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Neuropharmacology and Neurodegenerative 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 October 2022) | Viewed by 16909

Special Issue Editor

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are devastating conditions for which a cure has not yet been defined since the mechanisms involved are still little understood. The incidence of neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, among the others, has increased in recent decades, associated with an aging population and significant cost. Nowadays, increased inflammation and oxidative stress are considered key modulators and common denominators of these pathologies.

Neuropharmacology has been evolving rapidly in order to identify new strategies that can support the nervous system, reducing the load of these disorders. The few treatments that are known and used are hampered by the Blood–Brain Barrier (BBB), which does not allow for the translocation of many therapeutic agents from blood to the brain, thus preventing the development of specific and innovative therapies. Basic research on this topic moves in two important directions:

  • On the one hand, towards the synthesis of newly engineered materials, such as nanomaterials, and towards the development of nano- and biotechnology that can develop sophisticated drug delivery systems. In this case, in fact, nanodrugs, with particles smaller than 100 nm, could elude the BBB;
  • On the other hand, natural products or derivatives of plants, with known anti-inflammatory and antioxidant properties, could be tested.

Dr. Jessica Maiuolo
Guest Editor

Manuscript Submission Information

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Keywords

  • neurodegenerative diseases
  • demyelinating diseases
  • blood–brain barrier
  • inflammation
  • reactive chemical species
  • mitochondria
  • endoplasmic reticulum
  • autophagy
  • apoptosis
  • nanodrugs
  • natural compounds
  • polyphenols

Published Papers (8 papers)

