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25 pages, 12527 KiB

Open AccessArticle

A Soluble Epoxide Hydrolase Inhibitor Improves Cerebrovascular Dysfunction, Neuroinflammation, Amyloid Burden, and Cognitive Impairments in the hAPP/PS1 TgF344-AD Rat Model of Alzheimer’s Disease

by Xing Fang, Jane J. Border, Huawei Zhang, Lavanya Challagundla, Jasleen Kaur, Sung Hee Hwang, Bruce D. Hammock, Fan Fan and Richard J. Roman

Int. J. Mol. Sci. 2025, 26(6), 2433; https://doi.org/10.3390/ijms26062433 - 8 Mar 2025

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Abstract

Alzheimer’s disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We [...] Read more.

Alzheimer’s disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood–brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9–10-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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26 pages, 977 KiB

Open AccessArticle

Genetic Variant Analyses Identify Novel Candidate Autism Risk Genes from a Highly Consanguineous Cohort of 104 Families from Oman

by Vijay Gupta, Afif Ben-Mahmoud, Ahmed B. Idris, Jouke-Jan Hottenga, Wesal Habbab, Abeer Alsayegh, Hyung-Goo Kim, Watfa AL-Mamari and Lawrence W. Stanton

Int. J. Mol. Sci. 2024, 25(24), 13700; https://doi.org/10.3390/ijms252413700 - 21 Dec 2024

Cited by 2 | Viewed by 1516

Abstract

Deficits in social communication, restricted interests, and repetitive behaviours are hallmarks of autism spectrum disorder (ASD). Despite high genetic heritability, the majority of clinically diagnosed ASD cases have unknown genetic origins. We performed genome sequencing on mothers, fathers, and affected individuals from 104 [...] Read more.

Deficits in social communication, restricted interests, and repetitive behaviours are hallmarks of autism spectrum disorder (ASD). Despite high genetic heritability, the majority of clinically diagnosed ASD cases have unknown genetic origins. We performed genome sequencing on mothers, fathers, and affected individuals from 104 families with ASD in Oman, a Middle Eastern country underrepresented in international genetic studies. This approach identified 48 novel candidate genes significantly associated with ASD in Oman. In particular, 35 of these genes have been previously implicated in neurodevelopmental disorders (NDDs) in other populations, underscoring the conserved genetic basis of ASD across ethnicities. Genetic variants within these candidate genes that would impact the encoded protein included 1 insertion, 4 frameshift, 6 splicing, 12 nonsense, and 67 missense changes. Notably, 61% of the SNVs were homozygous, suggesting a prominent recessive genetic architecture for ASD in this unique population. The scarcity of genetic studies on ASD in the Arabian Peninsula has impeded the understanding of the unique genetic landscape of ASD in this region. These findings help bridge this knowledge gap and provide valuable insights into the complex genetic basis of ASD in Oman. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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24 pages, 795 KiB

Open AccessArticle

Genome Sequencing Identifies 13 Novel Candidate Risk Genes for Autism Spectrum Disorder in a Qatari Cohort

by Afif Ben-Mahmoud, Vijay Gupta, Alice Abdelaleem, Richard Thompson, Abdi Aden, Hamdi Mbarek, Chadi Saad, Mohamed Tolefat, Fouad Alshaban, Lawrence W. Stanton and Hyung-Goo Kim

Int. J. Mol. Sci. 2024, 25(21), 11551; https://doi.org/10.3390/ijms252111551 - 27 Oct 2024

Cited by 2 | Viewed by 2831

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Despite considerable research efforts, the genetic complexity of ASD remains poorly understood, complicating diagnosis and treatment, especially in the Arab population, with its genetic [...] Read more.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Despite considerable research efforts, the genetic complexity of ASD remains poorly understood, complicating diagnosis and treatment, especially in the Arab population, with its genetic diversity linked to migration, tribal structures, and high consanguinity. To address the scarcity of ASD genetic data in the Middle East, we conducted genome sequencing (GS) on 50 ASD subjects and their unaffected parents. Our analysis revealed 37 single-nucleotide variants from 36 candidate genes and over 200 CGG repeats in the FMR1 gene in one subject. The identified variants were classified as uncertain, likely pathogenic, or pathogenic based on in-silico algorithms and ACMG criteria. Notably, 52% of the identified variants were homozygous, indicating a recessive genetic architecture to ASD in this population. This finding underscores the significant impact of high consanguinity within the Qatari population, which could be utilized in genetic counseling/screening program in Qatar. We also discovered single nucleotide variants in 13 novel genes not previously associated with ASD: ARSF, BAHD1, CHST7, CUL2, FRMPD3, KCNC4, LFNG, RGS4, RNF133, SCRN2, SLC12A8, USP24, and ZNF746. Our investigation categorized the candidate genes into seven groups, highlighting their roles in cognitive development, including the ubiquitin pathway, transcription factors, solute carriers, kinases, glutamate receptors, chromatin remodelers, and ion channels. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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17 pages, 2658 KiB

