International Journal of Molecular Sciences

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13 pages, 1875 KiB

Open AccessArticle

Comparison of Extracellular Vesicles from Induced Pluripotent Stem Cell-Derived Brain Cells

by Gabriela Xavier, Alexander Navarrete Santos, Carla Hartmann, Marcos L. Santoro, Nicole Flegel, Jessica Reinsch, Annika Majer, Toni Ehrhardt, Jenny Pfeifer, Andreas Simm, Thomas Hollemann, Sintia I. Belangero, Dan Rujescu and Matthias Jung

Int. J. Mol. Sci. 2024, 25(7), 3575; https://doi.org/10.3390/ijms25073575 - 22 Mar 2024

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Abstract

The pathophysiology of many neuropsychiatric disorders is still poorly understood. Identification of biomarkers for these diseases could benefit patients due to better classification and stratification. Exosomes excreted into the circulatory system can cross the blood–brain barrier and carry a cell type-specific set of [...] Read more.

The pathophysiology of many neuropsychiatric disorders is still poorly understood. Identification of biomarkers for these diseases could benefit patients due to better classification and stratification. Exosomes excreted into the circulatory system can cross the blood–brain barrier and carry a cell type-specific set of molecules. Thus, exosomes are a source of potential biomarkers for many diseases, including neuropsychiatric disorders. Here, we investigated exosomal proteins produced from human-induced pluripotent stem cells (iPSCs) and iPSC-derived neural stem cells, neural progenitors, neurons, astrocytes, microglia-like cells, and brain capillary endothelial cells. Of the 31 exosome surface markers analyzed, a subset of biomarkers were significantly enriched in astrocytes (CD29, CD44, and CD49e), microglia-like cells (CD44), and neural stem cells (SSEA4). To identify molecular fingerprints associated with disease, circulating exosomes derived from healthy control (HC) individuals were compared against schizophrenia (SCZ) patients and late-onset Alzheimer’s disease (LOAD) patients. A significant epitope pattern was identified for LOAD (CD1c and CD2) but not for SCZ compared to HC. Thus, analysis of cell type- and disease-specific exosome signatures of iPSC-derived cell cultures may provide a valuable model system to explore proteomic biomarkers for the identification of novel disease profiles. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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18 pages, 8157 KiB

Open AccessArticle

Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways

by Mikel Gurrea-Rubio, Qin Wang, Elizabeth A. Mills, Qi Wu, David Pitt, Pei-Suen Tsou, David A. Fox and Yang Mao-Draayer

Int. J. Mol. Sci. 2024, 25(5), 2454; https://doi.org/10.3390/ijms25052454 - 20 Feb 2024

Viewed by 841

Abstract

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS [...] Read more.

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), in which neurological disability is thought to be linked to neurodegeneration. As a result, successful therapeutics for progressive MS likely need to have both anti-inflammatory and direct neuroprotective properties. The modulation of sphingosine-1-phosphate (S1P) receptors has been implicated in neuroprotection in preclinical animal models. Siponimod/BAF312, the first oral treatment approved for SPMS, may have direct neuroprotective benefits mediated by its activity as a selective (S1P receptor 1) S1P1 and (S1P receptor 5) S1P5 modulator. We showed that S1P1 was mainly present in cortical neurons in lesioned areas of the MS brain. To gain a better understanding of the neuroprotective effects of siponimod in MS, we used both rat neurons and human-induced pluripotent stem cell (iPSC)-derived neurons treated with the neuroinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Cell survival/apoptotic assays using flow cytometry and IncuCyte live cell analyses showed that siponimod decreased TNF-α induced neuronal cell apoptosis in both rat and human iPSCs. Importantly, a transcriptomic analysis revealed that mitochondrial oxidative phosphorylation, NFκB and cytokine signaling pathways contributed to siponimod’s neuroprotective effects. Our data suggest that the neuroprotection of siponimod/BAF312 likely involves the relief of oxidative stress in neuronal cells. Further studies are needed to explore the molecular mechanisms of such interactions to determine the relationship between mitochondrial dysfunction and neuroinflammation/neurodegeneration. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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15 pages, 1028 KiB

