Inflammatory Response In Central Nervous System Research Articles

Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Advances in the Understanding of the Correlation Between Neuroinflammation and Microglia in Alzheimer's Disease.

Alzheimer's disease (AD) is a fatal neurodegenerative disease with a subtle and progressive onset and is the most common type of dementia. However, its etiology and pathogenesis have not yet been fully elucidated. The common pathological manifestations of AD include extraneuronal β-amyloid deposition (Aβ), intraneuronal tau protein phosphorylation leading to the formation of 'neurofibrillary tangles' (NFTs), neuroinflammation, progressive loss of brain neurons/synapses, and glucose metabolism disorders. Current treatment approaches for AD primarily focus on the 'Aβ cascade hypothesis and abnormal aggregation of hyperphosphorylation of tau proteins', but have shown limited efficacy. Therefore, there is an ongoing need to identify more effective treatment targets for AD. The central nervous system (CNS) inflammatory response plays a key role in the occurrence and development of AD. Neuroinflammation is an immune response activated by glial cells in the CNS that usually occurs in response to stimuli such as nerve injury, infection and toxins or in response to autoimmunity. Neuroinflammation ranks as the third most prominent pathological feature in AD, following Aβ and NFTs. In recent years, the focus on the role of neuroinflammation and microglia in AD has increased due to the advancements in genome-wide association studies (GWAS) and sequencing technology. Furthermore, research has validated the pivotal role of microglia-mediated neuroinflammation in the progression of AD. Therefore, this article reviews the latest research progress on the role of neuroinflammation triggered by microglia in AD in recent years, aiming to provide a new theoretical basis for further exploring the role of neuroinflammation in the process of AD occurrence and development.

Adverse Outcome Phenomena and Toxicity Mechanisms of Micro and Nanoplastics in Human Health

The ubiquitous presence of micro and nanoplastics (MNPs) in the environment has become a pressing global concern, particularly regarding the potential impacts on human health. This review underscores the urgent need for an integrative research framework that bridges the gap between epidemiological observations and toxicological insights. Human exposure to MNPs occurs predominantly through ingestion, inhalation and dermal contact pathways. Epidemiological findings have consistently demonstrated the presence of MNPs in diverse human tissues, signaling a broad exposure and emphasizing the imperative to explore potential health risks. Population surveys have shown that the concentration of MNPs in the feces of people using disposable plastic tableware reaches 24.65 items/g. These results are associated with changes in microbiota composition and metabolite levels relevant to central nervous system disorders, energy metabolism and inflammatory responses. The detectable abundance of MNPs in the nasal mucus of individuals wearing N95 masks was measured to be 10.6 ± 2.3 items/mg. Moreover, population-based studies have linked MNP exposure to adverse health outcomes, suggesting correlation relationships between exposure levels and specific diseases such as inflammatory bowel disease (IBD) and human pulmonary ground-glass nodules (GGN). These associations underscore the necessity for in-depth toxicological investigations to elucidate the toxicity mechanisms of MNPs. Meanwhile, laboratory-based toxicological studies have the potential to reveal causative relationships and various in vitro and in vivo models have been used to explore the mechanisms of the toxicity of MNPs in the gastrointestinal tract, lungs and cardiovascular system. However, early studies failed to reflect on the complexity of the real environment. To foster interdisciplinary collaborations, this paper aims to reconcile the disparities between exposure risks and human health impacts. By critically reviewing recent advancements in understanding the exposure risks of MNPs, epidemiological observations and organ-specific toxicity, this work furnishes a comprehensive perspective on the health implications of MNPs.

Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis

BackgroundGut microbiota plays a critical role in the pathogenesis of depression and are a therapeutic target via maintaining the homeostasis of the host through the gut microbiota–brain axis (GMBA). A co-decoction of Lilii bulbus and Radix Rehmannia Recens (LBRD), in which verbascoside is the key active ingredient, improves brain and gastrointestinal function in patients with depression. However, in depression treatment using verbascoside or LBRD, mechanisms underlying the bidirectional communication between the intestine and brain via the GMBA are still unclear. PurposeThis study aimed to examine the role of verbascoside in alleviating depression via gut-brain bidirectional communication and to study the possible pathways involved in the GMBA. MethodsKey molecules and compounds involved in antidepressant action were identified using HPLC and transcriptomic analyses. The antidepressant effects of LBRD and verbascoside were observed in chronic stress induced depression model by behavioural test, neuronal morphology, and synaptic dendrite ultrastructure, and their neuroprotective function was measured in corticosterone (CORT)-stimulated nerve cell injury model. The causal link between the gut microbiota and the LBRD and verbascoside antidepressant efficacy was evaluate via gut microbiota composition analysis and faecal microbiota transplantation (FMT). ResultsLBRD and Verbascoside administration ameliorated depression-like behaviours and synaptic damage by reversing gut microbiota disturbance and inhibiting inflammatory responses as the result of impaired intestinal permeability or blood-brain barrier leakiness. Furthermore, verbascoside exerted neuroprotective effects against CORT-induced cytotoxicity in an in vitro depression model. FMT therapy indicated that verbascoside treatment attenuated gut inflammation and central nervous system inflammatory responses, as well as eliminated neurotransmitter and brain–gut peptide deficiencies in the prefrontal cortex by modulating the composition of gut microbiota. Lactobacillus, Parabacteroides, Bifidobacterium, and Ruminococcus might play key roles in the antidepressant effects of LBRD via the GMBA. ConclusionThe current study elucidates the multi-component, multi-target, and multi-pathway therapeutic effects of LBRD on depression by remodeling GMBA homeostasis and further verifies the causality between gut microbiota and the antidepressant effects of verbascoside and LBRD.

Th17 cell promotes apoptosis of IL-23R+ neurons in experimental autoimmune encephalomyelitis

Myelin antigen-reactive Th1 and Th17 cells are critical drivers of central nervous system (CNS) autoimmune inflammation. Transcription factors T-bet and RORγt play a crucial role in the differentiation and function of Th1 and Th17 cells, and impart them a pathogenic role in CNS autoimmune inflammation. Mice deficient in these two factors do not develop experimental autoimmune encephalomyelitis (EAE). While T-bet and RORγt are known to regulate the expression of several cell adhesion and migratory molecules in T cells, their role in supporting Th1 and Th17 trafficking to the CNS is not completely understood. More importantly, once Th1 and Th17 cells reach the CNS, how the function of these transcription factors modulates the local inflammatory response during EAE is unclear. In the present study, we showed that myelin oligodendrocyte glycoprotein 35–55 peptide (MOG35–55)-specific Th1 cells deficient in RORγt could cross the blood-brain barrier (BBB) but failed to induce demyelination, apoptosis of neurons, and EAE. Pathogenic Th17 cell-derived cytokines GM-CSF, TNF-α, IL-17A, and IL-21 significantly increased the surface expression of IL-23R on neuronal cells. Furthermore, we showed that, in EAE, neurons in the brain and spinal cord express IL-23R. IL-23-IL-23R signaling in neuronal cells caused phosphorylation of STAT3 (Ser727 and Tyr705) and induced cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1) molecules in an IL-23R-dependent manner and caused apoptosis. Thus, we provided a mechanism showing that T-bet is required to recruit pathogenic Th17 cells to the CNS and RORγt-mediated inflammatory response to drive the apoptosis of IL-23R+ neurons in the CNS and cause EAE. Understanding detailed molecular mechanisms will help to design better strategies to control neuroinflammation and autoimmunity. One Sentence SummaryIL-23-IL-23R signaling promotes apoptosis of CNS neurons.