Open AccessCommunication

Effect of Levetiracetam on Oxidant–Antioxidant Activity during Long-Term Temporal Lobe Epilepsy in Rats

by Iván Ignacio-Mejía, Itzel Jatziri Contreras-García, Luz Adriana Pichardo-Macías, Mercedes Edna García-Cruz, Blanca Alcira Ramírez Mendiola, Cindy Bandala, Omar Noel Medina-Campos, José Pedraza-Chaverri, Noemí Cárdenas-Rodríguez and Julieta Griselda Mendoza-Torreblanca

Int. J. Mol. Sci. 2024, 25(17), 9313; https://doi.org/10.3390/ijms25179313 - 28 Aug 2024

Cited by 1 | Viewed by 1160

Abstract

Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant–antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant–antioxidant activity during long-term epilepsy [...] Read more.

Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant–antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant–antioxidant activity during long-term epilepsy has not been studied. Therefore, the objective of the present study was to determine the effects of LEV on the concentrations of five antioxidant enzymes and on the levels of four oxidant stress markers in the hippocampus of rats with temporal lobe epilepsy at 5.7 months after status epilepticus (SE). The results revealed that superoxide dismutase (SOD) activity was significantly greater in the epileptic group (EPI) than in the control (CTRL), CTRL + LEV and EPI + LEV groups. No significant differences were found among the groups’ oxidant markers. However, the ratios of SOD/hydrogen peroxide (H₂O₂), SOD/glutathione peroxidase (GPx) and SOD/GPx + catalase (CAT) were greater in the EPI group than in the CTRL and EPI + LEV groups. Additionally, there was a positive correlation between SOD activity and GPx activity in the EPI + LEV group. LEV-mediated modulation of the antioxidant system appears to be time dependent; at 5.7 months after SE, the role of LEV may be as a stabilizer of the redox state. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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18 pages, 2931 KiB

Open AccessArticle

Physiological Features of the Neural Stem Cells Obtained from an Animal Model of Spinal Muscular Atrophy and Their Response to Antioxidant Curcumin

by Raffaella Adami, Matteo Pezzotta, Francesca Cadile, Beatrice Cuniolo, Gianenrico Rovati, Monica Canepari and Daniele Bottai

Int. J. Mol. Sci. 2024, 25(15), 8364; https://doi.org/10.3390/ijms25158364 - 31 Jul 2024

Viewed by 2118

Abstract

The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron (SMN) 1. The high heterogeneity of the SMA pathophysiology is determined by [...] Read more.

The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron (SMN) 1. The high heterogeneity of the SMA pathophysiology is determined by the number of copies of SMN2, a separate centromeric gene that can transcribe for the same protein, although it is expressed at a slower rate. SMA affects motor neurons. However, a variety of different tissues and organs may also be affected depending on the severity of the condition. Novel pharmacological treatments, such as Spinraza, Onasemnogene abeparvovec-xioi, and Evrysdi, are considered to be disease modifiers because their use can change the phenotypes of the patients. Since oxidative stress has been reported in SMA-affected cells, we studied the impact of antioxidant therapy on neural stem cells (NSCs) that have the potential to differentiate into motor neurons. Antioxidants can act through various pathways; for example, some of them exert their function through nuclear factor (erythroid-derived 2)-like 2 (NRF2). We found that curcumin is able to induce positive effects in healthy and SMA-affected NSCs by activating the nuclear translocation of NRF2, which may use a different mechanism than canonical redox regulation through the antioxidant-response elements and the production of antioxidant molecules. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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20 pages, 2013 KiB

Open AccessArticle

Bioenergetic and Inflammatory Alterations in Regressed and Non-Regressed Patients with Autism Spectrum Disorder

by Maria Gevezova, Zdravko Ivanov, Iliana Pacheva, Elena Timova, Maria Kazakova, Eleonora Kovacheva, Ivan Ivanov and Victoria Sarafian

Int. J. Mol. Sci. 2024, 25(15), 8211; https://doi.org/10.3390/ijms25158211 - 27 Jul 2024

Viewed by 1649

Abstract

Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), [...] Read more.

Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and inflammation-related molecules such as Cyclooxygenase-2 (COX-2), chitinase 3-like protein 1 (YKL-40), Interleukin-1 beta (IL-1β), Interleukin-9 (IL-9) in ASD children with and without regression compared to healthy controls. Children with ASD (n = 56) and typically developing children (TDC, n = 12) aged 1.11 to 11 years were studied. Mitochondrial activity was examined in peripheral blood mononuclear cells (PBMCs) isolated from children with ASD and from the control group, using a metabolic analyzer. Gene and protein levels of IL-1β, IL-9, COX-2, and YKL-40 were investigated in parallel. Our results showed that PBMCs of the ASD subgroup of regressed patients (ASD R(+), n = 21) had a specific pattern of mitochondrial activity with significantly increased maximal respiration, respiratory spare capacity, and proton leak compared to the non-regressed group (ASD R(-), n = 35) and TDC. Furthermore, we found an imbalance in the studied proinflammatory molecules and increased levels in ASD R(-) proving the involvement of inflammatory changes. The results of this study provide new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD. For the first time, data on a unique metabolic profile in ASD R(+) and its comparison with a random group of children of similar age and sex are provided. Our data show that mitochondrial dysfunction is more significant in ASD R(+), while in ASD R(-) inflammation is more pronounced. Probably, in the group without regression, immune mechanisms (immune dysregulation, leading to inflammation) begin initially, and at a later stage mitochondrial activity is also affected under exogenous factors. On the other hand, in the regressed group, the initial damage is in the mitochondria, and perhaps at a later stage immune dysfunction is involved. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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17 pages, 4937 KiB

Open AccessArticle

The Role of Changes in the Expression of Inflammation-Associated Genes in the Variants of Cerebral Small Vessel Disease

by Larisa A. Dobrynina, Angelina G. Makarova, Alla A. Shabalina, Anastasiia G. Burmak, Polina S. Shlapakova, Kamila V. Shamtieva, Maria M. Tsypushtanova, Elena I. Kremneva, Maryam R. Zabitova, Alexey S. Filatov and Elena V. Gnedovskaya

Int. J. Mol. Sci. 2024, 25(15), 8113; https://doi.org/10.3390/ijms25158113 - 25 Jul 2024

Viewed by 1276

Abstract

Age-dependent cerebral small vessel disease (CSVD) is a common disease with a high social burden characterized by heterogeneity of forms and frequent comorbidity with Alzheimer’s disease (AD). Previously, we identified two MRI types of CSVD with specific clinical presentation and, probably, different mechanisms. [...] Read more.

Age-dependent cerebral small vessel disease (CSVD) is a common disease with a high social burden characterized by heterogeneity of forms and frequent comorbidity with Alzheimer’s disease (AD). Previously, we identified two MRI types of CSVD with specific clinical presentation and, probably, different mechanisms. The present study included 34 patients with CSVD and white matter hyperintensity (WMH) of stage Fazekas (F) 3 (mean age 61.7 ± 8.9) and 11 volunteers (mean age 57.3 ± 9.7). Total RNA was isolated from peripheral blood leukocytes. The expression of 58 protein-coding genes associated with CSVD and/or AD and 4 reference genes were assessed as part of the original panel for the NanoString nCounter analyzer. Testing results were validated by real-time PCR. There was a significant decrease in the expression levels of the ACOX1, CD33, CD2AP, TNFR1, and VEGFC genes in MRI type 2 relative to the control group as well as a decrease in the expression level of the CD33 gene in MRI type 2 compared to MRI type 1. Processes associated with inflammatory pathways with decreased expression of the identified genes are important in the development of MRI type 2 of CSVD. Given the direct connection of the established genes with AD, the importance of this form of CSVD in comorbidity with AD has been assumed. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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14 pages, 1430 KiB

Open AccessArticle

Patients with Chronic Spinal Cord Injury Display a Progressive Alteration over the Years of the Activation Stages of the T Lymphocyte Compartment

by Sergio Haro, Ana M. Gomez-Lahoz, Jorge Monserrat, Mar Atienza-Pérez, Oscar Fraile-Martinez, Miguel A. Ortega, Cielo García-Montero, David Díaz, Elisa Lopez-Dolado and Melchor Álvarez-Mon

Int. J. Mol. Sci. 2023, 24(24), 17596; https://doi.org/10.3390/ijms242417596 - 18 Dec 2023

Viewed by 1319

Abstract

Spinal cord injury (SCI) is a serious medical condition associated with severe morbidities and disability. Chronic SCI patients present an enhanced susceptibility to infections and comorbidities with inflammatory pathogenesis. Chronic SCI appears to be associated with a systemic dysfunction of the immune system. [...] Read more.

