Pathogenesis Of Central Nervous System Diseases Research Articles

The Role of Adipokines in the Pathologies of the Central Nervous System.

Adipokines are protein hormones secreted by adipose tissue in response to disruptions in physiological homeostasis within the body's systems. The regulatory functions of adipokines within the central nervous system (CNS) are multifaceted and intricate, and they have been identified in a number of pathologies. Therefore, specific adipokines have the potential to be used as biomarkers for screening purposes in neurological dysfunctions. The systematic review presented herein focuses on the analysis of the functions of various adipokines in the pathogenesis of CNS diseases. Thirteen proteins were selected for analysis through scientific databases. It was found that these proteins can be identified within the cerebrospinal fluid either by their ability to modify their molecular complex and cross the blood-brain barrier or by being endogenously produced within the CNS itself. As a result, this can correlate with their measurability during pathological processes, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, or brain tumors.

The Role of SliTrk5 in Central Nervous System.

SLIT and NTRK-like protein-5 (SliTrk5) is one of the six members of SliTrk protein family, which is widely expressed in the central nervous system (CNS), regulating and participating in many essential steps of central nervous system development, including axon and dendritic growth, neuron differentiation, and synaptogenesis. SliTrk5, as a neuron transmembrane protein, contains two important conservative domains consisting of leucine repeats (LRRs) located at the amino terminal in the extracellular region and tyrosine residues (Tyr) located at the carboxyl terminal in the intracellular domains. These special structures make SliTrk5 play an important role in the pathological process of the CNS. A large number of studies have shown that SliTrk5 may be involved in the pathogenesis of CNS diseases, such as obsessive-compulsive-disorder (OCD), attention deficit/hyperactivity disorder (ADHD), glioma, autism spectrum disorders (ASDs), and Parkinson's disease (PD). Targeting SliTrk5 is expected to become a new target for the treatment of CNS diseases, promoting the functional recovery of CNS. The purpose of this article is to review the current research progression of the role of SliTrk5 in CNS and its potential mechanisms in CNS diseases.

Relationship between thyroid hormones and central nervous system metabolism in physiological and pathological conditions.

Thyroid hormones (THs) play an important role in the regulation of energy metabolism. They also take part in processes associated with the central nervous system (CNS), including survival and differentiation of neurons and energy expenditure. It has been reported that a correlation exists between the functioning of the thyroid gland and the symptoms of CNS such as cognitive impairment, depression, and dementia. Literature data also indicate the influence of THs on the pathogenesis of CNS diseases, such as Alzheimer's disease, epilepsy, depression, and Parkinson's disease. This review describes the relationship between THs and metabolism in the CNS, the effect of THs on the pathological conditions of the CNS, and novel options for treating these conditions with TH derivatives.

The Role of Brain-Derived Neurotrophic Factor Signaling in Central Nervous System Disease Pathogenesis.

Recent studies have found abnormal levels of brain-derived neurotrophic factor (BDNF) in a variety of central nervous system (CNS) diseases (e.g., stroke, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease). This suggests that BDNF may be involved in the pathogenesis of these diseases. Moreover, regulating BDNF signaling may represent a potential treatment for such diseases. With reference to recent research papers in related fields, this article reviews the production and regulation of BDNF in CNS and the role of BDNF signaling disorders in these diseases. A brief introduction of the clinical application status of BDNF is also provided.

Alpha-synuclein as a biomarker in Parkinson's disease: focus on neural derived extracelluar vesicles.

Alpha-synuclein as a biomarker in Parkinson's disease: focus on neural derived extracelluar vesicles.

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.

Studies of involvement of G-protein coupled receptor-3 in cannabidiol effects on inflammatory responses of mouse primary astrocytes and microglia.

Cannabidiol (CBD) exhibits anti-inflammatory and neuroprotective properties and is suggested to be effective in the pre-clinical and clinical treatment of illnesses of the central nervous system (CNS). Two major types of CNS glial cells, astrocytes and microglia, play critical roles in the development and pathogenesis of CNS diseases. However, the mechanisms by which CBD plays an anti-inflammatory and neuroprotective role for these glial cells have not been fully elucidated. In this study, we examined the effects of CBD on the inflammatory response of mouse primary astrocytes and microglia. We also investigated whether the effect of CBD on cytokine release is mediated by the G protein coupled receptor 3 (GPR3), which was recently identified as a novel receptor for CBD. Our results showed that CBD inhibited inflammatory responses of astrocytes and microglia stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand in vitro and in vivo. In addition, CBD reduced the phosphorylation of STAT3 and NF-κB signaling pathways in LPS-stimulated astrocytes. However, the inhibitory effect of CBD on pro-inflammatory cytokine production was independent of GPR3 expression in both types of glial cells. Thus, although CBD is effective in ameliorating the activation of astrocytes and microglia, its mechanism of action still requires further study. Our data support the concept that CBD may have therapeutic potential for neurological disorders that involve neuroinflammation.