Aging changes the expression of adenosine receptors, insulin-like growth factor 1 (IGF1), and hypoxia-inducible factor 1α (HIF1α) in hypothalamic astrocyte cultures

The aging process induces neurochemical alterations in different brain regions, including hypothalamus. This pivotal area of the central nervous system (CNS) is crucial for detection and integration of nutritional and hormonal signals from the periphery of the body to maintain metabolic homeostasis. Astrocytes support the CNS homeostasis, energy metabolism, and inflammatory response, as well as increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions and in gliocrine system. In this study, we aimed to investigate the age-dependent mRNA expression of adenosine receptors, the insulin-like growth factor 1 receptor (IGF1R), and the hypoxia-inducible factor 1α (HIF1α), in addition to the levels of IGF1 and HIF1α in hypothalamic astrocyte cultures derived from newborn, adult, and aged rats. Our results revealed age-dependent changes in adenosine receptors, as well as a decrease in IGF1R/IGF1 and HIF1α. Of note, adenosine receptors, IGF1, and HIF1α are affected by inflammatory, redox, and metabolic processes, which can remodel hypothalamic properties, as observed in aging brain, reinforcing the role of hypothalamic astrocytes as targets for understanding the onset and/or progression of age-related diseases.

Biosensors, Recent Advances in Determination of BDNF and NfL.

Key biomarkers such as Brain Derived Neurotrophic Factor (BDNF) and Neurofilament light chain (NfL) play important roles in the development and progression of many neurological diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. In these clinical conditions, the underlying biomarker processes are markedly heterogeneous. In this context, robust biomarker discovery is of critical importance for screening, early detection, and monitoring of neurological diseases. The difficulty of directly identifying biochemical processes in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory response have been identified in various body fluids such as blood, cerebrospinal fluid, and tears. Furthermore, biotechnology and nanotechnology have facilitated the development of biosensor platforms capable of real-time detection of multiple biomarkers in clinically relevant samples. Biosensing technology is approaching maturity and will be deployed in communities, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight clinical and current technological advances in the development of multiplex-based solutions for effective diagnosis and monitoring of neuroinflammatory and neurodegenerative diseases. The trend in the detection if BDNF and NfL.

SARS-CoV2 entry factors are expressed in primary human glioblastoma and recapitulated in cerebral organoid models.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults with a median overall survival of only 14.6months despite aggressive treatment. While immunotherapy has been successful in other cancers, its benefit has been proven elusive in GBM, mainly due to a markedly immunosuppressive tumor microenvironment. SARS-CoV-2 has been associated with the development of a pronounced central nervous system (CNS) inflammatory response when infecting different cells including astrocytes, endothelial cells, and microglia. While SARS-CoV2 entry factors have been described in different tissues, their presence and implication on GBM aggressiveness or microenvironment has not been studied on appropriate preclinical models. We evaluated the presence of crucial SARS-CoV-2 entry factors: ACE2, TMPRSS2, and NRP1 in matched surgically-derived GBM tissue, cells lines, and organoids; as well as in human brain derived specimens using immunohistochemistry, confocal pixel line intensity quantification, and transcriptome analysis. We show that patient derived-GBM tissue and cell cultures express SARS-CoV2 entry factors, being NRP1 the most crucial facilitator of SARS-CoV-2 infection in GBM. Moreover, we demonstrate that, receptor expression remains present in our GBM organoids, making them an adequate model to study the effect of this virus in GBM for the potential development of viral therapies in the future. Our findings suggest that the SARS-CoV-2 virus entry factors are expressed in primary tissues and organoid models and could be potentially utilized to study the susceptibility of GBM to this virus to target or modulate the tumor microenviroment.

Expression of Histone H1 in Rats with Traumatic Brain Injury and the Effect of the NLRP3 Inflammasome Pathway

To explore expression of histone H1 after traumatic brain injury (TBI) and the effect of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome pathway on its expression. Of 24 rats, 15 were randomly divided into a sham and 4 TBI groups, with 3 rats in each group; the remaining 9 rats were randomly divided into sham group, TBI group, and TBI+CY-09 group, with 3 rats in each group. The expression of histone H1 in rat serum was detected by enzyme-linked immunosorbent assay; Western blot was used to detect the expression of target protein in the injured brain tissue of rats. On the 3rd day after TBI, compared with the sham group, the expression of histone H1 was decreased (P < 0.05). After inhibiting the NLRP3 inflammasome pathway with CY-09, expressions of IL-1β, IL-18, and histone H1 in rat-injured brain tissue in the TBI+CY-09 group were decreased compared with the TBI group (P < 0.05). The expression of histone H1 decreased significantly from the 3rd day after TBI. Inhibiting the NLRP3 inflammasome pathway may reduce the expression of histone H1. The expression of histone H1 was affected by the microglia-related central nervous system inflammatory response.

Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy.

NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams-Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain-of-function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP-10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain-of-function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895-901.

Molecular Mechanism of Xingnao Kaiqiao Pill for Perioperative Neurocognitive Disorder and Its Correlation With Immune and Inflammatory Signaling Pathways Based on Network Pharmacology and Molecular Docking.

To investigate the molecular mechanism of Xingnao Kaiqiao Pill in the treatment of perioperative neurocognitive disorder (PND) from the perspective of network pharmacology and molecular docking technology. Active ingredients of Xingnao Kaiqiao Pill were screened from the traditional Chinese medicine database and analysis platform, and the putative targets were predicted. The GeneCards database was searched to obtain PND-related targets. The genes corresponding to the targets were searched and annotated on the UniProt database. The VennDiagram package in R was employed to obtain common target genes. The overlap genes were introduced into STRING to obtain a protein-protein interaction (PPI) network; thus, key targets were screened. The target relationship network of “Xingnao Kaiqiao Pill–traditional Chinese medicine–compound–common target” was constructed by Cytoscape software. Using R language package Bioconductor, Gene Ontology (GO) and pathway enrichment analysis (Kyoto Encyclopedia of Genes and Genomes Pathway, KEGG Pathway) were performed on the common target genes. A total of 45 active ingredients of Xingnao Kaiqiao Pill were screened, with 182 potential targets, and 1,579 PND-related targets were retrieved from the GeneCards databases (Score ≥ 1). Using VennDiagram, 132 overlap genes were gotten. Xingnao Kaiqiao Pill mainly acted on targets, such as MAPK and JUN. GO enrichment analysis displayed G protein-coupled amine receptor activity, nuclear receptor activity, ligand-activated transcription factor activity, G protein-coupled neurotransmitter receptor activity, steroid hormone receptor activity, and cytokine receptor activity. KEGG enrichment analysis exhibited 157 signaling pathways. The regulation of interleukin 17, tumor necrosis factor, hypoxia-inducible factor-1, and MAPK signaling pathways affected central nervous system (CNS) inflammatory response, cellular immunity, tumor-related signaling pathways, protected neurons, and inhibited PND. The active ingredients of Xingnao Kaiqiao Pill adjust interleukin 17, tumor necrosis factor, hypoxia-inducible factor-1, and MAPK signaling pathways by acting on cell targets, such as JUN, MAPK, AKT1, etc., and finally exert a therapeutic effect on PND.

Neuroprotective effects of CysLTR antagonist on Streptococcus pneumoniae-induced meningitis in rats.

Cysteinyl leukotrienes (CysLTs) modulate central nervous system inflammatory responses via their receptors, CysLT1R and CysLT2R. It has been demonstrated that CysLTR participates in the infection process of Streptococcus pneumoniae (SP)-induced meningitis. In the present study, the effects and possible underlying mechanisms of CysLTR antagonists (pranlukast and HAMI 3379) on SP meningitis were further determined. SP meningitis was induced by intracerebroventricular injection of serotype III SP in Sprague-Dawley rats which were administrated intraperitoneally with 0.1 mg/kg antagonists. The clinical disease status of rats was evaluated by body weight and behavioral changes with neurological scoring. Survival neuron density, activated microglial and astrocytes were assessed by Nissl staining and immunohistochemical staining. The expression levels of inflammatory cytokines and NLRP3 inflammasome were detected by reverse transcription-quantitative PCR and western blotting, respectively. Pranlukast and HAMI 3379 treatment markedly alleviated the clinical disease status, which was manifested by improving body weight loss and neurological deficit. Furthermore, pranlukast and HAMI 3379 treatment ameliorated neuronal injury and inhibited microgliosis and astrogliosis. In addition, significant downregulation of inflammatory cytokines and NLRP3 expression was observed in pranlukast and HAMI 3379-treated rats. These in vivo findings indicated the neuroprotective effects of CysLTR antagonists against experimental SP-induced meningitis, and the mechanism of anti-inflammatory effects may partly be by inhibiting NLRP3 inflammasome overactivation.