Spinal cord injury (SCI) is a serious medical condition associated with severe morbidities and disability. Chronic SCI patients present an enhanced susceptibility to infections and comorbidities with inflammatory pathogenesis. Chronic SCI appears to be associated with a systemic dysfunction of the immune system. We investigated the alteration of the pivotal CD4+ and CD8+ T lymphocytes in patients with chronic SCI at different years of evolution. A clinically homogenous population of 105 patients with chronic SCI (31 with time of evolution less than 5 years (SCI SP); 32 early chronic (SCI ECP) with time of evolution between 5 and 15 years; and 42 late chronic (SCI LCP) with time of evolution more than 15 years) and 38 healthy controls were enrolled. SCI ECP and SCI LCP patients showed significant CD4+ and CD8+ T lymphopenia, ascribed to a reduction in naïve and CM subsets. Furthermore, SCI ECP and SCI LCP patients showed a significant reduction in the expression of CD28 on CD8+ T lymphocytes. The expression of CCR6 by CD4+ T lymphocytes was decreased during the evolution of chronic SCI, but on CD8+ T lymphocytes, it was observed during the first 15 years of evolution. In conclusion, the chronic SCI course with severe damage to T lymphocytes mainly worsens over the years of disease evolution. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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17 pages, 2134 KiB

Open AccessArticle

Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance

by Abdullah A. Aldossari, Mohammed A. Assiri, Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Saleh A. Bakheet, Thamer H. Albekairi, Hatun A. Alomar, Haneen A. Al-Mazroua, Taghreed N. Almanaa, Mohammed A. Al-Hamamah, Mohammad Y. Alwetaid and Sheikh F. Ahmad

Int. J. Mol. Sci. 2023, 24(20), 15273; https://doi.org/10.3390/ijms242015273 - 17 Oct 2023

Cited by 9 | Viewed by 2236

Abstract

Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and [...] Read more.

Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and immunological responses. The role of H4R in neurons of the CNS has recently been revealed. However, the precise role of H4R in neuronal function remains inadequately understood. The objective of this work was to investigate the impact of JNJ 10191584 (JNJ), a highly effective and specific H4R antagonist, on the development of experimental autoimmune encephalomyelitis (EAE) and to gain insight into the underlying mechanism involved. In this study, we examined the potential impact of JNJ therapy on the course of EAE in SJL/J mice. EAE mice were administered an oral dose of JNJ at a concentration of 6 mg/kg once a day, starting from day 10 and continuing until day 42. Afterward, the mice’s clinical scores were assessed. In this study, we conducted additional research to examine the impact of JNJ on several types of immune cells, specifically Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγt), and regulatory T (Tregs; Foxp3 and TGF-β1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγt, Foxp3, and TGF-β1 in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4⁺IFN-γ⁺, CD4⁺T-bet⁺, CD4⁺IL-9⁺, CD4⁺IRF4⁺, CD4⁺IL-17A⁺, and CD4⁺RORγt⁺ cells were shown to decrease, whereas the percentages of CD4⁺TGF-β1⁺ and CD4⁺Foxp3⁺ cells were observed to increase in EAE mice treated with JNJ. Therefore, the HR4 antagonist positively affected the course of EAE by modulating the signaling of transcription factors. The identified results include possible ramifications in the context of MS treatment. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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17 pages, 3439 KiB

Open AccessArticle

Diaphragm Fatigue in SMNΔ7 Mice and Its Molecular Determinants: An Underestimated Issue

by Francesca Cadile, Deborah Recchia, Massimiliano Ansaldo, Paola Rossi, Giorgia Rastelli, Simona Boncompagni, Lorenza Brocca, Maria Antonietta Pellegrino and Monica Canepari

Int. J. Mol. Sci. 2023, 24(19), 14953; https://doi.org/10.3390/ijms241914953 - 6 Oct 2023

Cited by 2 | Viewed by 1937

Abstract

Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of spinal motor neurons leading to muscle weakness and respiratory failure. Mitochondrial dysfunctions are found in the skeletal muscle of patients with SMA. For obvious ethical reasons, the diaphragm muscle is [...] Read more.

Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of spinal motor neurons leading to muscle weakness and respiratory failure. Mitochondrial dysfunctions are found in the skeletal muscle of patients with SMA. For obvious ethical reasons, the diaphragm muscle is poorly studied, notwithstanding the very important role that respiratory involvement plays in SMA mortality. The main goal of this study was to investigate diaphragm functionality and the underlying molecular adaptations in SMNΔ7 mice, a mouse model that exhibits symptoms similar to that of patients with intermediate type II SMA. Functional, biochemical, and molecular analyses on isolated diaphragm were performed. The obtained results suggest the presence of an intrinsic energetic imbalance associated with mitochondrial dysfunction and a significant accumulation of reactive oxygen species (ROS). In turn, ROS accumulation can affect muscle fatigue, cause diaphragm wasting, and, in the long run, respiratory failure in SMNΔ7 mice. Exposure to the antioxidant molecule ergothioneine leads to the functional recovery of the diaphragm, confirming the presence of mitochondrial impairment and redox imbalance. These findings suggest the possibility of carrying out a dietary supplementation in SMNΔ7 mice to preserve their diaphragm function and increase their lifespan. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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20 pages, 3888 KiB

Open AccessArticle

Novel Conformation-Dependent Tau Antibodies Are Modulated by Adjacent Phosphorylation Sites

by Giavanna Paterno, Jose Torrellas, Brach M. Bell, Kimberly-Marie M. Gorion, Stephan S. Quintin, Gabriela P. Hery, Stefan Prokop and Benoit I. Giasson

Int. J. Mol. Sci. 2023, 24(18), 13676; https://doi.org/10.3390/ijms241813676 - 5 Sep 2023

Cited by 1 | Viewed by 2033

Abstract

Tau proteins within the adult central nervous system (CNS) are found to be abnormally aggregated into heterogeneous filaments in neurodegenerative diseases, termed tauopathies. These tau inclusions are pathological hallmarks of Alzheimer’s disease (AD), Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy [...] Read more.

Tau proteins within the adult central nervous system (CNS) are found to be abnormally aggregated into heterogeneous filaments in neurodegenerative diseases, termed tauopathies. These tau inclusions are pathological hallmarks of Alzheimer’s disease (AD), Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The neuropathological hallmarks of these diseases burden several cell types within the CNS, and have also been shown to be abundantly phosphorylated. The mechanism(s) by which tau aggregates in the CNS is not fully known, but it is hypothesized that hyperphosphorylated tau may precede and further promote filament formation, leading to the production of these pathological inclusions. In the studies herein, we generated and thoroughly characterized two novel conformation-dependent tau monoclonal antibodies that bind to residues Pro218-Glu222, but are sensitive to denaturing conditions and highly modulated by adjacent downstream phosphorylation sites. These epitopes are present in the neuropathological hallmarks of several tauopathies, including AD, PiD, CBD, and PSP. These novel antibodies will further enable investigation of tau-dependent pathological inclusion formation and enhance our understanding of the phosphorylation signatures within tauopathies with the possibility of new biomarker developments. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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16 pages, 1499 KiB

Open AccessArticle

Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model

by Abdulaziz M. S. Alsaad, Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Saleh A. Bakheet, Hatun A. Alomar and Sheikh F. Ahmad

Int. J. Mol. Sci. 2023, 24(16), 12991; https://doi.org/10.3390/ijms241612991 - 20 Aug 2023

Cited by 2 | Viewed by 1984

Abstract

We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of [...] Read more.

