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Neuroinflammation: Advancements in Pathophysiology and Therapies
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Neuroinflammation: Advancements in Pathophysiology and Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 11573

Special Issue Editor

Dr. David Martín-Hernández

E-Mail Website
Guest Editor
1. Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
2. Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain
Interests: neuropsychopharmacology; inflammation; microbiome; glía; barrier function; psychiatric diseases; schizophrenia; depression

Special Issue Information

Dear Colleagues,

Neuroinflammation stands as a pervasive phenomenon that cuts across various conditions that affect the central nervous system (CNS), encompassing neurological, neurodegenerative, cardiovascular, and psychiatric disorders. Furthermore, neuroinflammation might also have a role in physiological processes such as aging. In essence, inflammation is a homeostatic mechanism triggered by stimuli of diverse nature to protect the organism. However, if the inflammatory process falters in eliminating potential menaces and persists over time, it can hamper normal CNS function and contribute to disease development. Despite the etiological responsibilities of neuroinflammation sparking an intense debate, its concurrence and consequences represent a harmful threat and may exacerbate the progression and severity of CNS diseases. In this context, a wealth of meta-analyses and an expanding body of clinical and preclinical data underscore the efficacy of anti-inflammatory treatments in some facets of these pathologies, supporting the fact that uncontrolled and chronic neuroinflammation endangers the CNS. Nevertheless, the precise molecular mechanisms underpinning neuroinflammation, its significance for the pathophysiology of certain diseases, and the search for novel therapies aimed at modulating neuroinflammation for clinical improvement remain limited, thereby necessitating further research.

This Special Issue aims to provide a broad overview of the latest cutting-edge advancements in neuroinflammation research, emphasizing its role in the pathophysiology of diseases and innovative treatment strategies. We welcome original research articles, reviews, brief reports, or any other contributions dealing with the following:

  • Molecular, cellular, and tissue-level mechanisms governing neuroinflammation and their regulatory pathways;
  • Neuroinflammation in the pathophysiology of CNS or systemic diseases;
  • Emerging pharmacological approaches for managing or modulating neuroinflammation.

We hope that Special Issue will serve as a trove of recent and current knowledge for newcomers and experienced scientists in this dynamic field.

Dr. David Martín-Hernández
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuroinflammation
  • CNS diseases
  • pathophysiology
  • therapeutic strategies
  • pharmacological treatments
  • neurological disorders
  • neurodegenerative diseases
  • cardiovascular diseases
  • psychiatric disorders

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Published Papers (7 papers)

