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Neuroinflammation: From Molecular Mechanisms to Therapeutic Perspectives

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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: closed (30 July 2022) | Viewed by 14672

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Special Issue Editor

Dr. Marta Llansola

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Guest Editor

Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, 46012 Valencia, Spain
Interests: hepatic encephalopathy; neuroinflammation; cognitive impairment; cerebellum; hippocampus; motor coordination; cytokines; glutamate receptors; GABA transporters; microbiota metabolits

Special Issue Information

Dear Colleagues,

Diseases that involve the nervous system and different neuropsychiatric syndromes, including those simply associated with aging, are currently one of the great concerns in global health. There is no doubt that neuroinflammation is involved to a greater or lesser degree in most brain diseases, whether chronic, neurodegenerative, or involving acute brain damage, for a multitude of different causes. This means that knowing the different mechanisms involved in the appearance of neuroinflammation would be very useful to understand the mechanisms of the different alterations in brain function. Once the mechanisms are known in detail, a wide field of possible therapeutic targets will be opened, based on neuroinflammation processes, which undoubtedly must be developed to establish therapeutic strategies that can prevent or improve a multitude of brain diseases and symptoms, such as cognitive impairment (from mild to more severe), memory loss, motor impairment, mood, and even coma and death. This is necessary today in order to improve general health, given the high incidence of mental illnesses that affect the quality of life of many people, either due to illness or simply associated with aging.

The relationship between neuroinflammation and alterations in neurotransmission are still unknown, and it would be very important to advance the knowledge of these mechanisms in order to expand the therapeutic possibilities, since altered neurotransmission is the main basis of alterations in brain function, and therefore the cause of different neurological disorders.

The objective of this Special Issue is to update the knowledge about the mechanisms of neuroinflammation in different circumstances and the therapeutic implications that it entails—not only based on the mechanisms that lead to neuroinflammation, but also on how it interferes with brain mechanisms (mainly neurotransmission) to alter brain function.

Prof. Dr. Marta Llansola
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
Neurotransmission
Neurological disorders
Molecular mechanisms
Glia
Cytokines
Chemokines
Neurotransmitter receptors
Signal transduction
Therapeutic targets

Published Papers (5 papers)

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Research

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13 pages, 3776 KiB

Open AccessArticle

Necroptosis Contributes to LPS-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in a Piglet Model

by Bei Zhou, Qilong Xu, Junjie Guo, Qinliang Chen, Qingqing Lv, Kan Xiao, Huiling Zhu, Jiangchao Zhao and Yulan Liu

Int. J. Mol. Sci. 2022, 23(19), 11218; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911218 - 23 Sep 2022

Cited by 2 | Viewed by 1660

Abstract

Stressors cause activation of the hypothalamic-pituitary-adrenal (HPA) axis and a systemic inflammatory response. As a newly proposed cell death manner in recent years, necroptosis occurs in a variety of tissue damage and inflammation. However, the role of necroptosis in HPA axis activation remains to be elucidated. The aim of this study was to investigate the occurrence of necroptosis and its role in HPA activation in a porcine stress model induced by Escherichia coli lipopolysaccharide (LPS). Several typical stress behaviors like fever, anorexia, shivering and vomiting were observed in piglets after LPS injection. HPA axis was activated as shown by increased plasma cortisol concentration and mRNA expression of pituitary corticotropin-releasing hormone receptor 1 (CRHR1) and adrenal steroidogenic acute regulatory protein (StAR). The mRNA expression of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the hypothalamus, pituitary gland and adrenal gland was elevated by LPS, accompanied by the activation of necroptosis indicated by higher mRNA expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL). Furthermore, necrostatin-1 (Nec-1), an inhibitor of necroptosis, inhibited necroptosis indicated by decreased mRNA levels of RIP1, RIP3, MLKL, and phosphoglycerate mutase family member 5 (PGAM5) in the hypothalamus, pituitary gland and adrenal gland. Nec-1 also decreased the mRNA expression of TNF-α and IL-β and inhibited the activation of the HPA axis indicated by lower plasma cortisol concentration and mRNA expression of adrenal type 2 melanocortin receptor (MC2R) and StAR. These findings suggest that necroptosis is present and contributes to HPA axis activation induced by LPS. These findings provide a potential possibility for necroptosis as an intervention target for alleviating HPA axis activation and stress responses. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Mechanisms to Therapeutic Perspectives)