We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage, and neurodegeneration. Over the past decade, pharmacological research into the H4R has gained significance in immune and inflammatory disorders. For this study, Swiss Jim Lambert EAE mice were treated with 4-MeH (30 mg/kg/day) via intraperitoneal administration from days 14 to 42, and the control group was treated with a vehicle. Subsequently, we evaluated the clinical scores. In addition, flow cytometry was employed to estimate the impact of 4-Methylhistamine (4-MeH) on NF-κB p65, GM-CSF, MCP-1, IL-6, and TNF-α within CD19⁺ and CXCR5⁺ spleen B cells. Additionally, we investigated the effect of 4-MeH on the mRNA expression levels of Nf-κB p65, Gmcsf, Mcp1, Il6, and Tnfα in the brain of mice using RT-PCR. Notably, the clinical scores of EAE mice treated with 4-MeH showed a significant increase compared with those treated with the vehicle. The percentage of cells expressing CD19⁺NF-κB p65⁺, CXCR5⁺NF-κB p65⁺, CD19⁺GM-CSF⁺, CXCR5⁺GM-CSF⁺, CD19⁺MCP-1⁺, CXCR5⁺MCP-1⁺, CD19⁺IL-6⁺, CXCR5⁺IL-6⁺, CD19⁺TNF-α⁺, and CXCR5⁺TNF-α⁺ exhibited was more pronounced in 4-MeH-treated EAE mice when compared to vehicle-treated EAE mice. Moreover, the administration of 4-MeH led to increased expression of NfκB p65, Gmcsf, Mcp1, Il6, and Tnfα mRNA in the brains of EAE mice. This means that the H4R agonist promotes pro-inflammatory mediators aggravating EAE symptoms. Our results indicate the harmful role of H4R agonists in the pathogenesis of MS in an EAE mouse model. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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Review

Jump to: Research

23 pages, 1049 KiB

Open AccessReview

A Comprehensive Approach to Parkinson’s Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects

by Mauricio Muleiro Alvarez, Gabriela Cano-Herrera, María Fernanda Osorio Martínez, Joaquin Vega Gonzales-Portillo, Germán Rivera Monroy, Renata Murguiondo Pérez, Jorge Alejandro Torres-Ríos, Ximena A. van Tienhoven, Ernesto Marcelo Garibaldi Bernot, Felipe Esparza Salazar and Antonio Ibarra

Int. J. Mol. Sci. 2024, 25(13), 7183; https://doi.org/10.3390/ijms25137183 - 29 Jun 2024

Cited by 16 | Viewed by 5041

Abstract

Parkinson’s disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, [...] Read more.

Parkinson’s disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing “off” time, where non-motor and motor symptoms occur, and increasing “on” time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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27 pages, 3624 KiB

Open AccessReview

MicroRNAs as Potential Biomarkers of Post-Traumatic Epileptogenesis: A Systematic Review

by Anastasia A. Vasilieva, Elena E. Timechko, Kristina D. Lysova, Anastasia I. Paramonova, Alexey M. Yakimov, Elena A. Kantimirova and Diana V. Dmitrenko

Int. J. Mol. Sci. 2023, 24(20), 15366; https://doi.org/10.3390/ijms242015366 - 19 Oct 2023

Cited by 7 | Viewed by 2508

Abstract

Structural or post-traumatic epilepsy often develops after brain tissue damage caused by traumatic brain injury, stroke, infectious diseases of the brain, etc. Most often, between the initiating event and epilepsy, there is a period without seizures—a latent period. At this time, the process [...] Read more.

Structural or post-traumatic epilepsy often develops after brain tissue damage caused by traumatic brain injury, stroke, infectious diseases of the brain, etc. Most often, between the initiating event and epilepsy, there is a period without seizures—a latent period. At this time, the process of restructuring of neural networks begins, leading to the formation of epileptiform activity, called epileptogenesis. The prediction of the development of the epileptogenic process is currently an urgent and difficult task. MicroRNAs are inexpensive and minimally invasive biomarkers of biological and pathological processes. The aim of this study is to evaluate the predictive ability of microRNAs to detect the risk of epileptogenesis. In this study, we conducted a systematic search on the MDPI, PubMed, ScienceDirect, and Web of Science platforms. We analyzed publications that studied the aberrant expression of circulating microRNAs in epilepsy, traumatic brain injury, and ischemic stroke in order to search for microRNAs—potential biomarkers for predicting epileptogenesis. Thus, 31 manuscripts examining biomarkers of epilepsy, 19 manuscripts examining biomarkers of traumatic brain injury, and 48 manuscripts examining biomarkers of ischemic stroke based on circulating miRNAs were analyzed. Three miRNAs were studied: miR-21, miR-181a, and miR-155. The findings showed that miR-21 and miR-155 are associated with cell proliferation and apoptosis, and miR-181a is associated with protein modifications. These miRNAs are not strictly specific, but they are involved in processes that may be indirectly associated with epileptogenesis. Also, these microRNAs may be of interest when they are studied in a cohort with each other and with other microRNAs. To further study the microRNA-based biomarkers of epileptogenesis, many factors must be taken into account: the time of sampling, the type of biological fluid, and other nuances. Currently, there is a need for more in-depth and prolonged studies of epileptogenesis. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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