Inhalation of dimethyl fumarate-encapsulated solid lipid nanoparticles attenuate clinical signs of experimental autoimmune encephalomyelitis and pulmonary inflammatory dysfunction in mice.

The FDA-approved Dimethyl Fumarate (DMF) as an oral drug for Multiple Sclerosis (MS) treatment based on its immunomodulatory activities. However, it also caused severe adverse effects mainly related to the gastrointestinal system. Investigated the potential effects of solid lipid nanoparticles (SLNs) containing DMF, administered by inhalation on the clinical signs, central nervous system (CNS) inflammatory response, and lung function changes in mice with experimental autoimmune encephalomyelitis (EAE). EAE was induced using MOG35-55 peptide in female C57BL/6J mice and the mice were treated via inhalation with DMF-encapsulated SLN (CTRL/SLN/DMF and EAE/SLN/DMF), empty SLN (CTRL/SLN and EAE/SLN), or saline solution (CTRL/saline and EAE/saline), every 72 h during 21 days. After 21 days post-induction, EAE mice treated with DMF-loaded SLN, when compared with EAE/saline and EAE/SLN, showed decreased clinical score and weight loss, reduction in brain and spinal cord injury and inflammation, also related to the increased influx of Foxp3+ cells into the spinal cord and lung tissues. Moreover, our data revealed that EAE mice showed signs of respiratory disease, marked by increased vascular permeability, leukocyte influx, production of TNF-α and IL-17, perivascular and peribronchial inflammation, with pulmonary mechanical dysfunction associated with loss of respiratory volumes and elasticity, which DMF-encapsulated reverted in SLN nebulization. Our study suggests that inhalation of DMF-encapsulated SLN is an effective therapeutic protocol that reduces not only the CNS inflammatory process and disability progression, characteristic of EAE disease, but also protects mice from lung inflammation and pulmonary dysfunction.

A method to isolate and cryopreserve cerebrospinal fluid mononuclear cells from external ventricular drains to investigate immunological processes in acute brain injuries

The inflammatory response to acute brain injuries is a key contributor to subsequent outcome. The study of local central nervous system inflammatory responses is hindered by raised intracranial pressure precluding cerebrospinal fluid sampling by lumbar puncture. External ventricular drains are sited in some acute brain injury patients to divert cerebrospinal fluid and thus reduce intracranial pressure, and represent a potential route to safely gather large volumes of cerebrospinal fluid for immunological studies. In this manuscript we show that mononuclear cells can be isolated from cerebrospinal fluid collected from external ventricular drains, and that the large volumes of cerebrospinal fluid available yield sufficient mononuclear cells to allow cryopreservation. Prolonged storage of cerebrospinal fluid in the external ventricular drain collection bag can alter the phenotype of cells recovered, but the predicted effect of this can be estimated for a given flow cytometry panel by assessing the changes in peripheral blood mononuclear cells exposed to the same conditions. The described method will allow clinical studies of acute brain injuries to investigate the immunological processes occurring within the central nervous system compartment, rather than relying on changes in the peripheral circulation.

Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease.

The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.

Opioid Effects on the Central Nervous System and the Peripheral Immune System: Implications for Opioid Tolerance

Opioids exert differential effects in the central nervous system (CNS) and the peripheral immune system. Both systems may play a role in the development of opioid tolerance. This review provides a brief overview of the opioid effects on the CNS and peripheral immune system and discusses the potential roles of the connections between the two systems in opioid tolerance. Opioids induced pro-inflammatory response of the CNS immune cells through several mechanisms that involve mu-opioid receptor and Toll-like receptor 4. This neuroinflammation leads to enhanced neuron excitability and opioid tolerance and/or hyperalgesia. Opioid-exposed neuronal cells also contributed to CNS stress and inflammatory responses, further resulted in neuroinflammation. On the contrary, most studies have shown that opioids exert immunosuppressive effects in the peripheral immune system. There are, however, some evidence suggested that opioids may induce dose-, time-, and opioid agent-dependent pro-inflammatory responses. Though opioids have the opposite effects in the CNS and the peripheral immune system, newer evidence have suggested that the peripheral immune system plays a significant role in neuroinflammation and opioid tolerance. Opioid effects on the CNS and the peripheral immune system have been studied extensively; however, the integrated effects of opioids on tolerance development are yet to be explored. Further understanding of the integrated/interactive effects of opioids on peripheral immune cells and the CNS is required so that their interactions may be exploited for the identification of new therapeutics and biomarkers.