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18 pages, 6455 KiB

Open AccessArticle

CCL18 Expression Is Higher in a Glioblastoma Multiforme Tumor than in the Peritumoral Area and Causes the Migration of Tumor Cells Sensitized by Hypoxia

by Szymon Grochans, Jan Korbecki, Donata Simińska, Wojciech Żwierełło, Sylwia Rzeszotek, Agnieszka Kolasa, Klaudyna Kojder, Maciej Tarnowski, Dariusz Chlubek and Irena Baranowska-Bosiacka

Int. J. Mol. Sci. 2022, 23(15), 8536; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158536 - 01 Aug 2022

Cited by 3 | Viewed by 2159

Abstract

Glioblastoma multiforme (GBM) is a brain tumor with a very poor prognosis. For this reason, researchers worldwide study the impact of the tumor microenvironment in GBM, such as the effect of chemokines. In the present study, we focus on the role of the chemokine CCL18 and its receptors in the GBM tumor. We measured the expression of CCL18, CCR8 and PITPNM3 in the GMB tumor from patients (16 men and 12 women) using quantitative real-time polymerase chain reaction. To investigate the effect of CCL18 on the proliferation and migration of GBM cells, experiments were performed using U-87 MG cells. The results showed that CCL18 expression was higher in the GBM tumor than in the peritumoral area. The women had a decreased expression of PITPNM3 receptor in the GBM tumor, while in the men a lower expression of CCR8 was observed. The hypoxia-mimetic agent, cobalt chloride (CoCl₂), increased the expression of CCL18 and PITPNM3 and thereby sensitized U-87 MG cells to CCL18, which did not affect the proliferation of U-87 MG cells but increased the migration of the test cells. The results indicate that GBM cells migrate from hypoxic areas, which may be important in understanding the mechanisms of tumorigenesis. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Mechanisms to Therapeutic Perspectives)

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18 pages, 4016 KiB

Open AccessArticle

The Dual Role of the GABA_A Receptor in Peripheral Inflammation and Neuroinflammation: A Study in Hyperammonemic Rats

by Michele Malaguarnera, Tiziano Balzano, Mari Carmen Castro, Marta Llansola and Vicente Felipo

Int. J. Mol. Sci. 2021, 22(13), 6772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136772 - 24 Jun 2021

Cited by 16 | Viewed by 2143

Abstract

Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABA_A receptors can modulate cerebellar neuroinflammation. The GABA_A antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1β and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABA_A receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABA_A receptors could be a suitable target for improving neuroinflammation in MHE. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Mechanisms to Therapeutic Perspectives)

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21 pages, 4023 KiB

Open AccessArticle

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis

by Jacqueline V. Lara-Espinosa, María Fernanda Arce-Aceves, Dulce Mata-Espinosa, Jorge Barrios-Payán, Brenda Marquina-Castillo and Rogelio Hernández-Pando

Int. J. Mol. Sci. 2021, 22(11), 5997; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115997 - 01 Jun 2021

Cited by 3 | Viewed by 2734

Abstract

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone’s (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Mechanisms to Therapeutic Perspectives)

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Review

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18 pages, 881 KiB

Open AccessReview

The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer’s Disease

by Benita Wiatrak, Katarzyna Balon, Paulina Jawień, Dominika Bednarz, Izabela Jęśkowiak and Adam Szeląg

Int. J. Mol. Sci. 2022, 23(9), 4862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094862 - 27 Apr 2022

Cited by 24 | Viewed by 5086

Abstract

Along with the increase in life expectancy in the populations of developed and developing countries resulting from better access and improved health care, the number of patients with dementia, including Alzheimer’s disease (AD), is growing. The disease was first diagnosed and described at the beginning of the 20th century. However, to this day, there is no effective causal therapy, and symptomatic treatment often improves patients’ quality of life only for a short time. The current pharmacological therapies are based mainly on the oldest hypotheses of the disease—cholinergic (drugs affecting the cholinergic system are available), the hypothesis of amyloid-β aggregation (an anti-amyloid drug was conditionally approved by the FDA in 2020), and one drug is an N-methyl-D-aspartate receptor (NMDAR) antagonist (memantine). Hypotheses about AD pathogenesis focus on the nervous system and the brain. As research progresses, it has become known that AD can be caused by diseases that have been experienced over the course of a lifetime, which could also affect other organs. In this review, we focus on the potential association of AD with the digestive system, primarily the gut microbiota. The role of diet quality in preventing and alleviating Alzheimer’s disease is also discussed. The problem of neuroinflammation, which may be the result of microbiota disorders, is also described. An important aspect of the work is the chapter on the treatment strategies for changing the microbiota, potentially protecting against the disease and alleviating its course in the initial stages. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Mechanisms to Therapeutic Perspectives)

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