International Journal of Molecular Sciences

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5 pages, 218 KiB

Open AccessEditorial

Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders

by Ali Gorji

Int. J. Mol. Sci. 2022, 23(10), 5744; https://doi.org/10.3390/ijms23105744 - 20 May 2022

Cited by 13 | Viewed by 1746

Abstract

Neuroinflammation is implicated in the pathophysiology of several neurological diseases [...] Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

Research

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15 pages, 5061 KiB

Open AccessArticle

Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity

by Mercedeh Farhat Sabet, Sumanta Barman, Mathias Beller, Sven G. Meuth, Nico Melzer, Orhan Aktas, Norbert Goebels and Tim Prozorovski

Int. J. Mol. Sci. 2023, 24(1), 248; https://doi.org/10.3390/ijms24010248 - 23 Dec 2022

Viewed by 2430

Abstract

Anti-NMDA receptor (NMDAR) encephalitis is frequently associated with demyelinating disorders (e.g., multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD)) with regard to clinical presentation, neuropathological and cerebrospinal fluid findings. Indeed, autoantibodies (AABs) against the GluN1 (NR1) subunit of [...] Read more.

Anti-NMDA receptor (NMDAR) encephalitis is frequently associated with demyelinating disorders (e.g., multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD)) with regard to clinical presentation, neuropathological and cerebrospinal fluid findings. Indeed, autoantibodies (AABs) against the GluN1 (NR1) subunit of the NMDAR diminish glutamatergic transmission in both neurons and oligodendrocytes, leading to a state of NMDAR hypofunction. Considering the vital role of oligodendroglial NMDAR signaling in neuron-glia communication and, in particular, in tightly regulated trophic support to neurons, the influence of GluN1 targeting on the physiology of myelinated axon may be of importance. We applied a myelinating spinal cord cell culture model that contains all major CNS cell types, to evaluate the effects of a patient-derived GluN1-specific monoclonal antibody (SSM5) on neuronal and myelin integrity. A non-brain reactive (12D7) antibody was used as the corresponding isotype control. We show that in cultures at the late stage of myelination, prolonged treatment with SSM5, but not 12D7, leads to neuronal damage. This is characterized by neurite blebbing and fragmentation, and a reduction in the number of myelinated axons. However, this significant toxic effect of SSM5 was not observed in earlier cultures at the beginning of myelination. Anti-GluN1 AABs induce neurodegenerative changes and associated myelin loss in myelinated spinal cord cultures. These findings may point to the higher vulnerability of myelinated neurons towards interference in glutamatergic communication, and may refer to the disturbance of the NMDAR-mediated oligodendrocyte metabolic supply. Our work contributes to the understanding of the emerging association of NMDAR encephalitis with demyelinating disorders. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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Review

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20 pages, 2918 KiB

Open AccessReview

Cortical Spreading Depolarization and Delayed Cerebral Ischemia; Rethinking Secondary Neurological Injury in Subarachnoid Hemorrhage

by Ashir Mehra, Francisco Gomez, Holly Bischof, Daniel Diedrich and Krzysztof Laudanski

Int. J. Mol. Sci. 2023, 24(12), 9883; https://doi.org/10.3390/ijms24129883 - 08 Jun 2023

Viewed by 2038

Abstract

Poor outcomes in Subarachnoid Hemorrhage (SAH) are in part due to a unique form of secondary neurological injury known as Delayed Cerebral Ischemia (DCI). DCI is characterized by new neurological insults that continue to occur beyond 72 h after the onset of the [...] Read more.

