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Dissecting Neurological and Neuropsychiatric Diseases: Neurodegeneration and Neuroprotection

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 41703

Special Issue Editors


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Guest Editor
Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE), 6720 Szeged, Hungary
Interests: neurohormones; neuropeptides; tryptophan; kynurenine; psychiatry; neurology; depression; anxiety; dementia; cognition; antidepressant; translational research
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Faculty of Medicine, Department of Neurology, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary
2. MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
Interests: neurology; headache; multiple sclerosis; Parkinson's disease; kynurenines; neurotransmission
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegeneration is a common underlying pathomechanism in a wide range of neurologic diseases and psychiatric disorders which develop through polygenic interaction, multifactorial causative factors, and heterogenous pathogenesis. The neurologic diseases which manifest the neurodegeneration include Alzheimer’s diseases, Parkinson’s diseases, multiple sclerosis, amyotrophic lateralsclerosis, Huntington’s disease etc. while psychiatric disorders include depressive disorder, substance abuse disorder, anxiety disorder, post-traumatic stress disorder, bipolar disorder, schizophrenia, somatic symptom disorder, and autism spectrum disorder. Endogenous neuroprotective mechanisms play a crucial role in prodromal and remitting stages, preventing the onset and the exacerbation of the illness. Exogenous neuroprotective agents are under extensive investigation in attempt to intervene the course of neurodegenerative process to complement the endogenous neuroprotective operations and/or to counteract the neurodegenerative progression.

The Special Issue highlights the latest advance in research on pathomechanism, neurodegeneration, and neuroprotection, exploring novel interventional strategies in neurologic diseases and neuropsychiatric disorders.

We cordially invite authors to contribute original research articles focusing on, but not limited to the following:

  • Etiology, pathogenesis, and progression mechanism in neurodegeneration;
  • Early diagnosis including biomarker, bio-imaging, biosensors;
  • Prophylactic, disease-modifying, and therapeutic strategies, novel targets;
  • Novel drug discovery and development, naturally driven biomedicines, natural bioactive molecules, vaccines;
  • Nanobiotechnology, nanosimilars, nanobiosimilars;
  • Preclinical in vitro models, animal models, alternative methods;
  • Bench-to-bedside translation research;
  • Bedside-to-bench translational research.

Comprehensive review and research articles are also welcome.

Dr. Masaru Tanaka
Prof. Dr. László Vécsei
Guest Editors

Manuscript Submission Information

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

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (8 papers)

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Editorial

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6 pages, 536 KiB  
Editorial
Editorial of Special Issue ‘Dissecting Neurological and Neuropsychiatric Diseases: Neurodegeneration and Neuroprotection’
by Masaru Tanaka and László Vécsei
Int. J. Mol. Sci. 2022, 23(13), 6991; https://doi.org/10.3390/ijms23136991 - 23 Jun 2022
Cited by 47 | Viewed by 2900
Abstract
This Special Issue has focused on dissecting the neuroprotective and neurodegenerative components of neurological and neuropsychiatric diseases, highlighting the latest advance in understanding the etiology, pathomechanism, biomarkers, imaging techniques, and novel therapeutic targets of neurodegenerative diseases (NDDs) [...] Full article
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Research