Repulsive Guidance Molecule-a and Central Nervous System Diseases.

Repulsive guidance molecule-a (RGMa) is a member of glycosylphosphatidylinositol- (GPI-) anchored protein family, which has axon guidance function and is widely involved in the development and pathological processes of the central nervous system (CNS). On the one hand, the binding of RGMa and its receptor Neogenin can regulate axonal guidance, differentiation of neural stem cells into neurons, and the survival of these cells; on the other hand, RGMa can inhibit functional recovery of CNS by inhibiting axonal growth. A number of studies have shown that RGMa may be involved in the pathogenesis of CNS diseases, such as multiple sclerosis, neuromyelitis optica spectrum diseases, cerebral infarction, spinal cord injury, Parkinson's disease, and epilepsy. Targeting RGMa can enhance the functional recovery of CNS, so it may become a promising target for the treatment of CNS diseases. This article will comprehensively review the research progression of RGMa in various CNS diseases up to date.

Isolating Central Nervous System Tissues and Associated Meninges for the Downstream Analysis of Immune cells.

The central nervous system (CNS) is comprised of the brain and spinal cord and is enveloped by the meninges, membranous layers serving as a barrier between the periphery and the CNS. The CNS is an immunologically specialized site, and in steady state conditions, immune privilege is most evident in the CNS parenchyma. In contrast, the meninges harbor a diverse array of resident cells, including innate and adaptive immune cells. During inflammatory conditions triggered by CNS injury, autoimmunity, infection, or even neurodegeneration, peripherally derived immune cells may enter the parenchyma and take up residence within the meninges. These cells are thought to perform both beneficial and detrimental actions during CNS disease pathogenesis. Despite this knowledge, the meninges are often overlooked when analyzing the CNS compartment, because conventional CNS tissue extraction methods omit the meningeal layers. This protocol presents two distinct methods for the rapid isolation of murine CNS tissues (i.e., brain, spinal cord, and meninges) that are suitable for downstream analysis via single-cell techniques, immunohistochemistry, and in situ hybridization methods. The described methods provide a comprehensive analysis of CNS tissues, ideal for assessing the phenotype, function, and localization of cells occupying the CNS compartment under homeostatic conditions and during disease pathogenesis.

Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma

Monocytes/macrophages have begun to emerge as key cellular modulators of brain homeostasis and central nervous system (CNS) disease. In the healthy brain, resident microglia are the predominant macrophage cell population; however, under conditions of blood-brain barrier leakage, peripheral monocytes/macrophages can infiltrate the brain and participate in CNS disease pathogenesis. Distinguishing these two populations is often challenging, owing to a paucity of universally accepted and reliable markers. To identify discriminatory marker sets for microglia and peripheral monocytes/macrophages, we employed a large meta-analytic approach using five published murine transcriptional datasets. Following hierarchical clustering, we filtered the top differentially expressed genes (DEGs) through a brain cell type-specific sequencing database, which led to the identification of eight microglia and eight peripheral monocyte/macrophage markers. We then validated their differential expression, leveraging a published single cell RNA sequencing dataset and quantitative RT-PCR using freshly isolated microglia and peripheral monocytes/macrophages from two different mouse strains. We further verified the translation of these DEGs at the protein level. As top microglia DEGs, we identified P2ry12, Tmem119, Slc2a5 and Fcrls, whereas Emilin2, Gda, Hp and Sell emerged as the best DEGs for identifying peripheral monocytes/macrophages. Lastly, we evaluated their utility in discriminating monocyte/macrophage populations in the setting of brain pathology (glioma), and found that these DEG sets distinguished glioma-associated microglia from macrophages in both RCAS and GL261 mouse models of glioblastoma. Taken together, this unbiased bioinformatic approach facilitated the discovery of a robust set of microglia and peripheral monocyte/macrophage expression markers to discriminate these monocyte populations in both health and disease.

Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities

Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain's IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.

CB2R induces a protective response for epileptic seizure via the PI3K 110α-AKT signaling pathway.