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Research

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21 pages, 9695 KiB  
Article
Discovery and In Vivo Efficacy of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 4-(2-Aminoethyl)-N-(3,5-dimethylphenyl)piperidine-1-carboxamide Hydrochloride (AP163) for the Treatment of Psychotic Disorders
Int. J. Mol. Sci. 2022, 23(19), 11579; https://doi.org/10.3390/ijms231911579 - 30 Sep 2022
Cited by 1 | Viewed by 1624
Abstract
Starting from a screening hit, a set of analogs was synthesized based on a 4-(2-aminoethyl)piperidine core not associated previously with trace amine-associated receptor 1 (TAAR1) modulation in the literature. Several structure–activity relationship generalizations have been drawn from the observed data, some of which [...] Read more.
Starting from a screening hit, a set of analogs was synthesized based on a 4-(2-aminoethyl)piperidine core not associated previously with trace amine-associated receptor 1 (TAAR1) modulation in the literature. Several structure–activity relationship generalizations have been drawn from the observed data, some of which were corroborated by molecular modeling against the crystal structure of TAAR1. The four most active compounds (EC50 for TAAR1 agonistic activity ranging from 0.033 to 0.112 μM) were nominated for evaluation in vivo. The dopamine transporter knockout (DAT-KO) rat model of dopamine-dependent hyperlocomotion was used to evaluate compounds’ efficacy in vivo. Out of four compounds, only one compound (AP163) displayed a statistically significant and dose-dependent reduction in hyperlocomotion in DAT-KO rats. As such, compound AP163 represents a viable lead for further preclinical characterization as a potential novel treatment option for disorders associated with increased dopaminergic function, such as schizophrenia. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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12 pages, 2888 KiB  
Article
Stemazole Promotes Oligodendrocyte Precursor Cell Survival In Vitro and Remyelination In Vivo
Int. J. Mol. Sci. 2022, 23(18), 10756; https://doi.org/10.3390/ijms231810756 - 15 Sep 2022
Cited by 2 | Viewed by 1331
Abstract
Maintaining the normal function of oligodendrocyte precursor cells (OPCs) and protecting OPCs from damage is the basis of myelin regeneration in multiple sclerosis (MS). In this paper, we investigated the effect of stemazole, a novel small molecule, on the promotion of oligodendrocyte precursor [...] Read more.
Maintaining the normal function of oligodendrocyte precursor cells (OPCs) and protecting OPCs from damage is the basis of myelin regeneration in multiple sclerosis (MS). In this paper, we investigated the effect of stemazole, a novel small molecule, on the promotion of oligodendrocyte precursor cell survival and remyelination. The results show that stemazole enhanced the survival rate and the number of clone formation in a dose-dependent manner and decreased the percentage of cell apoptosis. In particular, the number of cell clones was increased up to 6-fold (p < 0.001) in the stemazole group compared with the control group. In vivo, we assessed the effect of stemazole on recovering the motor dysfunction and demyelination induced by cuprizone (CPZ). The results show that stemazole promoted the recovery of motor dysfunction and the repair of myelin sheaths. Compared with the CPZ group, the stemazole group showed a 30.46% increase in the myelin area (p < 0.001), a 37.08% increase in MBP expression (p < 0.01), and a 1.66-fold increase in Olig2 expression (p < 0.001). Histologically, stemazole had a better effect than the positive control drugs. In conclusion, stemazole promoted OPC survival in vitro and remyelination in vivo, suggesting that this compound may be used as a therapeutic agent against demyelinating disease. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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16 pages, 1175 KiB  
Article
Lipophilic Bioactive Compounds Transported in Triglyceride-Rich Lipoproteins Modulate Microglial Inflammatory Response
Int. J. Mol. Sci. 2022, 23(14), 7706; https://doi.org/10.3390/ijms23147706 - 12 Jul 2022
Cited by 4 | Viewed by 1738
Abstract
Microglial cells can contribute to Alzheimer’s disease by triggering an inflammatory response that leads to neuronal death. In addition, the presence of amyloid-β in the brain is consistent with alterations in the blood–brain barrier integrity and triglyceride-rich lipoproteins (TRL) permeation. In the present [...] Read more.
Microglial cells can contribute to Alzheimer’s disease by triggering an inflammatory response that leads to neuronal death. In addition, the presence of amyloid-β in the brain is consistent with alterations in the blood–brain barrier integrity and triglyceride-rich lipoproteins (TRL) permeation. In the present work, we used lab-made TRL as carriers of lipophilic bioactive compounds that are commonly present in dietary oils, namely oleanolic acid (OA), α-tocopherol (AT) and β-sitosterol (BS), to assess their ability to modulate the inflammatory response of microglial BV-2 cells. We show that treatment with lab-made TRL increases the release and gene-expression of IL-1β, IL-6, and TNF-α, as well as NO and iNOS in microglia. On the other hand, TRL revealed bioactive compounds α-tocopherol and β-sitosterol as suitable carriers for oleanolic acid. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. AT reduced IL-6 release by 72%, OA reduced TNF-α release by approximately 50%, and all three biomolecules together (M) reduced IL-1β release by 35% and TNF-α release by more than 70%. In addition, NO generation was reduced, with the inclusion of OA by 45%, BS by 80% and the presence of M by 88%. Finally, a recovery of the basal glutathione content was observed with the inclusion of OA and M in the TRL. Our results open the way to exploiting the neuro-pharmacological potential of these lipophilic bioactive compounds through their delivery to the brain as part of TRL. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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8 pages, 960 KiB  
Communication
Behavioral Evidence for a Tau and HIV-gp120 Interaction
Int. J. Mol. Sci. 2022, 23(10), 5514; https://doi.org/10.3390/ijms23105514 - 15 May 2022
Cited by 1 | Viewed by 1532
Abstract
Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 [...] Read more.
Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 years or older. Therefore, a new challenge looms as individuals living with HIV increase in age. There is concern that Alzheimer’s disease (AD) may become prevalent with an earlier onset of cognitive decline in people living with HIV (PLWH). Clinical data studies reported the presence of AD biomarkers in PLWH. However, the functional significance of the interaction between HIV or HIV viral proteins and AD biomarkers is still not well studied. The main goal of the present study is to address this knowledge gap by determining if the HIV envelope glycoprotein 120 (HIV-gp120) can affect the cognitive functions in the Tau mouse AD model. Male Tau and age-matched, wild-type (WT) control mice were treated intracerebroventricularly (ICV) with HIV-gp120. The animals were evaluated for cognitive function using a Y-maze. We found that HIV-gp120 altered cognitive function in Tau mice. Notably, HIV-gp120 was able to promote a cognitive decline in transgenic Tau (P301L) mice compared to the control (HIV-gp120 and WT). We provide the first in vivo evidence of a cognitive interaction between an HIV viral protein and Tau mice. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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23 pages, 15985 KiB  
Article
CDDO-Me Attenuates Clasmatodendrosis in CA1 Astrocyte by Inhibiting HSP25-AKT Mediated DRP1-S637 Phosphorylation in Chronic Epilepsy Rats
Int. J. Mol. Sci. 2022, 23(9), 4569; https://doi.org/10.3390/ijms23094569 - 20 Apr 2022
Cited by 4 | Viewed by 1879
Abstract
Clasmatodendrosis is one of the irreversible astroglial degeneration, which is involved in seizure duration and its progression in the epileptic hippocampus. Although sustained heat shock protein 25 (HSP25) induction leads to this autophagic astroglial death, dysregulation of mitochondrial dynamics (aberrant mitochondrial elongation) is [...] Read more.
Clasmatodendrosis is one of the irreversible astroglial degeneration, which is involved in seizure duration and its progression in the epileptic hippocampus. Although sustained heat shock protein 25 (HSP25) induction leads to this autophagic astroglial death, dysregulation of mitochondrial dynamics (aberrant mitochondrial elongation) is also involved in the pathogenesis in clasmatodendrosis. However, the underlying molecular mechanisms of accumulation of elongated mitochondria in clasmatodendritic astrocytes are elusive. In the present study, we found that clasmatodendritic astrocytes showed up-regulations of HSP25 expression, AKT serine (S) 473 and dynamin-related protein 1 (DRP1) S637 phosphorylations in the hippocampus of chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me; bardoxolone methyl or RTA 402) abrogated abnormal mitochondrial elongation by reducing HSP25 upregulation, AKT S473- and DRP1 S637 phosphorylations. Furthermore, HSP25 siRNA and 3-chloroacetyl-indole (3CAI, an AKT inhibitor) abolished AKT-DRP1-mediated mitochondrial elongation and attenuated clasmatodendrosis in CA1 astrocytes. These findings indicate that HSP25-AKT-mediated DRP1 S637 hyper-phosphorylation may lead to aberrant mitochondrial elongation, which may result in autophagic astroglial degeneration. Therefore, our findings suggest that the dysregulation of HSP25-AKT-DRP1-mediated mitochondrial dynamics may play an important role in clasmatodendrosis, which would have implications for the development of novel therapies against various neurological diseases related to astroglial degeneration. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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17 pages, 91385 KiB  
Article
Discovery of a Potent and Selective JNK3 Inhibitor with Neuroprotective Effect Against Amyloid β-Induced Neurotoxicity in Primary Rat Neurons
Int. J. Mol. Sci. 2021, 22(20), 11084; https://doi.org/10.3390/ijms222011084 - 14 Oct 2021
Cited by 9 | Viewed by 1745
Abstract
As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) [...] Read more.
As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC50 = 9.7 nM), as well as neuroprotective effects against Aβ-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (−10 fold). Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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Review