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15 pages, 3826 KiB  
Article
Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro
by Christopher Simon, Tomoko Soga, Nafees Ahemad, Saatheeyavaane Bhuvanendran and Ishwar Parhar
Int. J. Mol. Sci. 2022, 23(9), 5193; https://doi.org/10.3390/ijms23095193 - 6 May 2022
Cited by 7 | Viewed by 2811
Abstract
The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-β (Aβ) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aβ toxicity via an extracellular binding [...] Read more.
The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-β (Aβ) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aβ toxicity via an extracellular binding mechanism may provide a new horizon for innovative drug design endeavors. Considering the sequence similarities between α-syn’s non-amyloid-β component (NAC) and Aβ’s C-terminus, we hypothesized that KP-10 would enhance cholinergic neuronal resistance against α-syn’s deleterious consequences through preferential binding. Here, human cholinergic SH-SY5Y cells were transiently transformed to upsurge the mRNA expression of α-syn while α-syn-mediated cholinergic toxicity was quantified utilizing a standardized viability-based assay. Remarkably, the E46K mutant α-syn displayed elevated α-syn mRNA levels, which subsequently induced more cellular toxicity compared with the wild-type α-syn in choline acetyltransferase (ChAT)-positive cholinergic neurons. Treatment with a high concentration of KP-10 (10 µM) further decreased cholinergic cell viability, while low concentrations of KP-10 (0.01–1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated toxicity. Correlating with the in vitro observations are approximations from in silico algorithms, which inferred that KP-10 binds favorably to the C-terminal residues of wild-type and E46K mutant α-syn with CDOCKER energy scores of −118.049 kcal/mol and −114.869 kcal/mol, respectively. Over the course of 50 ns simulation time, explicit-solvent molecular dynamics conjointly revealed that the docked complexes were relatively stable despite small-scale fluctuations upon assembly. Taken together, our findings insinuate that KP-10 may serve as a novel therapeutic scaffold with far-reaching implications for the conceptualization of α-syn-based treatments. Full article
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14 pages, 5925 KiB  
Article
Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus
by Anji Song, Gwang-Won Cho, Karthikeyan A. Vijayakumar, Changjong Moon, Mary Jasmin Ang, Jahae Kim, Ilyong Park and Chul Ho Jang
Int. J. Mol. Sci. 2022, 23(1), 23; https://doi.org/10.3390/ijms23010023 - 21 Dec 2021
Cited by 10 | Viewed by 3279
Abstract
High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction [...] Read more.
High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction of excitotoxicity. Glutamate excitotoxicity is associated with failure in the maintenance of calcium homeostasis, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Valproic acid (VPA) is widely used for the management of bipolar disorder, epilepsy, and migraine headaches, and is known to regulate NMDA receptor activity. In this study, we examined the beneficial effects of VPA in a salicylate-induced tinnitus model in vitro and in vivo. Cells were pretreated with VPA followed by salicylate treatment. The expression levels of NMDA receptor subunit NR2B, phosphorylated cAMP response element-binding protein—an apoptosis marker, and intracellular levels of ROS were measured using several biochemical techniques. We observed increased expression of NR2B and its related genes TNFα and ARC, increased intracellular ROS levels, and induced expression of cleaved caspase-3. These salicylate-induced changes were attenuated in the neuronal cell line SH-SY5Y and rat cortical neurons after VPA pretreatment. Together, these results provide evidence of the beneficial effects of VPA in a salicylate-induced temporary hearing loss and tinnitus model. Full article
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19 pages, 3592 KiB  
Article
Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response
by Bárbara Mendes-Pinheiro, Carina Soares-Cunha, Ana Marote, Eduardo Loureiro-Campos, Jonas Campos, Sandra Barata-Antunes, Daniela Monteiro-Fernandes, Diogo Santos, Sara Duarte-Silva, Luísa Pinto and António José Salgado
Int. J. Mol. Sci. 2021, 22(21), 11530; https://doi.org/10.3390/ijms222111530 - 26 Oct 2021
Cited by 20 | Viewed by 5801
Abstract
Parkinson’s disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson’s disease (PD) in rodents. Despite [...] Read more.
Parkinson’s disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson’s disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry’s degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease. Full article
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Review