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Research

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23 pages, 2932 KiB  
Article
A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model
by Aleksandra Bober, Anna Piotrowska, Katarzyna Pawlik, Katarzyna Ciapała, Magdalena Maciuszek, Wioletta Makuch and Joanna Mika
Int. J. Mol. Sci. 2024, 25(13), 7410; https://doi.org/10.3390/ijms25137410 - 5 Jul 2024
Cited by 1 | Viewed by 1255
Abstract
The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these [...] Read more.
The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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19 pages, 6384 KiB  
Article
Ultrastructural Characterization of PBMCs and Extracellular Vesicles in Multiple Sclerosis: A Pilot Study
by Roberto De Masi, Stefania Orlando, Elisabetta Carata and Elisa Panzarini
Int. J. Mol. Sci. 2024, 25(13), 6867; https://doi.org/10.3390/ijms25136867 - 22 Jun 2024
Cited by 1 | Viewed by 927
Abstract
Growing evidence identifies extracellular vesicles (EVs) as important cell-to-cell signal transducers in autoimmune disorders, including multiple sclerosis (MS). If the etiology of MS still remains unknown, its molecular physiology has been well studied, indicating peripheral blood mononuclear cells (PBMCs) as the main pathologically [...] Read more.
Growing evidence identifies extracellular vesicles (EVs) as important cell-to-cell signal transducers in autoimmune disorders, including multiple sclerosis (MS). If the etiology of MS still remains unknown, its molecular physiology has been well studied, indicating peripheral blood mononuclear cells (PBMCs) as the main pathologically relevant contributors to the disease and to neuroinflammation. Recently, several studies have suggested the involvement of EVs as key mediators of neuroimmune crosstalk in central nervous system (CNS) autoimmunity. To assess the role of EVs in MS, we applied electron microscopy (EM) techniques and Western blot analysis to study the morphology and content of plasma-derived EVs as well as the ultrastructure of PBMCs, considering four MS patients and four healthy controls. Through its exploratory nature, our study was able to detect significant differences between groups. Pseudopods and large vesicles were more numerous at the plasmalemma interface of cases, as were endoplasmic vesicles, resulting in an activated aspect of the PBMCs. Moreover, PBMCs from MS patients also showed an increased number of multivesicular bodies within the cytoplasm and amorphous material around the vesicles. In addition, we observed a high number of plasma-membrane-covered extensions, with multiple associated large vesicles and numerous autophagosomal vacuoles containing undigested cytoplasmic material. Finally, the study of EV cargo evidenced a number of dysregulated molecules in MS patients, including GANAB, IFI35, Cortactin, Septin 2, Cofilin 1, and ARHGDIA, that serve as inflammatory signals in a context of altered vesicular dynamics. We concluded that EM coupled with Western blot analysis applied to PBMCs and vesiculation can enhance our knowledge in the physiopathology of MS. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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24 pages, 7642 KiB  
Article
The Effect of Prenatal and Neonatal Fluoride Exposure to Morphine-Induced Neuroinflammation
by Patrycja Kupnicka, Joanna Listos, Maciej Tarnowski, Agnieszka Kolasa, Patrycja Kapczuk, Anna Surówka, Jakub Kwiatkowski, Kamil Janawa, Dariusz Chlubek and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2024, 25(2), 826; https://doi.org/10.3390/ijms25020826 - 9 Jan 2024
Cited by 2 | Viewed by 1689
Abstract
Physical dependence is associated with the formation of neuroadaptive changes in the central nervous system (CNS), both at the molecular and cellular levels. Various studies have demonstrated the immunomodulatory and proinflammatory properties of morphine. The resulting neuroinflammation in drug dependence exacerbates substance abuse-related [...] Read more.
Physical dependence is associated with the formation of neuroadaptive changes in the central nervous system (CNS), both at the molecular and cellular levels. Various studies have demonstrated the immunomodulatory and proinflammatory properties of morphine. The resulting neuroinflammation in drug dependence exacerbates substance abuse-related behaviors and increases morphine tolerance. Studies prove that fluoride exposure may also contribute to the development of neuroinflammation and neurodegenerative changes. Morphine addiction is a major social problem. Neuroinflammation increases tolerance to morphine, and neurodegenerative effects caused by fluoride in structures related to the development of dependence may impair the functioning of neuronal pathways, change the concentration of neurotransmitters, and cause memory and learning disorders, which implies this element influences the development of dependence. Therefore, our study aimed to evaluate the inflammatory state of selected brain structures in morphine-dependent rats pre-exposed to fluoride, including changes in cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression as well as microglial and astroglial activity via the evaluation of Iba1 and GFAP expression. We provide evidence that both morphine administration and fluoride exposure have an impact on the inflammatory response by altering the expression of COX-1, COX-2, ionized calcium-binding adapter molecule (Iba1), and glial fibrillary acidic protein (GFAP) in brain structures involved in dependence development, such as the prefrontal cortex, striatum, hippocampus, and cerebellum. We observed that the expression of COX-1 and COX-2 in morphine-dependent rats is influenced by prior fluoride exposure, and these changes vary depending on the specific brain region. Additionally, we observed active astrogliosis, as indicated by increased GFAP expression, in all brain structures of morphine-dependent rats, regardless of fluoride exposure. Furthermore, the effect of morphine on Iba1 expression varied across different brain regions, and fluoride pre-exposure may influence microglial activation. However, it remains unclear whether these changes are a result of the direct or indirect actions of morphine and fluoride on the factors analyzed. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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Review