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

BackgroundMultiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE.MethodsChronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice.ResultsOur results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro.ConclusionsOur work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

Abstract Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, and neuronal damage. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. Presently, growing evidences show that phenolic compounds exert anti-inflammatory effects by inhibiting the production of inflammatory molecules. 4-ethylguaiacol (4-EG), a phenolic compound, which was detected in foods, such as green bell peppers, corns, sesames, and coffee has been shown to possess anti-inflammatory effects through attenuating peripheral immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unexplored. In this study we assessed the therapeutic effect of 4-EG in EAE using both chronical and relapsing-remitting animal models. Our results showed that 4-EG not only ameliorated disease severity in chronic EAE but also mitigated disease progression in relapsing-remitting EAE. Further investigations revealed that 4-EG suppressed MG activation, inhibited Th1 and Th17 infiltration, and mitigated BBB disruption in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE. Finally, 4-EG induced HO-1 expression in the CNS of EAE as well as in MG and macrophages. In summary, our work demonstrates for the first time that 4-EG confers a protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1/Th17 differentiation, suggesting that 4-EG could be developed as a therapeutic agent for the treatment of MS/EAE.

The Potentials of Melatonin in the Prevention and Treatment of Bacterial Meningitis Disease.

Bacterial meningitis (BM) is an acute infectious central nervous system (CNS) disease worldwide, occurring with 50% of the survivors left with a long-term serious sequela. Acute bacterial meningitis is more prevalent in resource-poor than resource-rich areas. The pathogenesis of BM involves complex mechanisms that are related to bacterial survival and multiplication in the bloodstream, increased permeability of blood–brain barrier (BBB), oxidative stress, and excessive inflammatory response in CNS. Considering drug-resistant bacteria increases the difficulty of meningitis treatment and the vaccine also has been limited to several serotypes, and the morbidity rate of BM still is very high. With recent development in neurology, there is promising progress for drug supplements of effectively preventing and treating BM. Several in vivo and in vitro studies have elaborated on understanding the significant mechanism of melatonin on BM. Melatonin is mainly secreted in the pineal gland and can cross the BBB. Melatonin and its metabolite have been reported as effective antioxidants and anti-inflammation, which are potentially useful as prevention and treatment therapy of BM. In bacterial meningitis, melatonin can play multiple protection effects in BM through various mechanisms, including immune response, antibacterial ability, the protection of BBB integrity, free radical scavenging, anti-inflammation, signaling pathways, and gut microbiome. This manuscript summarizes the major neuroprotective mechanisms of melatonin and explores the potential prevention and treatment approaches aimed at reducing morbidity and alleviating nerve injury of BM.

Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is marked by cardio-respiratory alterations, with increasing reports also indicating neurological and psychiatric symptoms in infected individuals. During COVID-19 pathology, the central nervous system (CNS) is possibly affected by direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion, exaggerated systemic inflammatory responses, or hypoxia. Psychosocial stress imposed by the pandemic further affects the CNS of COVID-19 patients, but also the non-infected population, potentially contributing to the emergence or exacerbation of various neurological or mental health disorders. Microglia are central players of the CNS homeostasis maintenance and inflammatory response that exert their crucial functions in coordination with other CNS cells. During homeostatic challenges to the brain parenchyma, microglia modify their density, morphology, and molecular signature, resulting in the adjustment of their functions. In this review, we discuss how microglia may be involved in the neuroprotective and neurotoxic responses against CNS insults deriving from COVID-19. We examine how these responses may explain, at least partially, the neurological and psychiatric manifestations reported in COVID-19 patients and the general population. Furthermore, we consider how microglia might contribute to increased CNS vulnerability in certain groups, such as aged individuals and people with pre-existing conditions.