Epilepsy is a chronic brain disease caused by abnormal discharging in the brain, which induces momentary brain dysfunction. Cannabinoid 2 receptor (CB2R) is expressed in central nervous system (CNS) and serves an important role in the pathogenesis of CNS diseases. The aim of the present study was to explore the effects of CB2R activation on phosphoinositide 3-kinase (PI3K) 110α-protein kinase B (AKT) signaling in an astrocyte model of epilepsy. Rat CTX TNA2 astrocytes were treated with Mg free solution to establish a cell model of epilepsy and were subsequently treated with a CB2R agonist (JWH133) and antagonist (AM630). Cell cycle analysis revealed that treatment using Mg free solution inhibited cell cycle transition. JWH133 facilitated cell cycle progression while AM630 inhibited it. Western blotting results demonstrated that treatment with Mg free solution downregulated the expression of cyclin D1, cyclin E, phosphorylated Retinoblastoma (p-Rb), B-cell lymphoma 2 (Bcl-2), PI3K 110α, p-AKT and p-mammalian target of rapamycin, whereas JWH133 treatment upregulated these proteins. AM630 ameliorated the JWH133-induced upregulation of these proteins. To confirm the involvement of AKT signaling, the AKT inhibitor wortmannin was used. The results revealed that wortmannin inhibited the effect of JWH133 on p-AKT, cyclin D1, p-Rb and Bcl-2 expression. In addition, the effects of JWH133 and AM630 on PI3K 110α-AKT signaling were verified using a rat model of epilepsy. In conclusion, the present study demonstrates that CB2R activation induces astrocyte proliferation and survival via activation of the PI3K 110α-AKT signaling pathway.

Effect of animal medicines for "extinguishing wind to arrest convulsions" on central nervous system diseases

The human health is seriously affected by central nervous system(CNS) diseases, but the pathogenesis of CNS diseases is still not completely clear. Currently, the drugs used to treat CNS diseases are mainly receptor modulators and neurotransmitter inhibitors, which have serious side effects; and there are short of drugs for treating CNS diseases clinically. Studies suggest that animal medicines mainly include protein, polypeptide and small-molecule compounds, and have such pharmacological effects in calming, resisting convulsions and improving brain tissues. Plenty of studies suggest that animal medicines usually have a strong activity and good curative effect on these diseases, with a promising prospect in research and development of drugs treating CNS diseases. Based on systematic reviews of literatures, this paper summarizes active ingredients and main pharmacological effects of animal medicines in "extinguishing wind to arrest convulsions" for the CNS diseases, epilepsy and cerebral ischemia, and discusses their study value and application prospects. The results showed that the studies of protein and peptides were relatively simple, and some animal medicines were still blank. The authors believed that amino acids and small molecular compounds should be transferred to oligopeptide, advanced protein extraction and separation techniques shall be adopted for identifying the protein polypeptide composition structure and studying the efficacy, and the methods of biological technology were used to develop peptide biological products for the treatment of CNS diseases. This paper could provide ideas and reference for developing animal medicine products for the treatment of CNS diseases.

Reactive gliosis in the pathogenesis of CNS diseases

Astrocytes maintain the homeostasis of the central nervous system (CNS) by e.g. recycling of neurotransmitters and providing nutrients to neurons. Astrocytes function also as key regulators of synaptic plasticity and adult neurogenesis. Any insult to the CNS tissue triggers a range of molecular, morphological and functional changes of astrocytes jointly called reactive (astro)gliosis. Reactive (astro)gliosis is highly heterogeneous and also context-dependent process that aims at the restoration of homeostasis and limits tissue damage. However, under some circumstances, dysfunctional (astro)gliosis can become detrimental and inhibit adaptive neural plasticity mechanisms needed for functional recovery. Understanding the multifaceted and context-specific functions of astrocytes will contribute to the development of novel therapeutic strategies that, when applied at the right time-point, will improve the outcome of diverse neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

High mobility group box 1 protein in the central nervous system

High-mobility group box 1 protein (HMGB1) is a multifunctional protein originally identified as a nuclear transcription modifier. Two pathways are leading to HMGB1 release to the extracellular space i.e. active secretion triggered by noxious stimulation and passive leakage due to necrotic membrane damage. Binding with receptors for advanced glycation end products (RAGE) as well as Toll-like receptor 2 (TLR2) and TLR4 leads to nuclear factor ?B (NF-?B) activation and proinflammatory reaction in target cells. Secretion of cytokines, upregulation of adhesion molecules and chemoattraction are triggered by the extracellular HMGB1. Such ubiquitous and numerous protein plays a role in pathogenesis of many common diseases like sepsis, rheumatoid arthritis and pneumonia. Central nervous system (CNS) disorders are also mediated by HMGB1. Multiple studies highlight pivotal role of HMGB1 in acute pathologies of CNS like cerebral ischemia, aneurysmal subarachnoid hemorrhage as well as chronic degenerative disorders such as Alzheimer’s disease and multiple sclerosis. Wide range of HMGB1 antagonists are currently investigated as novel therapeutic agents in sepsis, colitis and stroke. This review article provides basic information about HMGB1 protein and its role in the pathogenesis of CNS diseases.

