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New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases
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New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 36919

Special Issue Editor

Dr. Ashu Johri

E-Mail Website
Guest Editor
Independent Researcher, New York, NY 10021, USA
Interests: neurological diseases; pathophysiology; therapeutics; animal models; molecular mechanisms; drug development; mitochondria; biomarker; posttranslational modification; transcription factor; gut-brain axis; Huntington’s disease; Parkinson’s disease; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you are aware, neurological diseases exert a major societal and financial burden worldwide and remain a major cause of disability. With population expansion and greater life expectancies, the overall burden of neurological diseases is increasing. Promising strides have been made in solving the jigsaw puzzle of the molecular mechanisms on many of them providing insights into the etiopathology of the diseases, how the disease progresses, etc. This knowledge furthers our overarching goal of how to best tackle the disease pathogenesis producing symptom alleviation or in best case scenario, the magic word, a cure. This special issue focuses on new and fast developing knowledge base about the disease mechanisms and therapeutic approaches for neurological diseases.

This issue intends to highlight the advances made in our understanding of the disease processes as well as provide a cumulative summary of the new and existing therapies for neurological diseases. With this issue we hope to provide a comprehensive roadmap of the landscape in neurological diseases for the broad readership of the journal.

Dr. Ashu Johri
Guest Editor

Manuscript Submission Information

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

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

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Keywords

  • neurological diseases
  • neurodegeneration
  • pathophysiology
  • therapeutics
  • animal models
  • molecular mechanisms
  • drug development
  • mitochondria
  • biomarker
  • posttranslational modification
  • transcription factors

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 811 KiB  
Editorial
Editorial: Special Issue on “New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases”
by Ashu Johri
Int. J. Mol. Sci. 2023, 24(6), 5601; https://doi.org/10.3390/ijms24065601 - 15 Mar 2023
Viewed by 1049
Abstract
We launched our Special Issue (SI) at the beginning of 2021, with the hope to bring together current research in the field of neurodegeneration [...] Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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Research

Jump to: Editorial, Review

32 pages, 11347 KiB  
Article
Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model
by Bushra Shal, Adnan Khan, Ashraf Ullah Khan, Rahim Ullah, Gowhar Ali, Salman Ul Islam, Ihsan ul Haq, Hussain Ali, Eun-Kyoung Seo and Salman Khan
Int. J. Mol. Sci. 2021, 22(12), 6603; https://doi.org/10.3390/ijms22126603 - 20 Jun 2021
Cited by 35 | Viewed by 5116
Abstract
The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed [...] Read more.
The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aβ) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aβ (1–42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains. Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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27 pages, 34416 KiB  
Article
Suppression of TRPV1/TRPM8/P2Y Nociceptors by Withametelin via Downregulating MAPK Signaling in Mouse Model of Vincristine-Induced Neuropathic Pain
by Adnan Khan, Bushra Shal, Ashraf Ullah Khan, Rahim Ullah, Muhammad Waleed Baig, Ihsan ul Haq, Eun Kyoung Seo and Salman Khan
Int. J. Mol. Sci. 2021, 22(11), 6084; https://doi.org/10.3390/ijms22116084 - 4 Jun 2021
Cited by 45 | Viewed by 5997
Abstract
Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis [...] Read more.
Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis of neuropathic pain. Withametelin (WMT), a potential Phytosteroid isolated from datura innoxa, exhibits remarkable neuroprotective properties. The present investigation was designed to explore the effect of withametelin on VCR-induced neuropathic pain and its underlying molecular mechanism. Initially, the neuroprotective potential of WMT was confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. To develop potential candidates for neuropathic pain treatment, a VCR-induced neuropathic pain model was established. Vincristine (75 μg/kg) was administered intraperitoneally (i.p.) for 10 consecutive days (day 1–10) for the induction of neuropathic pain. Gabapentin (GBP) (60 mg/kg, i.p.) and withametelin (0.1 and 1 mg/kg i.p.) treatments were given after the completion of VCR injection on the 11th day up to 21 days. The results revealed that WMT significantly reduced VCR-induced pain hypersensitivity, including mechanical allodynia, cold allodynia, and thermal hyperalgesia. It reversed the VCR-induced histopathological changes in the brain, spinal cord, and sciatic nerve. It inhibited VCR-induced changes in the biochemical composition of the myelin sheath of the sciatic nerve. It markedly downregulated the expression levels of TRPV1 (transient receptor potential vanilloid 1); TRPM8 (Transient receptor potential melastatin 8); and P2Y nociceptors and MAPKs signaling, including ERK (Extracellular Signal-Regulated Kinase), JNK (c-Jun N-terminal kinase), and p-38 in the spinal cord. It suppressed apoptosis by regulating Bax (Bcl2-associated X-protein), Bcl-2 (B-cell-lymphoma-2), and Caspase-3 expression. It considerably attenuated inflammatory cytokines, oxidative stress, and genotoxicity. This study suggests that WMT treatment suppressed vincristine-induced neuropathic pain by targeting the TRPV1/TRPM8/P2Y nociceptors and MAPK signaling. Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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18 pages, 4028 KiB  
Article
Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies
by Alejandro Castro-Alvarez, Emigdio Chávez-Ángel and Ronald Nelson
Int. J. Mol. Sci. 2021, 22(7), 3602; https://doi.org/10.3390/ijms22073602 - 30 Mar 2021
Cited by 7 | Viewed by 3268
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT4 receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT4 receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures’ field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R2training = 0.821, and for the test set R2test = 0.667, while for Gaussian-field QSAR the training and the test were R2training = 0.898 and R2test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q2LOO = 0.804 and Q2LOO = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT4 partial agonists with potential biological activity (pEC50 8.209–9.417 for force-field QSAR and 9.111–9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT4 partial agonists. Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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Review

