleinschnitz and Tim Hagenacker
Int. J. Mol. Sci. 2019, 20(21), 5397; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215397 - 30 Oct 2019
Cited by 32 | Viewed by 3472
Abstract
Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, [...] Read more.
Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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Review

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15 pages, 561 KiB  
Review
Approved and Emerging Disease Modifying Therapies on Neurodegeneration in Multiple Sclerosis
by Madeline Bross, Melody Hackett and Evanthia Bernitsas
Int. J. Mol. Sci. 2020, 21(12), 4312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124312 - 17 Jun 2020
Cited by 38 | Viewed by 5363
Abstract
Multiple sclerosis (MS) is an autoimmune, chronic, progressive disease leading to a combination of inflammation, demyelination, and neurodegeneration throughout the central nervous system (CNS). The outcome of these processes can be visualized in magnetic resonance imaging (MRI) scans as brain atrophy, or brain [...] Read more.
Multiple sclerosis (MS) is an autoimmune, chronic, progressive disease leading to a combination of inflammation, demyelination, and neurodegeneration throughout the central nervous system (CNS). The outcome of these processes can be visualized in magnetic resonance imaging (MRI) scans as brain atrophy, or brain volume loss (BVL), as well as lesions, “black holes” and spinal cord atrophy. MRI outcomes such as BVL have been used as biomarkers of neurodegeneration and other measures of MS disease progression in clinical research settings. Several FDA-approved medications seek to alleviate disease progression by reducing the impact of such factors as demyelination and neurodegeneration, but there are still many shortcomings that current clinical research aims to mitigate. This review attempts to provide an overview of the FDA-approved medications available for treating multiple sclerosis and their effect on neurodegeneration, measured by BVL. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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49 pages, 2193 KiB  
Review
Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System
by Kim M. A. De Kleijn and Gerard J. M. Martens
Int. J. Mol. Sci. 2020, 21(12), 4229; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124229 - 13 Jun 2020
Cited by 21 | Viewed by 5806
Abstract
Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these [...] Read more.
Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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21 pages, 1271 KiB  
Review
Neural Stem Cell Transplantation for Neurodegenerative Diseases
by Roberta De Gioia, Fabio Biella, Gaia Citterio, Federica Rizzo, Elena Abati, Monica Nizzardo, Nereo Bresolin, Giacomo Pietro Comi and Stefania Corti
Int. J. Mol. Sci. 2020, 21(9), 3103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093103 - 28 Apr 2020
Cited by 104 | Viewed by 13657
Abstract
Neurodegenerative diseases are disabling and fatal neurological disorders that currently lack effective treatment. Neural stem cell (NSC) transplantation has been studied as a potential therapeutic approach and appears to exert a beneficial effect against neurodegeneration via different mechanisms, such as the production of [...] Read more.
Neurodegenerative diseases are disabling and fatal neurological disorders that currently lack effective treatment. Neural stem cell (NSC) transplantation has been studied as a potential therapeutic approach and appears to exert a beneficial effect against neurodegeneration via different mechanisms, such as the production of neurotrophic factors, decreased neuroinflammation, enhanced neuronal plasticity and cell replacement. Thus, NSC transplantation may represent an effective therapeutic strategy. To exploit NSCs’ potential, some of their essential biological characteristics must be thoroughly investigated, including the specific markers for NSC subpopulations, to allow profiling and selection. Another key feature is their secretome, which is responsible for the regulation of intercellular communication, neuroprotection, and immunomodulation. In addition, NSCs must properly migrate into the central nervous system (CNS) and integrate into host neuronal circuits, enhancing neuroplasticity. Understanding and modulating these aspects can allow us to further exploit the therapeutic potential of NSCs. Recent progress in gene editing and cellular engineering techniques has opened up the possibility of modifying NSCs to express select candidate molecules to further enhance their therapeutic effects. This review summarizes current knowledge regarding these aspects, promoting the development of stem cell therapies that could be applied safely and effectively in clinical settings. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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22 pages, 379 KiB  
Review
Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies
by Yu-Shuan Chen, Zhen-Xiang Hong, Shinn-Zong Lin and Horng-Jyh Harn
Int. J. Mol. Sci. 2020, 21(9), 3063; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093063 - 26 Apr 2020
Cited by 28 | Viewed by 5734
Abstract
Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers [...] Read more.
Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers and related pathogenic processes. The three major conclusions from the current studies are summarized as follows: (i) for the drugs currently being tested in clinical trials; a weak connection was observed between drugs and SCA3/MJD biomarkers. The only two exceptions are the drugs suppressing glutamate-induced calcium influx and chemical chaperon. (ii) For most of the drugs that have been tested in animal studies, there is a direct association with pathological biomarkers. We further found that many drugs are associated with inducing autophagy, which is supported by the evidence of deficient autophagy biomarkers in SCA3/MJD, and that there may be more promising therapeutics. (iii) Some reported biomarkers lack relatively targeted drugs. Low glucose utilization, altered amino acid metabolism, and deficient insulin signaling are all implicated in SCA3/MJD, but there have been few studies on treatment strategies targeting these abnormalities. Therapeutic strategies targeting multiple pathological SCA3/MJD biomarkers may effectively block disease progression and preserve neurological function. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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15 pages, 931 KiB  
Review
The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration
by Maria Sofia Basile, Giuseppe Battaglia, Valeria Bruno, Katia Mangano, Paolo Fagone, Maria Cristina Petralia, Ferdinando Nicoletti and Eugenio Cavalli
Int. J. Mol. Sci. 2020, 21(8), 3023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083023 - 24 Apr 2020
Cited by 15 | Viewed by 3984
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), [...] Read more.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients’ survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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16 pages, 2050 KiB  
Review
Fluorinated Molecules and Nanotechnology: Future ‘Avengers’ against the Alzheimer’s Disease?
by Meghna Dabur, Joana A. Loureiro and Maria Carmo Pereira
Int. J. Mol. Sci. 2020, 21(8), 2989; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082989 - 23 Apr 2020
Cited by 15 | Viewed by 4312
Abstract
Alzheimer’s disease (AD) is a serious health concern, affecting millions of people globally, which leads to cognitive impairment, dementia, and inevitable death. There is still no medically accepted treatment for AD. Developing therapeutic treatments for AD is an overwhelming challenge in the medicinal [...] Read more.
Alzheimer’s disease (AD) is a serious health concern, affecting millions of people globally, which leads to cognitive impairment, dementia, and inevitable death. There is still no medically accepted treatment for AD. Developing therapeutic treatments for AD is an overwhelming challenge in the medicinal field, as the exact mechanics underlying its devastating symptoms is still not completely understood. Rather than the unknown mechanism of the disease, one of the limiting factors in developing new drugs for AD is the blood–brain barrier (BBB). A combination of nanotechnology with fluorinated molecules is proposed as a promising therapeutic treatment to meet the desired pharmacokinetic/physiochemical properties for crossing the BBB passage. This paper reviews the research conducted on fluorine-containing compounds and fluorinated nanoparticles (NPs) that have been designed and tested for the inhibition of amyloid-beta (Aβ) peptide aggregation. Additionally, this study summarizes fluorinated molecules and NPs as promising agents and further future work is encouraged to be effective for the treatment of AD. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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19 pages, 554 KiB  
Review
Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy
by Lisa Mészáros, Alana Hoffmann, Jeanette Wihan and Jürgen Winkler
Int. J. Mol. Sci. 2020, 21(8), 2775; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082775 - 16 Apr 2020
Cited by 16 | Viewed by 6015
Abstract
Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa [...] Read more.
Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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16 pages, 1851 KiB  
Review
Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia
by Masahiro Kawahara, Yutaka Sadakane, Keiko Mizuno, Midori Kato-Negishi and Ken-ichiro Tanaka
Int. J. Mol. Sci. 2020, 21(7), 2570; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072570 - 07 Apr 2020
Cited by 16 | Viewed by 4035
Abstract
Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles [...] Read more.
Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (β-alanyl histidine) as a possible therapeutic agent for vascular dementia. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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33 pages, 5310 KiB  
Review
Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines
by Masaru Tanaka, József Toldi and László Vécsei
Int. J. Mol. Sci. 2020, 21(7), 2431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072431 - 31 Mar 2020
Cited by 156 | Viewed by 10185
Abstract
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic [...] Read more.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington’s disease (HD), Creutzfeldt–Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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12 pages, 254 KiB  
Review
Treatment of Delirium in Older Persons: What We Should Not Do!
by Fulvio Lauretani, Giuseppe Bellelli, Giovanna Pelà, Simonetta Morganti, Sara Tagliaferri and Marcello Maggio
Int. J. Mol. Sci. 2020, 21(7), 2397; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072397 - 31 Mar 2020
Cited by 19 | Viewed by 8246
Abstract
The presentation of common acute diseases in older age is often referred to as “atypical”. Frequently, the symptoms are neither single nor tissue related. In most cases, the onset of symptoms and diseases is the expression of a diminished reserve with a failure [...] Read more.
The presentation of common acute diseases in older age is often referred to as “atypical”. Frequently, the symptoms are neither single nor tissue related. In most cases, the onset of symptoms and diseases is the expression of a diminished reserve with a failure of the body system and imbalance of brain function. Delirium is one of the main devastating and prevalent atypical symptoms and could be considered as a geriatric syndrome. It encompasses an array of neuropsychiatric symptoms and represents a disarrangement of the cerebral function in response to one or more stressors. The most recent definition, reported in the DSM-V, depicts delirium as a clear disturbance in attention and awareness. The deficit is to be developed in a relatively short time period (usually hours or days). The attention disorder must be associated with another cognitive impairment in memory, orientation, language, visual-spatial or perception abilities. For the treatment, it is imperative to remove the potential causes of delirium before prescribing drugs. Even a non-pharmacological approach to reducing the precipitating causes should be identified and planned. When we are forced to approach the pharmacological treatment of hyperactive delirium in older persons, we should select highly cost-effective drugs. High attention should be devoted to the correct balance between improvement of psychiatric symptoms and occurrence of side effects. Clinicians should be guided in the correct choice of drugs following cluster symptoms presentation, excluding drugs that could potentially produce complications rather than advantages. In this brief point-of-view, we propose a novel pharmacological flow-chart of treatment in relation to the basic clusters of diseases of an older patient acutely admitted to the hospital and, in particular, we emphasize “What We Should Not Do!”, with the intention of avoiding possible side effects of drugs used. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
16 pages, 265 KiB  
Review
Anti-Epileptogenic Effects of Antiepileptic Drugs
by Barbara Miziak, Agnieszka Konarzewska, Marzena Ułamek-Kozioł, Monika Dudra-Jastrzębska, Ryszard Pluta and Stanisław J. Czuczwar
Int. J. Mol. Sci. 2020, 21(7), 2340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072340 - 28 Mar 2020
Cited by 32 | Viewed by 4019
Abstract
Generally, the prevalence of epilepsy does not exceed 0.9% of the population and approximately 70% of epilepsy patients may be adequately controlled with antiepileptic drugs (AEDs). Moreover, status epilepticus (SE) or even a single seizure may produce neurodegeneration within the brain and SE [...] Read more.
Generally, the prevalence of epilepsy does not exceed 0.9% of the population and approximately 70% of epilepsy patients may be adequately controlled with antiepileptic drugs (AEDs). Moreover, status epilepticus (SE) or even a single seizure may produce neurodegeneration within the brain and SE has been recognized as one of acute brain insults leading to acquired epilepsy via the process of epileptogenesis. Two questions thus arise: (1) Are AEDs able to inhibit SE-induced neurodegeneration? and (2) if so, can a probable neuroprotective potential of particular AEDs stop epileptogenesis? An affirmative answer to the second question would practically point to the preventive potential of a given neuroprotective AED following acute brain insults. The available experimental data indicate that diazepam (at low and high doses), gabapentin, pregabalin, topiramate and valproate exhibited potent or moderate neuroprotective effects in diverse models of SE in rats. However, only diazepam (at high doses), gabapentin and pregabalin exerted some protective activity against acquired epilepsy (spontaneous seizures). As regards valproate, its effects on spontaneous seizures were equivocal. With isobolography, some supra-additive combinations of AEDs have been delineated against experimental seizures. One of such combinations, levetiracetam + topiramate proved highly synergistic in two models of seizures and this particular combination significantly inhibited epileptogenesis in rats following status SE. Importantly, no neuroprotection was evident. It may be strikingly concluded that there is no correlation between neuroprotection and antiepileptogenesis. Probably, preclinically verified combinations of AEDs may be considered for an anti-epileptogenic therapy. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
13 pages, 1262 KiB  
Review
Huntingtin Lowering Strategies
by Franz Marxreiter, Judith Stemick and Zacharias Kohl
Int. J. Mol. Sci. 2020, 21(6), 2146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062146 - 20 Mar 2020
Cited by 30 | Viewed by 5668
Abstract
Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in [...] Read more.
Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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25 pages, 1223 KiB  
Review
Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium
by Michael Enders, Thorsten Heider, Andreas Ludwig and Stefanie Kuerten
Int. J. Mol. Sci. 2020, 21(5), 1663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051663 - 28 Feb 2020
Cited by 23 | Viewed by 6194
Abstract
Calcium ions are vital for maintaining the physiological and biochemical processes inside cells. The central nervous system (CNS) is particularly dependent on calcium homeostasis and its dysregulation has been associated with several neurodegenerative disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s [...] Read more.
Calcium ions are vital for maintaining the physiological and biochemical processes inside cells. The central nervous system (CNS) is particularly dependent on calcium homeostasis and its dysregulation has been associated with several neurodegenerative disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD), as well as with multiple sclerosis (MS). Hence, the modulation of calcium influx into the cells and the targeting of calcium-mediated signaling pathways may present a promising therapeutic approach for these diseases. This review provides an overview on calcium channels in neurons and glial cells. Special emphasis is put on MS, a chronic autoimmune disease of the CNS. While the initial relapsing-remitting stage of MS can be treated effectively with immune modulatory and immunosuppressive drugs, the subsequent progressive stage has remained largely untreatable. Here we summarize several approaches that have been and are currently being tested for their neuroprotective capacities in MS and we discuss which role calcium could play in this regard. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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6 pages, 786 KiB  
Case Report
Fulminant MS Reactivation Following Combined Fingolimod Cessation and Yellow Fever Vaccination
by Leoni Rolfes, Marc Pawlitzki, Steffen Pfeuffer, Christian Thomas, Jonas Schmidt-Chanasit, Catharina C. Gross, Andreas Schulte-Mecklenbeck, Heinz Wiendl, Sven G. Meuth, Oliver M. Grauer and Tobias Ruck
Int. J. Mol. Sci. 2019, 20(23), 5985; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235985 - 28 Nov 2019
Cited by 7 | Viewed by 2979
Abstract
A major concern caused by the discontinuation of disease modifying treatment for multiple sclerosis (MS) is a rebound of disease activity. Hypotheses about the underlying mechanism of fingolimod (FTY) induced exaggerated inflammatory responses are diverse. So far, vaccinations as a trigger for rebound [...] Read more.
A major concern caused by the discontinuation of disease modifying treatment for multiple sclerosis (MS) is a rebound of disease activity. Hypotheses about the underlying mechanism of fingolimod (FTY) induced exaggerated inflammatory responses are diverse. So far, vaccinations as a trigger for rebound activity following FTY suspension have not been described. However, several reports have highlighted the occurrence of neurological and autoimmune side effects after single or combined multi-vaccination procedures. Here, we describe the case of a highly active female MS patient demonstrating recurrent, severe MS relapses accompanied by extensive MRI activity, subsequent to yellow fever vaccination two months following FTY withdrawal. Blood and cerebrospinal fluid immunophenotyping indicated a B cell/plasma cell autoreactivity. Following a therapy with natalizumab the clinical, laboratory, MRI, and disease course improved significantly. This case hints towards a combined immunological mechanism characterized by molecular mimicry, bystander activation, and lymphocyte re-egress, resulting in extensive neurological impairment and shows that natalizumab represents a therapeutic option to counteract B cell mediated autoreactivity. Especially, the diagnostic and therapeutic management of this complex scenario might be instructive for clinical practice. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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