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Molecular Mechanism and Regulation in Neuroinflammation

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 14113

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Dr. Hung-Pei Tsai

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Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Interests: neuropathic pain; subarachnoid hemorrhage; nerve repair; brain tumor; neuroinflammation
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Special Issue Information

Dear Colleagues,

Neuroinflammation is defined as an inflammatory response within the brain or spinal cord, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. This inflammation is mediated by the production of cytokines, chemokines, reactive oxygen species and second messengers. These mediators are produced by resident CNS glial cells (microglia and astrocytes), endothelial cells, and immune cells of peripheral origin. These neuroinflammatory responses have immunological, physiological, biochemical, and psychological consequences. From a pathological point of view, in the central nervous system, neuroinflammation is associated with damage from direct penetrating physical injury: e.g., traumatic brain injury (TBI), spinal cord injury (SCI), or neurodegenerative multiple sclerosis (MS) and other biochemical diseases), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), tumors (gliomas) or senescence. Research and development of solutions to slow or suppress this neuroinflammation is highly warranted. The research topics of this special issue aim to cover promising, recent and novel molecular regulation and research mechanisms for the diagnosis and treatment of neuroinflammation.

Dr. Hung-Pei Tsai
Guest Editor

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Published Papers (10 papers)

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Research

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8 pages, 741 KiB

Open AccessCommunication

Genetic Variant of DNAM-1 rs763361 C>T Is Associated with Ankylosing Spondylitis in a Mexican Population

by Alejandro Vázquez-Reyes, José Francisco Zambrano-Zaragoza, Juan Manuel Agraz-Cibrián, Miriam Fabiola Ayón-Pérez, Gloria Yareli Gutiérrez-Silerio, Susana Del Toro-Arreola, Alan Guillermo Alejandre-González, Liliana Ortiz-Martínez, Jesse Haramati, Iris Celeste Tovar-Ocampo, Marcelo Victorio-De los Santos and Jorge Gutiérrez-Franco

Curr. Issues Mol. Biol. 2024, 46(4), 2819-2826; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46040176 - 23 Mar 2024

Viewed by 357

Abstract

DNAM-1 (CD226) is an activating receptor expressed in CD8+ T cells, NK cells, and monocytes. It has been reported that two SNPs in the DNAM-1 gene, rs763361 C>T and rs727088 G>A, have been associated with different autoimmune diseases; however, the role of DNAM-1 in ankylosing spondylitis has been less studied. For this reason, we focused on the study of these two SNPs in association with ankylosing spondylitis. For this, 34 patients and 70 controls were analyzed using endpoint PCR with allele-specific primers. Our results suggest that rs763361 C>T is involved as a possible protective factor under the CT co-dominant model (OR = 0.34, 95% CI = 0.13–0.88, p = 0.022) and the CT + TT dominant model (OR = 0.39, 95% CI = 0.17–0.90, p = 0.025), while rs727088 G>A did not show an association with the disease in any of the inheritance models. When analyzing the relationships of the haplotypes, we found that the T + A haplotype (OR = 0.31, 95% CI = 0.13–0.73, p = 0.0083) is a protective factor for developing the disease. In conclusion, the CT and CT + TT variants of rs763361 C>T and the T + A haplotype were considered as protective factors for developing ankylosing spondylitis. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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15 pages, 3268 KiB

Open AccessArticle

6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Alleviates Oxidative Stress and NF-κB-Mediated Inflammation in Rats with Experimental Parkinson’s Disease

by Evgenii D. Kryl’skii, Grigorii A. Razuvaev, Tatyana N. Popova, Svetlana M. Medvedeva and Khidmet S. Shikhaliev

Curr. Issues Mol. Biol. 2023, 45(9), 7653-7667; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45090483 - 21 Sep 2023