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19 pages, 905 KiB  
Review
Novelties on Neuroinflammation in Alzheimer’s Disease–Focus on Gut and Oral Microbiota Involvement
by Cristina Popescu, Constantin Munteanu, Aurelian Anghelescu, Vlad Ciobanu, Aura Spînu, Ioana Andone, Mihaela Mandu, Roxana Bistriceanu, Mihai Băilă, Ruxandra-Luciana Postoiu, Andreea-Iulia Vlădulescu-Trandafir, Sebastian Giuvara, Alin-Daniel Malaelea and Gelu Onose
Int. J. Mol. Sci. 2024, 25(20), 11272; https://doi.org/10.3390/ijms252011272 - 19 Oct 2024
Viewed by 1591
Abstract
Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota–gut–brain axis, including in Alzheimer’s disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the [...] Read more.
Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota–gut–brain axis, including in Alzheimer’s disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the neuroinflammatory processes associated with AD, emphasizing novel insights and therapeutic implications. This review reveals that dysbiosis in AD patients’ gut and oral microbiota is linked to heightened peripheral and central inflammatory responses. Specific bacterial taxa, such as Bacteroides and Firmicutes in the gut, as well as Porphyromonas gingivalis in the oral cavity, are notably altered in AD, leading to significant changes in microglial activation and cytokine production. Gut microbiota alterations are associated with increased intestinal permeability, facilitating the translocation of endotoxins like lipopolysaccharides (LPS) into the bloodstream and exacerbating neuroinflammation by activating the brain’s toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and amyloid peptides, can cross the blood-brain barrier and modulate neuroinflammatory responses. While microbial amyloids may contribute to amyloid-beta aggregation in the brain, certain SCFAs like butyrate exhibit anti-inflammatory properties, suggesting a potential therapeutic avenue to mitigate neuroinflammation. This review not only highlights the critical role of microbiota in AD pathology but also offers a ray of hope by suggesting that modulating gut and oral microbiota could represent a novel therapeutic strategy for reducing neuroinflammation and slowing disease progression. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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47 pages, 1658 KiB  
Review
Inflammaging and Brain Aging
by Maria Carolina Jurcau, Anamaria Jurcau, Alexander Cristian, Vlad Octavian Hogea, Razvan Gabriel Diaconu and Vharoon Sharma Nunkoo
Int. J. Mol. Sci. 2024, 25(19), 10535; https://doi.org/10.3390/ijms251910535 - 30 Sep 2024
Cited by 1 | Viewed by 1712
Abstract
Progress made by the medical community in increasing lifespans comes with the costs of increasing the incidence and prevalence of age-related diseases, neurodegenerative ones included. Aging is associated with a series of morphological changes at the tissue and cellular levels in the brain, [...] Read more.
Progress made by the medical community in increasing lifespans comes with the costs of increasing the incidence and prevalence of age-related diseases, neurodegenerative ones included. Aging is associated with a series of morphological changes at the tissue and cellular levels in the brain, as well as impairments in signaling pathways and gene transcription, which lead to synaptic dysfunction and cognitive decline. Although we are not able to pinpoint the exact differences between healthy aging and neurodegeneration, research increasingly highlights the involvement of neuroinflammation and chronic systemic inflammation (inflammaging) in the development of age-associated impairments via a series of pathogenic cascades, triggered by dysfunctions of the circadian clock, gut dysbiosis, immunosenescence, or impaired cholinergic signaling. In addition, gender differences in the susceptibility and course of neurodegeneration that appear to be mediated by glial cells emphasize the need for future research in this area and an individualized therapeutic approach. Although rejuvenation research is still in its very early infancy, accumulated knowledge on the various signaling pathways involved in promoting cellular senescence opens the perspective of interfering with these pathways and preventing or delaying senescence. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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26 pages, 3741 KiB  
Review
Emerging Roles of Bile Acids and TGR5 in the Central Nervous System: Molecular Functions and Therapeutic Implications
by Lorenzo Romero-Ramírez and Jörg Mey
Int. J. Mol. Sci. 2024, 25(17), 9279; https://doi.org/10.3390/ijms25179279 - 27 Aug 2024
Viewed by 1467
Abstract
Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other [...] Read more.
Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other tissues through the bloodstream. The presence of BAs in the central nervous system (CNS) has been related to their capacity to cross the blood–brain barrier (BBB) from the systemic circulation. However, the expression of enzymes and receptors involved in their synthesis and signaling, respectively, support the hypothesis that there is an endogenous source of BAs with a specific function in the CNS. Over the last decades, BAs have been tested as treatments for many CNS pathologies, with beneficial effects. Although they were initially reported as neuroprotective substances, they are also known to reduce inflammatory processes. Most of these effects have been related to the activation of the Takeda G protein-coupled receptor 5 (TGR5). This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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17 pages, 1615 KiB  
Review
Neuroinflammation and Epilepsy: From Pathophysiology to Therapies Based on Repurposing Drugs
by Pascual Sanz, Teresa Rubio and Maria Adelaida Garcia-Gimeno
Int. J. Mol. Sci. 2024, 25(8), 4161; https://doi.org/10.3390/ijms25084161 - 9 Apr 2024
Cited by 3 | Viewed by 2187
Abstract
Neuroinflammation and epilepsy are different pathologies, but, in some cases, they are so closely related that the activation of one of the pathologies leads to the development of the other. In this work, we discuss the three main cell types involved in neuroinflammation, [...] Read more.
Neuroinflammation and epilepsy are different pathologies, but, in some cases, they are so closely related that the activation of one of the pathologies leads to the development of the other. In this work, we discuss the three main cell types involved in neuroinflammation, namely (i) reactive astrocytes, (ii) activated microglia, and infiltration of (iii) peripheral immune cells in the central nervous system. Then, we discuss how neuroinflammation and epilepsy are interconnected and describe the use of different repurposing drugs with anti-inflammatory properties that have been shown to have a beneficial effect in different epilepsy models. This review reinforces the idea that compounds designed to alleviate seizures need to target not only the neuroinflammation caused by reactive astrocytes and microglia but also the interaction of these cells with infiltrated peripheral immune cells. Full article
(This article belongs to the Special Issue Neuroinflammation: Advancements in Pathophysiology and Therapies)
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