Open AccessArticle

Prognostic Value of Gut Microbiome for Conversion from Mild Cognitive Impairment to Alzheimer’s Disease Dementia within 4 Years: Results from the AlzBiom Study

by Christoph Laske, Stephan Müller, Matthias H. J. Munk, Iris Honold, Matthias Willmann, Silke Peter and Ulrich Schoppmeier

Int. J. Mol. Sci. 2024, 25(3), 1906; https://doi.org/10.3390/ijms25031906 - 05 Feb 2024

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Abstract

Alterations in the gut microbiome are associated with the pathogenesis of Alzheimer’s disease (AD) and can be used as a diagnostic measure. However, longitudinal data of the gut microbiome and knowledge about its prognostic significance for the development and progression of AD are [...] Read more.

Alterations in the gut microbiome are associated with the pathogenesis of Alzheimer’s disease (AD) and can be used as a diagnostic measure. However, longitudinal data of the gut microbiome and knowledge about its prognostic significance for the development and progression of AD are limited. The aim of the present study was to develop a reliable predictive model based on gut microbiome data for AD development. In this longitudinal study, we investigated the intestinal microbiome in 49 mild cognitive impairment (MCI) patients over a mean (SD) follow-up of 3.7 (0.6) years, using shotgun metagenomics. At the end of the 4-year follow-up (4yFU), 27 MCI patients converted to AD dementia and 22 MCI patients remained stable. The best taxonomic model for the discrimination of AD dementia converters from stable MCI patients included 24 genera, yielding an area under the receiver operating characteristic curve (AUROC) of 0.87 at BL, 0.92 at 1yFU and 0.95 at 4yFU. The best models with functional data were obtained via analyzing 25 GO (Gene Ontology) features with an AUROC of 0.87 at BL, 0.85 at 1yFU and 0.81 at 4yFU and 33 KO [Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog] features with an AUROC of 0.79 at BL, 0.88 at 1yFU and 0.82 at 4yFU. Using ensemble learning for these three models, including a clinical model with the four parameters of age, gender, body mass index (BMI) and Apolipoprotein E (ApoE) genotype, yielded an AUROC of 0.96 at BL, 0.96 at 1yFU and 0.97 at 4yFU. In conclusion, we identified novel and timely stable gut microbiome algorithms that accurately predict progression to AD dementia in individuals with MCI over a 4yFU period. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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21 pages, 3718 KiB

Open AccessArticle

E3 Ubiquitin Ligase Uhrf2 Knockout Reveals a Critical Role in Social Behavior and Synaptic Plasticity in the Hippocampus

by Yinghan Zhuang, Chuhan Li, Fang Zhao, Yan Yan, Hongjie Pan, Jianmin Zhan and Thomas Behnisch

Int. J. Mol. Sci. 2024, 25(3), 1543; https://doi.org/10.3390/ijms25031543 - 26 Jan 2024

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Abstract

The hippocampal formation, particularly the CA2 subregion, is critical for social memory formation and memory processing, relying on synaptic plasticity—a fundamental mechanism by which synapses strengthen. Given the role of the ubiquitin–proteasome system (UPS) in various nervous system processes, including learning and memory, [...] Read more.

The hippocampal formation, particularly the CA2 subregion, is critical for social memory formation and memory processing, relying on synaptic plasticity—a fundamental mechanism by which synapses strengthen. Given the role of the ubiquitin–proteasome system (UPS) in various nervous system processes, including learning and memory, we were particularly interested in exploring the involvement of RING-type ubiquitin E3 ligases, such as UHRF2 (NIRF), in social behavior and synaptic plasticity. Our results revealed altered social behavior in mice with systemic Uhrf2 knockout, including changes in nest building, tube dominance, and the three-chamber social novelty test. In Uhrf2 knockout mice, the entorhinal cortex-CA2 circuit showed significant reductions in synaptic plasticity during paired-pulse facilitation and long-term potentiation, while the inability to evoke synaptic plasticity in the Schaffer-collateral CA2 synapses remained unaffected. These changes in synaptic plasticity correlated with significant changes in gene expression including genes related to vesicle trafficking and transcriptional regulation. The effects of Uhrf2 knockout on synaptic plasticity and the observed gene expression changes highlight UHRF2 as a regulator of learning and memory processes at both the cellular and systemic levels. Targeting E3 ubiquitin ligases, such as UHRF2, may hold therapeutic potential for memory-related disorders, warranting further investigation. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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22 pages, 3154 KiB

