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Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders

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

Deadline for manuscript submissions: closed (28 May 2021) | Viewed by 42408

Special Issue Editor

Epilepsy Research Center, Neurosurgery Department, Westfälische Wilhelms-Universität Münster, Münster, Germany
Interests: neuroinflammation; epilepsy; spreading depression; stem cells; neuroprotection; brain cancer; biomaterials; brain injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuroinflammation is an essential mechanism in the development and progression of several neurological and psychological diseases. Although neuroinflammation is a natural defense mechanism against versatile pathologic insults within the central nervous system (CNS), immune responses may play a potentially detrimental role by excessive inflammatory reactions. A better understanding of the inflammatory processes that are triggered before or at the time when the damage to the CNS occurs as well as the subsequent cascades of inflammatory reactions could lead to the development of novel treatments. This Special Issue of the International Journal of Molecular Sciences welcomes both original research articles and reviews on our molecular and conceptual understanding of neuroinflammation in disorders of the CNS, including cerebrovascular diseases, multiple sclerosis, brain trauma, epilepsy, various neurodegenerative diseases, brain tumors, different psychological disorders, and migraine. We are particularly interested in articles that focus on the recent advances in targeting neuroinflammation as a novel approach to the treatment of CNS disorders.

Prof. Dr. Ali Gorji
Guest Editor

Manuscript Submission Information

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Keywords

  • cerebrovascular disorders
  • neurotrauma
  • epilepsy
  • multiple sclerosis
  • psychological disorders
  • neurodegenerative disorders
  • brain cancer
  • stem cell therapy
  • imaging brain
  • spinal cord

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Published Papers (10 papers)