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27 pages, 8635 KiB  
Review
The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?
by Davide Bassani, Matteo Pavan, Stephanie Federico, Giampiero Spalluto, Mattia Sturlese and Stefano Moro
Int. J. Mol. Sci. 2022, 23(9), 4504; https://doi.org/10.3390/ijms23094504 - 19 Apr 2022
Cited by 5 | Viewed by 4216
Abstract
Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease. Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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Graphical abstract

30 pages, 1002 KiB  
Review
New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders
by Berhanu Geresu Kibret, Hiroki Ishiguro, Yasue Horiuchi and Emmanuel S. Onaivi
Int. J. Mol. Sci. 2022, 23(2), 975; https://doi.org/10.3390/ijms23020975 - 17 Jan 2022
Cited by 41 | Viewed by 7902
Abstract
The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 [...] Read more.
The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1R, CB2R), endocannabinoids (eCBs), and the metabolic enzyme machinery for their synthesis and catabolism. The activation of CB1R is associated with adverse effects on the central nervous system (CNS), which has limited the therapeutic use of drugs that bind this receptor. The discovery of the functional neuronal CB2R raised new possibilities for the potential and safe targeting of the ECS for the treatment of CNS disorders. Previous studies were not able to detect CB2R mRNA transcripts in brain tissue and suggested that CB2Rs were absent in the brain and were considered peripheral receptors. Studies done on the role of CB2Rs as a potential therapeutic target for treating different disorders revealed the important putative role of CB2Rs in certain CNS disorders, which requires further clinical validation. This review addresses recent advances on the role of CB2Rs in neuropsychiatric and neurodegenerative disorders, including, but not limited to, anxiety, depression, schizophrenia, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and addiction. Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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28 pages, 1536 KiB  
Review
Disentangling Mitochondria in Alzheimer’s Disease
by Ashu Johri
Int. J. Mol. Sci. 2021, 22(21), 11520; https://doi.org/10.3390/ijms222111520 - 26 Oct 2021
Cited by 49 | Viewed by 7754
Abstract
Alzheimer’s disease (AD) is a major cause of dementia in older adults and is fast becoming a major societal and economic burden due to an increase in life expectancy. Age seems to be the major factor driving AD, and currently, only symptomatic treatments [...] Read more.
Alzheimer’s disease (AD) is a major cause of dementia in older adults and is fast becoming a major societal and economic burden due to an increase in life expectancy. Age seems to be the major factor driving AD, and currently, only symptomatic treatments are available. AD has a complex etiology, although mitochondrial dysfunction, oxidative stress, inflammation, and metabolic abnormalities have been widely and deeply investigated as plausible mechanisms for its neuropathology. Aβ plaques and hyperphosphorylated tau aggregates, along with cognitive deficits and behavioral problems, are the hallmarks of the disease. Restoration of mitochondrial bioenergetics, prevention of oxidative stress, and diet and exercise seem to be effective in reducing Aβ and in ameliorating learning and memory problems. Many mitochondria-targeted antioxidants have been tested in AD and are currently in development. However, larger streamlined clinical studies are needed to provide hard evidence of benefits in AD. This review discusses the causative factors, as well as potential therapeutics employed in the treatment of AD. Full article
(This article belongs to the Special Issue New Frontiers in Molecular Mechanisms and Therapies in Neurological Diseases)
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