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45 pages, 718 KiB  
Review
Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations
by Tamás Biernacki, Zsófia Kokas, Dániel Sandi, Judit Füvesi, Zsanett Fricska-Nagy, Péter Faragó, Tamás Zsigmond Kincses, Péter Klivényi, Krisztina Bencsik and László Vécsei
Int. J. Mol. Sci. 2022, 23(6), 3383; https://doi.org/10.3390/ijms23063383 - 21 Mar 2022
Cited by 12 | Viewed by 4631
Abstract
Introduction: Multiple Sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS) affecting young people. This is due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on a patient’s health-related quality [...] Read more.
Introduction: Multiple Sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS) affecting young people. This is due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on a patient’s health-related quality of life. It is of great importance to recognise it in time and commence adequate treatment at an early stage. The currently used disease-modifying therapies (DMT) aim to reduce disease activity and thus halt disability development, which in current clinical practice are monitored by clinical and imaging parameters but not by biomarkers found in blood and/or the cerebrospinal fluid (CSF). Both clinical and radiological measures routinely used to monitor disease activity lack information on the fundamental pathophysiological features and mechanisms of MS. Furthermore, they lag behind the disease process itself. By the time a clinical relapse becomes evident or a new lesion appears on the MRI scan, potentially irreversible damage has already occurred in the CNS. In recent years, several biomarkers that previously have been linked to other neurological and immunological diseases have received increased attention in MS. Additionally, other novel, potential biomarkers with prognostic and diagnostic properties have been detected in the CSF and blood of MS patients. Areas covered: In this review, we summarise the most up-to-date knowledge and research conducted on the already known and most promising new biomarker candidates found in the CSF and blood of MS patients. Discussion: the current diagnostic criteria of MS relies on three pillars: MRI imaging, clinical events, and the presence of oligoclonal bands in the CSF (which was reinstated into the diagnostic criteria by the most recent revision). Even though the most recent McDonald criteria made the diagnosis of MS faster than the prior iteration, it is still not an infallible diagnostic toolset, especially at the very early stage of the clinically isolated syndrome. Together with the gold standard MRI and clinical measures, ancillary blood and CSF biomarkers may not just improve diagnostic accuracy and speed but very well may become agents to monitor therapeutic efficacy and make even more personalised treatment in MS a reality in the near future. The major disadvantage of these biomarkers in the past has been the need to obtain CSF to measure them. However, the recent advances in extremely sensitive immunoassays made their measurement possible from peripheral blood even when present only in minuscule concentrations. This should mark the beginning of a new biomarker research and utilisation era in MS. Full article
23 pages, 608 KiB  
Review
Tau Biomarkers in Dementia: Positron Emission Tomography Radiopharmaceuticals in Tauopathy Assessment and Future Perspective
by Maria Ricci, Andrea Cimini, Riccardo Camedda, Agostino Chiaravalloti and Orazio Schillaci
Int. J. Mol. Sci. 2021, 22(23), 13002; https://doi.org/10.3390/ijms222313002 - 30 Nov 2021
Cited by 15 | Viewed by 3002
Abstract
Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer’s disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. [...] Read more.
Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer’s disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. Beyond the fluid biomarkers of tauopathy described in this review in relationship with the brain glucose metabolic patterns, this review aims to focus on tauopathy assessment by using Tau PET imaging. In recent years, several first-generation Tau PET tracers have been developed and applied in the dementia field. Common limitations of first-generation tracers include off-target binding and subcortical white-matter uptake; therefore, several institutions are working on developing second-generation Tau tracers. The increasing knowledge about the distribution of first- and second-generation Tau PET tracers in the brain may support physicians with Tau PET data interpretation, both in the research and in the clinical field, but an updated description of differences in distribution patterns among different Tau tracers, and in different clinical conditions, has not been reported yet. We provide an overview of first- and second-generation tracers used in ongoing clinical trials, also describing the differences and the properties of novel tracers, with a special focus on the distribution patterns of different Tau tracers. We also describe the distribution patterns of Tau tracers in AD, in atypical AD, and further neurodegenerative diseases in the dementia field. Full article
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24 pages, 2337 KiB  
Review
Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease
by Grzegorz A. Czapski and Joanna B. Strosznajder
Int. J. Mol. Sci. 2021, 22(21), 11677; https://doi.org/10.3390/ijms222111677 - 28 Oct 2021
Cited by 62 | Viewed by 9399
Abstract
The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of [...] Read more.
The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches. Full article
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19 pages, 33561 KiB  
Review
Cyanobacteria, Cyanotoxins, and Neurodegenerative Diseases: Dangerous Liaisons
by Paola Sini, Thi Bang Chau Dang, Milena Fais, Manuela Galioto, Bachisio Mario Padedda, Antonella Lugliè, Ciro Iaccarino and Claudia Crosio
Int. J. Mol. Sci. 2021, 22(16), 8726; https://doi.org/10.3390/ijms22168726 - 13 Aug 2021
Cited by 33 | Viewed by 6062
Abstract
The prevalence of neurodegenerative disease (ND) is increasing, partly owing to extensions in lifespan, with a larger percentage of members living to an older age, but the ND aetiology and pathogenesis are not fully understood, and effective treatments are still lacking. Neurodegenerative diseases [...] Read more.
The prevalence of neurodegenerative disease (ND) is increasing, partly owing to extensions in lifespan, with a larger percentage of members living to an older age, but the ND aetiology and pathogenesis are not fully understood, and effective treatments are still lacking. Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are generally thought to progress as a consequence of genetic susceptibility and environmental influences. Up to now, several environmental triggers have been associated with NDs, and recent studies suggest that some cyanotoxins, produced by cyanobacteria and acting through a variety of molecular mechanisms, are highly neurotoxic, although their roles in neuropathy and particularly in NDs are still controversial. In this review, we summarize the most relevant and recent evidence that points at cyanotoxins as environmental triggers in NDs development. Full article
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