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Research

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17 pages, 2119 KiB  
Article
Brainstem and Cortical Spreading Depolarization in a Closed Head Injury Rat Model
by Refat Aboghazleh, Ellen Parker, Lynn T. Yang, Daniela Kaufer, Jens P. Dreier, Alon Friedman and Gerben van Hameren
Int. J. Mol. Sci. 2021, 22(21), 11642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111642 - 28 Oct 2021
Cited by 7 | Viewed by 2727
Abstract
Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not [...] Read more.
Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not been fully elucidated. To investigate the electrophysiological events that immediately follow traumatic brain injury, a weight-drop model of traumatic brain injury was used in rats pre-implanted with epidural and intracerebral electrodes. Electrophysiological (near-direct current) recordings and simultaneous alternating current recordings of brain activity were started within seconds following impact. Cortical spreading depolarization (SD) and SD-induced spreading depression occurred in approximately 50% of mild and severe impacts. SD was recorded within three minutes after injury in either one or both brain hemispheres. Electrographic seizures were rare. While both TBI- and electrically induced SDs resulted in elevated oxidative stress, TBI-exposed brains showed a reduced antioxidant defense. In severe TBI, brainstem SD could be recorded in addition to cortical SD, but this did not lead to the death of the animals. Severe impact, however, led to immediate death in 24% of animals, and was electrocorticographically characterized by non-spreading depression (NSD) of activity followed by terminal SD in both cortex and brainstem. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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31 pages, 5795 KiB  
Article
Behavioral Alterations and Decreased Number of Parvalbumin-Positive Interneurons in Wistar Rats after Maternal Immune Activation by Lipopolysaccharide: Sex Matters
by Iveta Vojtechova, Kristyna Maleninska, Viera Kutna, Ondrej Klovrza, Klara Tuckova, Tomas Petrasek and Ales Stuchlik
Int. J. Mol. Sci. 2021, 22(6), 3274; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063274 - 23 Mar 2021
Cited by 17 | Viewed by 3472
Abstract
Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat [...] Read more.
Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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23 pages, 18364 KiB  
Article
TRAIL Mediates Neuronal Death in AUD: A Link between Neuroinflammation and Neurodegeneration
by Liya Qin, Jian Zou, Alexandra Barnett, Ryan P. Vetreno, Fulton T. Crews and Leon G. Coleman, Jr.
Int. J. Mol. Sci. 2021, 22(5), 2547; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052547 - 04 Mar 2021
Cited by 27 | Viewed by 3284
Abstract
Although the cause of progressive neurodegeneration is often unclear, neuronal death can occur through several mechanisms. In conditions such as Alzheimer’s or alcohol use disorder (AUD), Toll-like receptor (TLR) induction is observed with neurodegeneration. However, links between TLR activation and neurodegeneration are lacking. [...] Read more.
Although the cause of progressive neurodegeneration is often unclear, neuronal death can occur through several mechanisms. In conditions such as Alzheimer’s or alcohol use disorder (AUD), Toll-like receptor (TLR) induction is observed with neurodegeneration. However, links between TLR activation and neurodegeneration are lacking. We report a role of apoptotic neuronal death in AUD through TLR7-mediated induction of death receptor signaling. In postmortem human cortex, a two-fold increase in apoptotic terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in neurons was found in AUD versus controls. This occurred with the increased expression of TLR7 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors. Binge ethanol treatment in C57BL/6 mice increased TLR7 and induced neuronal apoptosis in cortical regions that was blocked by TLR7 antagonism. Mechanistic studies in primary organotypic brain slice culture (OBSC) found that the inhibition of TLR7 and its endogenous ligand let-7b blocked ethanol-induced neuronal cell death. Both IMQ and ethanol induced the expression of TRAIL and its death receptor. In addition, TRAIL-neutralizing monoclonal antibodies blocked both imiquimod (IMQ) and ethanol induced neuronal death. These findings implicate TRAIL as a mediator of neuronal apoptosis downstream of TLR7 activation. TLR7 and neuronal apoptosis are implicated in other neurodegenerative diseases, including Alzheimer’s disease. Therefore, TRAIL may represent a therapeutic target to slow neurodegeneration in multiple diseases. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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12 pages, 9667 KiB  
Communication
Mesencephalic Electrical Stimulation Reduces Neuroinflammation after Photothrombotic Stroke in Rats by Targeting the Cholinergic Anti-Inflammatory Pathway
by Michael K. Schuhmann, Lena Papp, Guido Stoll, Robert Blum, Jens Volkmann and Felix Fluri
Int. J. Mol. Sci. 2021, 22(3), 1254; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031254 - 27 Jan 2021
Cited by 10 | Viewed by 2277
Abstract
Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune [...] Read more.
Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)+ CD4+-cells and α7nAchR+-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT+ CD4+-cells increased after MLR-HFS, whereas the amount of α7nAchR+-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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15 pages, 1848 KiB  
Article
The STING-IFN-β-Dependent Axis Is Markedly Low in Patients with Relapsing-Remitting Multiple Sclerosis
by Lars Masanneck, Susann Eichler, Anna Vogelsang, Melanie Korsen, Heinz Wiendl, Thomas Budde and Sven G. Meuth
Int. J. Mol. Sci. 2020, 21(23), 9249; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239249 - 04 Dec 2020
Cited by 8 | Viewed by 2349
Abstract
Cyclic GMP-AMP-synthase is a sensor of endogenous nucleic acids, which subsequently elicits a stimulator of interferon genes (STING)-dependent type I interferon (IFN) response defending us against viruses and other intracellular pathogens. This pathway can drive pathological inflammation, as documented for type I interferonopathies. [...] Read more.
Cyclic GMP-AMP-synthase is a sensor of endogenous nucleic acids, which subsequently elicits a stimulator of interferon genes (STING)-dependent type I interferon (IFN) response defending us against viruses and other intracellular pathogens. This pathway can drive pathological inflammation, as documented for type I interferonopathies. In contrast, specific STING activation and subsequent IFN-β release have shown beneficial effects on experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Although less severe cases of relapse-remitting MS (RRMS) are treated with IFN-β, there is little information correlating aberrant type I IFN signaling and the pathologic conditions of MS. We hypothesized that there is a link between STING activation and the endogenous production of IFN-β during neuroinflammation. Gene expression analysis in EAE mice showed that Sting level decreased in the peripheral lymphoid tissue, while its level increased within the central nervous system over the course of the disease. Similar patterns could be verified in peripheral immune cells during the acute phases of RRMS in comparison to remitting phases and appropriately matched healthy controls. Our study is the first to provide evidence that the STING/IFN-β-axis is downregulated in RRMS patients, meriting further intensified research to understand its role in the pathophysiology of MS and potential translational applications. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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Review