Cited by 1 | Viewed by 917

Abstract

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) factor, and the inflammatory response in rats during the development of rotenone-induced Parkinsonism. The findings indicate that HTHQ, with its antioxidant attributes, reduced the levels of 8-isoprostane, lipid oxidation products, and protein oxidation products. The decrease in oxidative stress due to HTHQ led to a reduction in the mRNA content of proinflammatory cytokines and myeloperoxidase activity, accompanying the drop in the expression of the factor NF-κB. These alterations promoted an improvement in motor coordination scores and increased tyrosine hydroxylase levels, whereas histopathological changes in the brain tissue of the experimental animals were attenuated. HTHQ exhibited greater effectiveness than the comparative drug rasagiline based on the majority of variables. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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16 pages, 2391 KiB

Open AccessArticle

Administration of Tamoxifen Can Regulate Changes in Gene Expression during the Acute Phase of Traumatic Spinal Cord Injury

by Eibar E. Cabrera-Aldana, Yalbi I. Balderas-Martinez, Rafael Velázquez-Cruz, Luis B. Tovar-y-Romo, Rosalba Sevilla-Montoya, Angelina Martínez-Cruz, Claudia Martinez-Cordero, Margarita Valdes-Flores, Monica Santamaria-Olmedo, Alberto Hidalgo-Bravo and Gabriel Guízar-Sahagún

Curr. Issues Mol. Biol. 2023, 45(9), 7476-7491; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45090472 - 13 Sep 2023

Viewed by 971

Abstract

Traumatic spinal cord injury (SCI) causes irreversible damage leading to incapacity. Molecular mechanisms underlying SCI damage are not fully understood, preventing the development of novel therapies. Tamoxifen (TMX) has emerged as a promising therapy. Our aim was to identify transcriptome changes in the acute phase of SCI and the effect of Tamoxifen on those changes in a rat model of SCI. Four groups were considered: (1) Non-injured without TMX (Sham/TMX-), (2) Non-injured with TMX (Sham/TMX+), (3) injured without TMX (SCI/TMX-), and (4) injured with TMX (SCI/TMX+). Tamoxifen was administered intraperitoneally 30 min after injury, and spinal cord tissues were collected 24 h after injury. Clariom S Assays Array was used for transcriptome analysis. After comparing Sham/TMX- versus SCI/TMX-, 708 genes showed differential expression. The enriched pathways were the SCI pathway and pathways related to the inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression, with no pathways enriched. Our results showed differential expression of genes related to the inflammatory response after SCI, and Tamoxifen seems to regulate gene expression changes in Ccr2 and Mmp12. Our study contributes data regarding the potential value of tamoxifen as a therapeutic resource for traumatic SCI during the acute phase. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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17 pages, 3787 KiB

Open AccessArticle

NMOSD IgG Impact Retinal Cells in Murine Retinal Explants

by Hannah Nora Wolf, Veronika Ehinger, Larissa Guempelein, Pratiti Banerjee, Tania Kuempfel, Joachim Havla and Diana Pauly

Curr. Issues Mol. Biol. 2023, 45(9), 7319-7335; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45090463 - 07 Sep 2023

Viewed by 991

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory diseases of the central nervous system, characterized by autoantibodies against aquaporin-4. The symptoms primarily involve severe optic neuritis and longitudinally extensive transverse myelitis. Although the disease progression is typically relapse-dependent, recent studies revealed retinal neuroaxonal degeneration unrelated to relapse activity, potentially due to anti-aquaporin-4-positive antibodies interacting with retinal glial cells such as Müller cells. In this exploratory study, we analysed the response of mouse retinal explants to NMOSD immunoglobulins (IgG). Mouse retinal explants were treated with purified IgG from patient or control sera for one and three days. We characterized tissue response patterns through morphological changes, chemokine secretion, and complement expression. Mouse retinal explants exhibited a basic proinflammatory response ex vivo, modified by IgG addition. NMOSD IgG, unlike control IgG, increased gliosis and decreased chemokine release (CCL2, CCL3, CCL4, and CXCL-10). Complement component expression by retinal cells remained unaltered by either IgG fraction. We conclude that human NMOSD IgG can possibly bind in the mouse retina, altering the local cellular environment. This intraretinal stress may contribute to retinal degeneration independent of relapse activity in NMOSD, suggesting a primary retinopathy. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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17 pages, 2309 KiB