Open AccessArticle

Experimental Study: Interleukin-31 Augments Morphine-Induced Antinociceptive Activity and Suppress Tolerance Development in Mice

by Iwao Arai, Minoru Tsuji, Saburo Saito and Hiroshi Takeda

Int. J. Mol. Sci. 2023, 24(22), 16548; https://doi.org/10.3390/ijms242216548 - 20 Nov 2023

Viewed by 913

Abstract

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and [...] Read more.

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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21 pages, 5907 KiB

Open AccessArticle

Early Neuroprotective Effects of Bovine Lactoferrin Associated with Hypothermia after Neonatal Brain Hypoxia-Ischemia in Rats

by Eduardo Sanches, Yohan van de Looij, Dini Ho, Laura Modernell, Analina da Silva and Stéphane Sizonenko

Int. J. Mol. Sci. 2023, 24(21), 15583; https://doi.org/10.3390/ijms242115583 - 25 Oct 2023

Viewed by 1179

Abstract

Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, [...] Read more.

Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic properties and has been shown to protect very immature brains against HI damage. We hypothesized that combining early oral administration of LF with whole body hypothermia could enhance neuroprotection in a HIE rat model. Pregnant Wistar rats were fed an LF-supplemented diet (1 mg/kg) or a control diet from (P6). At P7, the male and female pups had the right common carotid artery occluded followed by hypoxia (8% O₂ for 60′) (HI). Immediately after hypoxia, hypothermia (target temperature of 32.5–33.5 °C) was performed (5 h duration) using Criticool^®. The animals were divided according to diet, injury and thermal condition. At P8 (24 h after HI), the brain neurochemical profile was assessed using magnetic resonance spectroscopy (¹H-MRS) and a hyperintense T₂W signal was used to measure the brain lesions. The mRNA levels of the genes related to glutamatergic excitotoxicity, energy metabolism and inflammation were assessed in the right hippocampus. The cell markers and apoptosis expression were assessed using immunofluorescence in the right hippocampus. HI decreased the energy metabolites and increased lactate. The neuronal–astrocytic coupling impairments observed in the HI groups were reversed mainly by HT. LF had an important effect on astrocyte function, decreasing the levels of the genes related to glutamatergic excitotoxicity and restoring the mRNA levels of the genes related to metabolic support. When combined, LF and HT presented a synergistic effect and prevented lactate accumulation, decreased inflammation and reduced brain damage, pointing out the benefits of combining these therapies. Overall, we showed that through distinct mechanisms lactoferrin can enhance neuroprotection induced by HT following neonatal brain hypoxia-ischemia. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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15 pages, 3159 KiB

Open AccessArticle

Pharmacological Inhibition of NHE1 Protein Increases White Matter Resilience and Neurofunctional Recovery after Ischemic Stroke

by Shamseldin Ayman Hassan Metwally, Satya Siri Paruchuri, Lauren Yu, Okan Capuk, Nicholas Pennock, Dandan Sun and Shanshan Song

Int. J. Mol. Sci. 2023, 24(17), 13289; https://doi.org/10.3390/ijms241713289 - 27 Aug 2023

Cited by 2 | Viewed by 1305

Abstract

To date, recanalization interventions are the only available treatments for ischemic stroke patients; however, there are no effective therapies for reducing stroke-induced neuroinflammation. We recently reported that H⁺ extrusion protein Na⁺/H⁺ exchanger-1 (NHE1) plays an important role in stroke-induced [...] Read more.