Poor outcomes in Subarachnoid Hemorrhage (SAH) are in part due to a unique form of secondary neurological injury known as Delayed Cerebral Ischemia (DCI). DCI is characterized by new neurological insults that continue to occur beyond 72 h after the onset of the hemorrhage. Historically, it was thought to be a consequence of hypoperfusion in the setting of vasospasm. However, DCI was found to occur even in the absence of radiographic evidence of vasospasm. More recent evidence indicates that catastrophic ionic disruptions known as Cortical Spreading Depolarizations (CSD) may be the culprits of DCI. CSDs occur in otherwise healthy brain tissue even without demonstrable vasospasm. Furthermore, CSDs often trigger a complex interplay of neuroinflammation, microthrombi formation, and vasoconstriction. CSDs may therefore represent measurable and modifiable prognostic factors in the prevention and treatment of DCI. Although Ketamine and Nimodipine have shown promise in the treatment and prevention of CSDs in SAH, further research is needed to determine the therapeutic potential of these as well as other agents. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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16 pages, 1557 KiB

Open AccessReview

The Role of BDNF in Multiple Sclerosis Neuroinflammation

by Viviana Nociti and Marina Romozzi

Int. J. Mol. Sci. 2023, 24(9), 8447; https://doi.org/10.3390/ijms24098447 - 08 May 2023

Cited by 10 | Viewed by 2987

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism [...] Read more.

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism for the neuroprotective effect in MS involves the release of brain-derived neurotrophic factor (BDNF) by immune cells in peripheral blood and inflammatory lesions, as well as by microglia and astrocytes within the CNS. BDNF is a neurotrophic factor that plays a key role in neuroplasticity and neuronal survival. This review aims to analyze the current understanding of the role that inflammation plays in MS, including the factors that contribute to both beneficial and detrimental effects. Additionally, it explores the potential role of BDNF in MS, as it may modulate neuroinflammation and provide neuroprotection. By obtaining a deeper understanding of the intricate relationship between inflammation and BDNF, new therapeutic strategies for MS may be developed. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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18 pages, 1711 KiB

Open AccessReview

Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers

by Oscar-Danilo Ortega-Hernandez, Eva M. Martínez-Cáceres, Silvia Presas-Rodríguez and Cristina Ramo-Tello

Int. J. Mol. Sci. 2023, 24(8), 7407; https://doi.org/10.3390/ijms24087407 - 17 Apr 2023

Cited by 3 | Viewed by 2775

Abstract

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS [...] Read more.

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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18 pages, 1162 KiB

Open AccessReview

Relationship between Hypoxic and Immune Pathways Activation in the Progression of Neuroinflammation: Role of HIF-1α and Th17 Cells

by Consuelo Arias, Paulina Sepúlveda, Rodrigo L. Castillo and Luis A. Salazar

Int. J. Mol. Sci. 2023, 24(4), 3073; https://doi.org/10.3390/ijms24043073 - 04 Feb 2023

Cited by 7 | Viewed by 2407

Abstract

Neuroinflammation is a common event in degenerative diseases of the central and peripheral nervous system, triggered by alterations in the immune system or inflammatory cascade. The pathophysiology of these disorders is multifactorial, whereby the therapy available has low clinical efficacy. This review propounds [...] Read more.

Neuroinflammation is a common event in degenerative diseases of the central and peripheral nervous system, triggered by alterations in the immune system or inflammatory cascade. The pathophysiology of these disorders is multifactorial, whereby the therapy available has low clinical efficacy. This review propounds the relationship between the deregulation of T helper cells and hypoxia, mainly Th17 and HIF-1α molecular pathways, events that are involved in the occurrence of the neuroinflammation. The clinical expression of neuroinflammation is included in prevalent pathologies such as multiple sclerosis, Guillain–Barré syndrome, and Alzheimer’s disease, among others. In addition, therapeutic targets are analyzed in relation to the pathways that induced neuroinflammation. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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22 pages, 1733 KiB

Open AccessReview

Chemokine Dysregulation and Neuroinflammation in Schizophrenia: A Systematic Review

by Evgeny A. Ermakov, Irina A. Mednova, Anastasiia S. Boiko, Valentina N. Buneva and Svetlana A. Ivanova

Int. J. Mol. Sci. 2023, 24(3), 2215; https://doi.org/10.3390/ijms24032215 - 22 Jan 2023

Cited by 19 | Viewed by 2740

Abstract

Chemokines are known to be immunoregulatory proteins involved not only in lymphocyte chemotaxis to the site of inflammation, but also in neuromodulation, neurogenesis, and neurotransmission. Multiple lines of evidence suggest a peripheral proinflammatory state and neuroinflammation in at least a third of patients [...] Read more.