Open AccessArticle

The Effect of Ethanol Extract from Mesua ferrea Linn Flower on Alzheimer’s Disease and Its Underlying Mechanism

by Kusawadee Plekratoke, Chantana Boonyarat, Orawan Monthakantirat, Natsajee Nualkaew, Jinda Wangboonskul, Suresh Awale, Yaowared Chulikhit, Supawadee Daodee, Charinya Khamphukdee, Suchada Chaiwiwatrakul and Pornthip Waiwut

Curr. Issues Mol. Biol. 2023, 45(5), 4063-4079; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45050259 - 06 May 2023

Cited by 1 | Viewed by 1891

Abstract

The effects of Mesua ferrea Linn flower (MFE) extract on the pathogenic cascade of Alzheimer’s disease (AD) were determined by an in vitro and cell culture model in the search for a potential candidate for the treatment of AD. The 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay exhibited that the MFE extract had antioxidant activities. According to the Ellman and the thioflavin T method’s result, the extracts could inhibit acetylcholinesterase and β-amyloid (Aβ) aggregation. Studies on neuroprotection in cell culture found that the MFE extract could reduce the death of human neuroblastoma cells (SH-SY5Y) caused by H₂O₂ and Aβ. Western blot analysis exhibited that the MFE extract alleviated H₂O₂-induced neuronal cell damage by downregulating the pro-apoptotic proteins, including cleaved caspase-3, Bax, and by enhancing the expression of anti-apoptotic markers including MCl₁, BCl_xl, and survivin. Moreover, MFE extract inhibited the expression of APP, presenilin 1, and BACE, and increased the expression of neprilysin. In addition, the MFE extract could enhance scopolamine-induced memory deficit in mice. Overall, results showed that the MFE extract had several modes of action related to the AD pathogenesis cascade, including antioxidants, anti-acetylcholinesterase, anti-Aβ aggregation, and neuroprotection against oxidative stress and Aβ. Therefore, the M. ferrea L. flower might be a possibility for further development as a medication for AD. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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Review

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24 pages, 640 KiB

Open AccessReview

Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies

by Ryder Davidson, Reese I. Krider, Philip Borsellino, Keith Noorda, George Alhwayek and Thomas A. Vida

Curr. Issues Mol. Biol. 2023, 45(11), 8816-8839; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110553 - 02 Nov 2023

Cited by 1 | Viewed by 1456

Abstract

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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21 pages, 1149 KiB

Open AccessReview

Mitochondrial DNA and Inflammation in Alzheimer’s Disease

by Giacoma Galizzi and Marta Di Carlo

Curr. Issues Mol. Biol. 2023, 45(11), 8586-8606; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110540 - 25 Oct 2023

Cited by 2 | Viewed by 2098

Abstract

Mitochondrial dysfunction and neuroinflammation are implicated in the pathogenesis of most neurodegenerative diseases, such as Alzheimer’s disease (AD). In fact, although a growing number of studies show crosstalk between these two processes, there remain numerous gaps in our knowledge of the mechanisms involved, which requires further clarification. On the one hand, mitochondrial dysfunction may lead to the release of mitochondrial damage-associated molecular patterns (mtDAMPs) which are recognized by microglial immune receptors and contribute to neuroinflammation progression. On the other hand, inflammatory molecules released by glial cells can influence and regulate mitochondrial function. A deeper understanding of these mechanisms may help identify biomarkers and molecular targets useful for the treatment of neurodegenerative diseases. This review of works published in recent years is focused on the description of the mitochondrial contribution to neuroinflammation and neurodegeneration, with particular attention to mitochondrial DNA (mtDNA) and AD. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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34 pages, 2691 KiB

Open AccessReview

Neuroinflammation in the Evolution of Motor Function in Stroke and Trauma Patients: Treatment and Potential Biomarkers

by Ane Larrea, Ane Elexpe, Eguzkiñe Díez-Martín, María Torrecilla, Egoitz Astigarraga and Gabriel Barreda-Gómez

Curr. Issues Mol. Biol. 2023, 45(11), 8552-8585; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110539 - 25 Oct 2023