To date, recanalization interventions are the only available treatments for ischemic stroke patients; however, there are no effective therapies for reducing stroke-induced neuroinflammation. We recently reported that H⁺ extrusion protein Na⁺/H⁺ exchanger-1 (NHE1) plays an important role in stroke-induced inflammation and white matter injury. In this study, we tested the efficacy of two potent NHE1 inhibitors, HOE642 and Rimeporide, with a delayed administration regimen starting at 24 h post-stroke in adult C57BL/6J mice. Post-stroke HOE642 and Rimeporide treatments accelerated motor and cognitive function recovery without affecting the initial ischemic infarct, neuronal damage, or reactive astrogliosis. However, the delayed administration of NHE1 blockers after ischemic stroke significantly reduced microglial inflammatory activation while enhanced oligodendrogenesis and white matter myelination, with an increased proliferation and decreased apoptosis of the oligodendrocytes. Our findings suggest that NHE1 protein plays an important role in microglia-mediated inflammation and white matter damage. The pharmacological blockade of NHE1 protein activity reduced microglia inflammatory responses and enhanced oligodendrogenesis and white matter repair, leading to motor and cognitive function recovery after stroke. Our study reveals the potential of targeting NHE1 protein as a therapeutic strategy for ischemic stroke therapy. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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22 pages, 14238 KiB

Open AccessArticle

N-Acetylglucosamine Kinase–Small Nuclear Ribonucleoprotein Polypeptide N Interaction Promotes Axodendritic Branching in Neurons via Dynein-Mediated Microtubule Transport

by Binod Timalsina, Ho Jin Choi and Il Soo Moon

Int. J. Mol. Sci. 2023, 24(14), 11672; https://doi.org/10.3390/ijms241411672 - 19 Jul 2023

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Abstract

N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small nuclear ribonucleoprotein polypeptide N (SNRPN) regulates neurodevelopment and cognitive ability. In our previous study, we revealed the interaction between NAGK and SNRPN in [...] Read more.

N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small nuclear ribonucleoprotein polypeptide N (SNRPN) regulates neurodevelopment and cognitive ability. In our previous study, we revealed the interaction between NAGK and SNRPN in the neuron. However, the precise role in neurodevelopment is elusive. In this study, we investigate the role of NAGK and SNRPN in the axodendritic development of neurons. NAGK and SNRPN interaction is significantly increased in neurons at the crucial stages of neurodevelopment. Furthermore, overexpression of the NAGK and SNRPN proteins increases axodendritic branching and neuronal complexity, whereas the knockdown inhibits neurodevelopment. We also observe the interaction of NAGK and SNRPN with the dynein light-chain roadblock type 1 (DYNLRB1) protein variably during neurodevelopment, revealing the microtubule-associated delivery of the complex. Interestingly, NAGK and SNRPN proteins rescued impaired axodendritic development in an SNRPN depletion model of Prader–Willi syndrome (PWS) patient-derived induced pluripotent stem cell neurons. Taken together, these findings are crucial in developing therapeutic approaches for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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22 pages, 4337 KiB

Open AccessArticle

MIC19 Exerts Neuroprotective Role via Maintaining the Mitochondrial Structure in a Rat Model of Intracerebral Hemorrhage

by Siyuan Yang, Xulong Yin, Jiahe Wang, Haiying Li, Haitao Shen, Qing Sun and Xiang Li

Int. J. Mol. Sci. 2023, 24(14), 11553; https://doi.org/10.3390/ijms241411553 - 17 Jul 2023

Cited by 1 | Viewed by 1025

Abstract

As an essential constituent of the mitochondrial contact site and cristae organization system (MICOS), MIC19 plays a crucial role in maintaining the stability of mitochondrial function and microstructure. However, the mechanisms and functions of MIC19 in intracerebral hemorrhage (ICH) remain unknown and need [...] Read more.

