International Journal of Molecular Sciences

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21 pages, 9695 KiB

Open AccessArticle

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

by Mikhail Krasavin, Anatoly A. Peshkov, Alexey Lukin, Kristina Komarova, Lyubov Vinogradova, Daria Smirnova, Evgeny V. Kanov, Savelii R. Kuvarzin, Ramilya Z. Murtazina, Evgeniya V. Efimova, Maxim Gureev, Kirill Onokhin, Konstantin Zakharov and Raul R. Gainetdinov

Int. J. Mol. Sci. 2022, 23(19), 11579; https://doi.org/10.3390/ijms231911579 - 30 Sep 2022

Cited by 5 | Viewed by 2381

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

Open AccessArticle

Stemazole Promotes Oligodendrocyte Precursor Cell Survival In Vitro and Remyelination In Vivo

by Yizi Zhu, Mingzhu Chen, Yubo Zhang and Mei Han

Int. J. Mol. Sci. 2022, 23(18), 10756; https://doi.org/10.3390/ijms231810756 - 15 Sep 2022

Cited by 2 | Viewed by 1842

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

Open AccessArticle

Lipophilic Bioactive Compounds Transported in Triglyceride-Rich Lipoproteins Modulate Microglial Inflammatory Response

by Juan M. Espinosa, Jose M. Castellano, Silvia Garcia-Rodriguez, Angélica Quintero-Flórez, Natalia Carrasquilla and Javier S. Perona

Int. J. Mol. Sci. 2022, 23(14), 7706; https://doi.org/10.3390/ijms23147706 - 12 Jul 2022

Cited by 5 | Viewed by 2347

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

Open AccessCommunication

Behavioral Evidence for a Tau and HIV-gp120 Interaction

by Murali Vijayan, Linda Yin, P. Hemachandra Reddy and Khalid Benamar

Int. J. Mol. Sci. 2022, 23(10), 5514; https://doi.org/10.3390/ijms23105514 - 15 May 2022

Cited by 2 | Viewed by 2081

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

Open AccessArticle

CDDO-Me Attenuates Clasmatodendrosis in CA1 Astrocyte by Inhibiting HSP25-AKT Mediated DRP1-S637 Phosphorylation in Chronic Epilepsy Rats

by Duk-Shin Lee, Tae-Hyun Kim, Hana Park and Ji-Eun Kim

Int. J. Mol. Sci. 2022, 23(9), 4569; https://doi.org/10.3390/ijms23094569 - 20 Apr 2022

Cited by 5 | Viewed by 2378

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

Open AccessArticle

Discovery of a Potent and Selective JNK3 Inhibitor with Neuroprotective Effect Against Amyloid β-Induced Neurotoxicity in Primary Rat Neurons

by Joonhong Jun, Jihyun Baek, Songyi Yang, Hyungwoo Moon, Hyejin Kim, Hyunwook Cho and Jung-Mi Hah

Int. J. Mol. Sci. 2021, 22(20), 11084; https://doi.org/10.3390/ijms222011084 - 14 Oct 2021

Cited by 12 | Viewed by 2321

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

Open AccessReview

Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions

by Vijay Kumar, So-Hyeon Kim and Kausik Bishayee

Int. J. Mol. Sci. 2022, 23(17), 9540; https://doi.org/10.3390/ijms23179540 - 23 Aug 2022

Cited by 35 | Viewed by 5103

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

Open AccessReview

The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis

by Elías Marlin, Cristina Viu-Idocin, Montserrat Arrasate and Tomás Aragón

Int. J. Mol. Sci. 2022, 23(14), 7823; https://doi.org/10.3390/ijms23147823 - 15 Jul 2022

Cited by 11 | Viewed by 4590

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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