Cited by 2 | Viewed by 1444

Abstract

Neuroinflammation has a significant impact on different pathologies, such as stroke or spinal cord injury, intervening in their pathophysiology: expansion, progression, and resolution. Neuroinflammation involves oxidative stress, damage, and cell death, playing an important role in neuroplasticity and motor dysfunction by affecting the neuronal connection responsible for motor control. The diagnosis of this pathology is performed using neuroimaging techniques and molecular diagnostics based on identifying and measuring signaling molecules or specific markers. In parallel, new therapeutic targets are being investigated via the use of bionanomaterials and electrostimulation to modulate the neuroinflammatory response. These novel diagnostic and therapeutic strategies have the potential to facilitate the development of anticipatory patterns and deliver the most beneficial treatment to improve patients’ quality of life and directly impact their motor skills. However, important challenges remain to be solved. Hence, the goal of this study was to review the implication of neuroinflammation in the evolution of motor function in stroke and trauma patients, with a particular focus on novel methods and potential biomarkers to aid clinicians in diagnosis, treatment, and therapy. A specific analysis of the strengths, weaknesses, threats, and opportunities was conducted, highlighting the key challenges to be faced in the coming years. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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16 pages, 1394 KiB

Open AccessReview

Alzheimer’s Disease beyond Calcium Dysregulation: The Complex Interplay between Calmodulin, Calmodulin-Binding Proteins and Amyloid Beta from Disease Onset through Progression

by Danton H. O’Day

Curr. Issues Mol. Biol. 2023, 45(8), 6246-6261; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45080393 - 27 Jul 2023

Cited by 2 | Viewed by 1292

Abstract

A multifactorial syndrome, Alzheimer’s disease is the main cause of dementia, but there is no existing therapy to prevent it or stop its progression. One of the earliest events of Alzheimer’s disease is the disruption of calcium homeostasis but that is just a prelude to the disease’s devastating impact. Calcium does not work alone but must interact with downstream cellular components of which the small regulatory protein calmodulin is central, if not primary. This review supports the idea that, due to calcium dyshomeostasis, calmodulin is a dominant regulatory protein that functions in all stages of Alzheimer’s disease, and these regulatory events are impacted by amyloid beta. Amyloid beta not only binds to and regulates calmodulin but also multiple calmodulin-binding proteins involved in Alzheimer’s. Together, they act on the regulation of calcium dyshomeostasis, neuroinflammation, amyloidogenesis, memory formation, neuronal plasticity and more. The complex interactions between calmodulin, its binding proteins and amyloid beta may explain why many therapies have failed or are doomed to failure unless they are considered. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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15 pages, 1064 KiB

Open AccessReview

Insights into Advanced Neurological Dysfunction Mechanisms Following DBS Surgery in Parkinson’s Patients: Neuroinflammation and Pyroptosis

by Hao Meng, Jia-Hang Wei, Peng-Zheng Yu, Jia-Xin Ren, Meng-Yao Tang, Jun-Yi Sun, Xiao-Yu Yan and Jing Su

Curr. Issues Mol. Biol. 2023, 45(5), 4480-4494; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45050284 - 20 May 2023

Cited by 1 | Viewed by 1695

Abstract

Parkinson’s disease is a severe neurodegenerative disorder. Currently, deep brain electrical stimulation (DBS) is the first line of surgical treatment. However, serious neurological impairments such as speech disorders, disturbances of consciousness, and depression after surgery limit the efficacy of treatment. In this review, we summarize the recent experimental and clinical studies that have explored the possible causes of neurological deficits after DBS. Furthermore, we tried to identify clues from oxidative stress and pathological changes in patients that could lead to the activation of microglia and astrocytes in DBS surgical injury. Notably, reliable evidence supports the idea that neuroinflammation is caused by microglia and astrocytes, which may contribute to caspase-1 pathway-mediated neuronal pyroptosis. Finally, existing drugs and treatments may partially ameliorate the loss of neurological function in patients following DBS surgery by exerting neuroprotective effects. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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