As an essential constituent of the mitochondrial contact site and cristae organization system (MICOS), MIC19 plays a crucial role in maintaining the stability of mitochondrial function and microstructure. However, the mechanisms and functions of MIC19 in intracerebral hemorrhage (ICH) remain unknown and need to be investigated. Sprague Dawley (SD) rats injected with autologous blood obtained from the caudal artery, and cultured neurons exposed to oxygen hemoglobin (OxyHb) were used to establish and emulate the ICH model in vivo and in vitro. Lentiviral vector encoding MIC19 or MIC19 short hairpin ribonucleic acid (shRNA) was constructed and administered to rats by intracerebroventricular injection to overexpress or knock down MIC19, respectively. First, MIC19 protein levels were increased after ICH modeling. After virus transfection and subsequent ICH modeling, we observed that overexpression of MIC19 could mitigate cell apoptosis and neuronal death, as well as abnormalities in mitochondrial structure and function, oxidative stress within mitochondria, and neurobehavioral deficits in rats following ICH. Conversely, knockdown of MIC19 had the opposite effect. Moreover, we found that the connection between MIC19 and SAM50 was disrupted after ICH, which may be a reason for the impairment of the mitochondrial structure after ICH. In conclusion, MIC19 exerts a protective role in the subsequent injury induced by ICH. The investigation of MIC19 may offer clinicians novel therapeutic insights for patients afflicted with ICH. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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Review

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19 pages, 2446 KiB

Open AccessReview

The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials

by Andrea D. Rivera, John R. Normanton, Arthur M. Butt and Kasum Azim

Int. J. Mol. Sci. 2024, 25(8), 4452; https://doi.org/10.3390/ijms25084452 - 18 Apr 2024

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Abstract

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to a potential reduction in life expectancy by up to 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue to remain enigmatic, with previous research [...] Read more.

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to a potential reduction in life expectancy by up to 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue to remain enigmatic, with previous research yielding diverse and occasionally conflicting findings. Nonetheless, one consistently observed phenomenon in brain imaging studies of schizophrenia patients is the disruption of white matter, the bundles of myelinated axons that provide connectivity and rapid signalling between brain regions. Myelin is produced by specialised glial cells known as oligodendrocytes, which have been shown to be disrupted in post-mortem analyses of schizophrenia patients. Oligodendrocytes are generated throughout life by a major population of oligodendrocyte progenitor cells (OPC), which are essential for white matter health and plasticity. Notably, a decline in a specific subpopulation of OPC has been identified as a principal factor in oligodendrocyte disruption and white matter loss in the aging brain, suggesting this may also be a factor in schizophrenia. In this review, we analysed genomic databases to pinpoint intersections between aging and schizophrenia and identify shared mechanisms of white matter disruption and cognitive dysfunction. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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34 pages, 508 KiB

Open AccessReview

Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies

by Huichun Tong, Tianqi Yang, Shuying Xu, Xinhui Li, Li Liu, Gongke Zhou, Sitong Yang, Shurui Yin, Xiao-Jiang Li and Shihua Li

Int. J. Mol. Sci. 2024, 25(7), 3845; https://doi.org/10.3390/ijms25073845 - 29 Mar 2024

Viewed by 604

Abstract

Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and [...] Read more.

Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant HTT gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

39 pages, 17774 KiB

Open AccessReview

What Can Inflammation Tell Us about Therapeutic Strategies for Parkinson’s Disease?

by Jinsong Xue, Keju Tao, Weijia Wang and Xiaofei Wang

Int. J. Mol. Sci. 2024, 25(3), 1641; https://doi.org/10.3390/ijms25031641 - 29 Jan 2024

Viewed by 1344

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder with a complicated etiology and pathogenesis. α-Synuclein aggregation, dopaminergic (DA) neuron loss, mitochondrial injury, oxidative stress, and inflammation are involved in the process of PD. Neuroinflammation has been recognized as a key element in the [...] Read more.