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13 pages, 944 KiB  
Review
The Role of Microglia in Modulating Neuroinflammation after Spinal Cord Injury
by Sydney Brockie, James Hong and Michael G. Fehlings
Int. J. Mol. Sci. 2021, 22(18), 9706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189706 - 08 Sep 2021
Cited by 46 | Viewed by 5837
Abstract
The pathobiology of traumatic and nontraumatic spinal cord injury (SCI), including degenerative myelopathy, is influenced by neuroinflammation. The neuroinflammatory response is initiated by a multitude of injury signals emanating from necrotic and apoptotic cells at the lesion site, recruiting local and infiltrating immune [...] Read more.
The pathobiology of traumatic and nontraumatic spinal cord injury (SCI), including degenerative myelopathy, is influenced by neuroinflammation. The neuroinflammatory response is initiated by a multitude of injury signals emanating from necrotic and apoptotic cells at the lesion site, recruiting local and infiltrating immune cells that modulate inflammatory cascades to aid in the protection of the lesion site and encourage regenerative processes. While peripheral immune cells are involved, microglia, the resident immune cells of the central nervous system (CNS), are known to play a central role in modulating this response. Microglia are armed with numerous cell surface receptors that interact with neurons, astrocytes, infiltrating monocytes, and endothelial cells to facilitate a dynamic, multi-faceted injury response. While their origin and essential nature are understood, their mechanisms of action and spatial and temporal profiles warrant extensive additional research. In this review, we describe the role of microglia and the cellular network in SCI, discuss tools for their investigation, outline their spatiotemporal profile, and propose translationally-relevant therapeutic targets to modulate neuroinflammation in the setting of SCI. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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20 pages, 854 KiB  
Review
Dysregulation of microRNA and Intracerebral Hemorrhage: Roles in Neuroinflammation
by Hisham Kashif, Dilan Shah and Sangeetha Sukumari-Ramesh
Int. J. Mol. Sci. 2021, 22(15), 8115; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158115 - 29 Jul 2021
Cited by 9 | Viewed by 3114
Abstract
Intracerebral hemorrhage (ICH) is a major public health problem and devastating subtype of stroke with high morbidity and mortality. Notably, there is no effective treatment for ICH. Neuroinflammation, a pathological hallmark of ICH, contributes to both brain injury and repair and hence, it [...] Read more.
Intracerebral hemorrhage (ICH) is a major public health problem and devastating subtype of stroke with high morbidity and mortality. Notably, there is no effective treatment for ICH. Neuroinflammation, a pathological hallmark of ICH, contributes to both brain injury and repair and hence, it is regarded as a potential target for therapeutic intervention. Recent studies document that microRNAs, small non-coding RNA molecules, can regulate inflammatory brain response after ICH and are viable molecular targets to alter brain function. Therefore, there is an escalating interest in studying the role of microRNAs in the pathophysiology of ICH. Herein, we provide, for the first time, an overview of the microRNAs that play roles in ICH-induced neuroinflammation and identify the critical knowledge gap in the field, as it would help design future studies. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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12 pages, 625 KiB  
Review
Towards a Treatment for Neuroinflammation in Epilepsy: Interleukin-1 Receptor Antagonist, Anakinra, as a Potential Treatment in Intractable Epilepsy
by Gaku Yamanaka, Yu Ishida, Kanako Kanou, Shinji Suzuki, Yusuke Watanabe, Tomoko Takamatsu, Shinichiro Morichi, Soken Go, Shingo Oana, Takashi Yamazaki and Hisashi Kawashima
Int. J. Mol. Sci. 2021, 22(12), 6282; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126282 - 11 Jun 2021
Cited by 28 | Viewed by 6969
Abstract
Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized [...] Read more.
Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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21 pages, 817 KiB  
Review
Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders
by Rezan Ashayeri Ahmadabad, Zahra Mirzaasgari, Ali Gorji and Maryam Khaleghi Ghadiri
Int. J. Mol. Sci. 2021, 22(11), 6153; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116153 - 07 Jun 2021
Cited by 21 | Viewed by 5858
Abstract
Toll-like receptors (TLRs), a class of pattern recognition proteins, play an integral role in the modulation of systemic inflammatory responses. Cerebrovascular diseases (CVDs) are a group of pathological conditions that temporarily or permanently affect the brain tissue mostly via the decrease of oxygen [...] Read more.
Toll-like receptors (TLRs), a class of pattern recognition proteins, play an integral role in the modulation of systemic inflammatory responses. Cerebrovascular diseases (CVDs) are a group of pathological conditions that temporarily or permanently affect the brain tissue mostly via the decrease of oxygen and glucose supply. TLRs have a critical role in the activation of inflammatory cascades following hypoxic-ischemic events and subsequently contribute to neuroprotective or detrimental effects of CVD-induced neuroinflammation. The TLR signaling pathway and downstream cascades trigger immune responses via the production and release of various inflammatory mediators. The present review describes the modulatory role of the TLR signaling pathway in the inflammatory responses developed following various CVDs and discusses the potential benefits of the modulation of different TLRs in the improvement of functional outcomes after brain ischemia. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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25 pages, 9813 KiB  
Review
Impact of Stress on Epilepsy: Focus on Neuroinflammation—A Mini Review
by Claudia Espinosa-Garcia, Helena Zeleke and Asheebo Rojas
Int. J. Mol. Sci. 2021, 22(8), 4061; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084061 - 14 Apr 2021
Cited by 18 | Viewed by 5051
Abstract
Epilepsy, one of the most common neurological disorders worldwide, is characterized by recurrent seizures and subsequent brain damage. Despite strong evidence supporting a deleterious impact on seizure occurrence and outcome severity, stress is an overlooked component in people with epilepsy. With regard to [...] Read more.
Epilepsy, one of the most common neurological disorders worldwide, is characterized by recurrent seizures and subsequent brain damage. Despite strong evidence supporting a deleterious impact on seizure occurrence and outcome severity, stress is an overlooked component in people with epilepsy. With regard to stressor duration and timing, acute stress can be protective in epileptogenesis, while chronic stress often promotes seizure occurrence in epilepsy patients. Preclinical research suggests that chronic stress promotes neuroinflammation and leads to a depressive state. Depression is the most common psychiatric comorbidity in people with epilepsy, resulting in a poor quality of life. Here, we summarize studies investigating acute and chronic stress as a seizure trigger and an important factor that worsens epilepsy outcomes and psychiatric comorbidities. Mechanistic insight into the impact of stress on epilepsy may create a window of opportunity for future interventions targeting neuroinflammation-related disorders. Full article
(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders)
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