Chemokines are known to be immunoregulatory proteins involved not only in lymphocyte chemotaxis to the site of inflammation, but also in neuromodulation, neurogenesis, and neurotransmission. Multiple lines of evidence suggest a peripheral proinflammatory state and neuroinflammation in at least a third of patients with schizophrenia. Therefore, chemokines can be active players in these processes. In this systematic review, we analyzed the available data on chemokine dysregulation in schizophrenia and the association of chemokines with neuroinflammation. It has been shown that there is a genetic association of chemokine and chemokine receptor gene polymorphisms in schizophrenia. Besides, the most reliable data confirmed by the results of meta-analyses showed an increase in CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1β, CCL11/eotaxin-1 in the blood of patients with schizophrenia. An increase in CXCL8 has been found in cerebrospinal fluid, but other chemokines have been less well studied. Increased/decreased expression of genes of chemokine and their receptors have been found in different areas of the brain and peripheral immune cells. The peripheral proinflammatory state may influence the expression of chemokines since their expression is regulated by pro- and anti-inflammatory cytokines. Mouse models have shown an association of schizophrenia with dysregulation of the CX3CL1-CX3CR1 and CXCL12-CXCR4 axes. Altogether, dysregulation in chemokine expression may contribute to neuroinflammation in schizophrenia. In conclusion, this evidence indicates the involvement of chemokines in the neurobiological processes associated with schizophrenia. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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17 pages, 1865 KiB

Open AccessReview

CD40–CD40L in Neurological Disease

by Heather D. Ots, Jovanna A. Tracz, Katherine E. Vinokuroff and Alberto E. Musto

Int. J. Mol. Sci. 2022, 23(8), 4115; https://doi.org/10.3390/ijms23084115 - 08 Apr 2022

Cited by 20 | Viewed by 4839

Abstract

Immune-inflammatory conditions in the central nervous system (CNS) rely on molecular and cellular interactions which are homeostatically maintained to protect neural tissue from harm. The CD40–CD40L interaction upregulates key proinflammatory molecules, a function best understood in the context of infection, during which B-cells [...] Read more.

Immune-inflammatory conditions in the central nervous system (CNS) rely on molecular and cellular interactions which are homeostatically maintained to protect neural tissue from harm. The CD40–CD40L interaction upregulates key proinflammatory molecules, a function best understood in the context of infection, during which B-cells are activated via CD40 signaling to produce antibodies. However, the role of CD40 in neurological disease of non-infectious etiology is unclear. We review the role of CD40–CD40L in traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis, ALS, myasthenia gravis and brain tumors. We also highlight therapeutic advancements targeting the CD40 system to either attenuate the neuroinflammatory response or leverage the downstream effects of CD40 signaling for direct tumor cell lysis. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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Other

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6 pages, 534 KiB

Open AccessCase Report

AQP4-MOG Double-Positive Neuromyelitis Optica Spectrum Disorder: Case Report with Central and Peripheral Nervous System Involvement and Review of Literature

by Antonio Luca Spiezia, Antonio Carotenuto, Aniello Iovino, Marcello Moccia, Matteo Gastaldi, Rosa Iodice, Enrico Tedeschi, Maria Petracca, Luigi Lavorgna, Alessandro d’Ambrosio, Vincenzo Brescia Morra and Roberta Lanzillo

Int. J. Mol. Sci. 2022, 23(23), 14559; https://doi.org/10.3390/ijms232314559 - 23 Nov 2022

Cited by 7 | Viewed by 3194

Abstract

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder [...] Read more.

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

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