Parkinson’s disease (PD) is a common neurodegenerative disorder with a complicated etiology and pathogenesis. α-Synuclein aggregation, dopaminergic (DA) neuron loss, mitochondrial injury, oxidative stress, and inflammation are involved in the process of PD. Neuroinflammation has been recognized as a key element in the initiation and progression of PD. In this review, we summarize the inflammatory response and pathogenic mechanisms of PD. Additionally, we describe the potential anti-inflammatory therapies, including nod-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome inhibition, nuclear factor κB (NF-κB) inhibition, microglia inhibition, astrocyte inhibition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, the peroxisome proliferator-activated receptor γ (PPARγ) agonist, targeting the mitogen-activated protein kinase (MAPK) pathway, targeting the adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway, targeting α-synuclein, targeting miRNA, acupuncture, and exercise. The review focuses on inflammation and will help in designing new prevention strategies for PD. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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29 pages, 2093 KiB

Open AccessReview

Functional Dimerization of Serotonin Receptors: Role in Health and Depressive Disorders

by Elena V. Mitroshina, Ekaterina A. Marasanova and Maria V. Vedunova

Int. J. Mol. Sci. 2023, 24(22), 16416; https://doi.org/10.3390/ijms242216416 - 16 Nov 2023

Cited by 2 | Viewed by 1442

Abstract

Understanding the neurobiological underpinnings of depressive disorder constitutes a pressing challenge in the fields of psychiatry and neurobiology. Depression represents one of the most prevalent forms of mental and behavioral disorders globally. Alterations in dimerization capacity can influence the functional characteristics of serotonin [...] Read more.

Understanding the neurobiological underpinnings of depressive disorder constitutes a pressing challenge in the fields of psychiatry and neurobiology. Depression represents one of the most prevalent forms of mental and behavioral disorders globally. Alterations in dimerization capacity can influence the functional characteristics of serotonin receptors and may constitute a contributing factor to the onset of depressive disorders. The objective of this review is to consolidate the current understanding of interactions within the 5-HT receptor family and between 5-HT receptors and members of other receptor families. Furthermore, it aims to elucidate the role of such complexes in depressive disorders and delineate the mechanisms through which antidepressants exert their effects. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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28 pages, 8005 KiB

Open AccessReview

High-Tech Methods of Cytokine Imbalance Correction in Intervertebral Disc Degeneration

by Natalia A. Shnayder, Azamat V. Ashhotov, Vera V. Trefilova, Maxim A. Novitsky, German V. Medvedev, Marina M. Petrova, Ekaterina A. Narodova, Daria S. Kaskaeva, Galina A. Chumakova, Natalia P. Garganeeva, Natalia V. Lareva, Mustafa Al-Zamil, Azat R. Asadullin and Regina F. Nasyrova

Int. J. Mol. Sci. 2023, 24(17), 13333; https://doi.org/10.3390/ijms241713333 - 28 Aug 2023

Cited by 2 | Viewed by 1238

Abstract

An important mechanism for the development of intervertebral disc degeneration (IDD) is an imbalance between anti-inflammatory and pro-inflammatory cytokines. Therapeutic and non-therapeutic approaches for cytokine imbalance correction in IDD either do not give the expected result, or give a short period of time. [...] Read more.

An important mechanism for the development of intervertebral disc degeneration (IDD) is an imbalance between anti-inflammatory and pro-inflammatory cytokines. Therapeutic and non-therapeutic approaches for cytokine imbalance correction in IDD either do not give the expected result, or give a short period of time. This explains the relevance of high-tech medical care, which is part of specialized care and includes the use of new resource-intensive methods of treatment with proven effectiveness. The aim of the review is to update knowledge about new high-tech methods based on cytokine imbalance correction in IDD. It demonstrates promise of new approaches to IDD management in patients resistant to previously used therapies, including: cell therapy (stem cell implantation, implantation of autologous cultured cells, and tissue engineering); genetic technologies (gene modifications, microRNA, and molecular inducers of IDD); technologies for influencing the inflammatory cascade in intervertebral discs mediated by abnormal activation of inflammasomes; senolytics; exosomal therapy; and other factors (hypoxia-induced factors; lysyl oxidase; corticostatin; etc.). Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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21 pages, 2000 KiB

Open AccessReview

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

by Zhong-Xuan Wang, Yao-Lin Li, Jia-Li Pu and Bao-Rong Zhang

Int. J. Mol. Sci. 2023, 24(7), 6313; https://doi.org/10.3390/ijms24076313 - 28 Mar 2023

Cited by 6 | Viewed by 3123

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed. Full article

(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)

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