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16 pages, 2412 KiB  
Review
Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions
Int. J. Mol. Sci. 2022, 23(17), 9540; https://doi.org/10.3390/ijms23179540 - 23 Aug 2022
Cited by 19 | Viewed by 3180
Abstract
Alzheimer’s disease (AD) is the most common age-related dementia. The alteration in metabolic characteristics determines the prognosis. Patients at risk show reduced glucose uptake in the brain. Additionally, type 2 diabetes mellitus increases the risk of AD with increasing age. Therefore, changes in [...] Read more.
Alzheimer’s disease (AD) is the most common age-related dementia. The alteration in metabolic characteristics determines the prognosis. Patients at risk show reduced glucose uptake in the brain. Additionally, type 2 diabetes mellitus increases the risk of AD with increasing age. Therefore, changes in glucose uptake in the cerebral cortex may predict the histopathological diagnosis of AD. The shifts in glucose uptake and metabolism, insulin resistance, oxidative stress, and abnormal autophagy advance the pathogenesis of AD syndrome. Here, we summarize the role of altered glucose metabolism in type 2 diabetes for AD prognosis. Additionally, we discuss diagnosis and potential pharmacological interventions for glucose metabolism defects in AD to encourage the development of novel therapeutic methods. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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20 pages, 7778 KiB  
Review
The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis
Int. J. Mol. Sci. 2022, 23(14), 7823; https://doi.org/10.3390/ijms23147823 - 15 Jul 2022
Cited by 7 | Viewed by 3070
Abstract
In amyotrophic lateral sclerosis (ALS) patients, loss of cellular homeostasis within cortical and spinal cord motor neurons triggers the activation of the integrated stress response (ISR), an intracellular signaling pathway that remodels translation and promotes a gene expression program aimed at coping with [...] Read more.
In amyotrophic lateral sclerosis (ALS) patients, loss of cellular homeostasis within cortical and spinal cord motor neurons triggers the activation of the integrated stress response (ISR), an intracellular signaling pathway that remodels translation and promotes a gene expression program aimed at coping with stress. Beyond its neuroprotective role, under regimes of chronic or excessive stress, ISR can also promote cell/neuronal death. Given the two-edged sword nature of ISR, many experimental attempts have tried to establish the therapeutic potential of ISR enhancement or inhibition in ALS. This review discusses the complex interplay between ISR and disease progression in different models of ALS, as well as the opportunities and limitations of ISR modulation in the hard quest to find an effective therapy for ALS. Full article
(This article belongs to the Special Issue Neuropharmacology and Neurodegenerative Diseases)
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