Pericyte function in the physiological central nervous system

Damage to the central nervous system (CNS) leads to disruption of the vascular network, causing vascular dysfunction. Vascular dysfunction is the major event in the pathogenesis of CNS diseases and is closely associated with the severity of neuronal dysfunction. The suppression of vascular dysfunction has been considered a promising avenue to limit damage to the CNS, leading to efforts to clarify the cellular and molecular basis of vascular homeostasis maintenance. A reduction of trophic support and oxygen delivery due to circulatory insufficiency has long been regarded as a major cause of vascular damage. Moreover, recent studies provide a new perspective on the importance of the structural stability of blood vessels in CNS diseases. This updated article discusses emerging information on the key role of vascular integrity in CNS diseases, specially focusing on pericyte function.

P031 Pandemic influenza a H1N1 viruses elicit weak cytokine responses in human astrocytic and neuronal cells

Introduction Seasonal, pandemic and avian influenza H5N1 virus infections may be associated with pathology in the central nervous system (CNS), albeit with varying frequency and by different mechanisms. Studies have demonstrated that highly pathogenic avian influenza H5N1 and pandemic H1N1 viruses could be detected within the CNS. Seasonal influenza is regularly associated with encephalopathy in Japan and the Far East. With the exception of influenza associated encephalopathy in Japan, there has been little attention paid to the pathogenesis of CNS disease associated with influenza. In particular, the neuropathogenicity of these viruses remains largely unknown. We have previously demonstrated that differentiated human astrocytic and neuronal cells could be infected with H5N1 viruses. Productive virus replication and strong innate immune response with release of proinflammatory cytokines were detected in the H5N1-infected human astrocytic cells. Seasonal influenza viruses replicated as well as H5N1 viruses in these two cell types but induced much weaker cytokine responses. Methods Here, we extended the study to investigate cytokine response and virus replication kinetics of human brain cells infected with two pandemic H1N1 influenza A viruses that were isolated from the respiratory tract of a neurological complicated and a mild case of infection respectively. Results We found that the two pandemic H1N1 viruses infected both the human astrocytic and neuronal cells but in contrast with H5N1 and seasonal H1N1 viruses, pandemic H1N1 failed to produce progeny viruses efficiently in either infected astrocytes or neurons. Interestingly, both pandemic H1N1 viruses induced very low expression of proinflammatory cytokines including TNF-alpha, IL-6 and type I interferon, IFN-beta which intensity is much lower compared to that induced by seasonal H1N1 virus. Conclusion Taken together, results here suggest that pandemic H1N1 virus differs from H5N1 and seasonal H1N1 viruses in the ability to produce progeny viruses in infected human astrocytic and neuronal cells. Virus replication kinetics and cytokine expression profile induced by both pandemic H1N1 viruses are similar. In contrast to H5N1 viruses, pandemic H1N1 viruses inhibit the expression of cytokines that might contribute to the pathogenesis of this virus. Viral and host factors related to these differences are now under investigation.

Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases

Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood-brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells.

PPAR Regulation of Inflammatory Signaling in CNS Diseases

Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARα, γ, and δ isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-κB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.

Low Expression of IL-15 in Adult B-Lineage Acute Lymphoblastic Leukemia Is Associated with Central Nervous System Involvement at Initial Presentation.

The biologic mechanisms of the development of central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is unknown. Risk factors associated with CNS involvement include the immunophenotype (e.g. T-ALL), high white blood cell (WBC) count and cytokine expression. Among the latter, interleukin (IL)-15 has shown to enhance the proliferation of both normal and malignant lymphocytes, thus, suggesting its potential role in leukemogenesis. It has been shown that in childhood ALL, CNS involvement is associated with higher IL-15 expression (Cario et al. 2006, Blood 108a:2270). In this study, we analyzed the expression of IL-15 and its alternatively spliced variants in leukemic cells from adult ALL patients with CNS involvement (CNS+) at initial presentation (n=31) and at first relapse (n=8), as well as in patients without CNS involvement at diagnosis (CNS−; n=57). Experiments were performed by real-time RT-PCR and the values were presented ratios comparing IL-15 to expression of the reference gene belta-actin. mRNA expression levels were also correlated with protein expression by western blot analysis. We found that the expression of total IL-15 was significantly lower in ALL patients with CNS+ at initial presentation (n=31, median=0.02, range 0–0.45, P<0.001) and at first relapse (n=8; median=0.03, range 0–0.08, P=0.019), in comparison to ALL patients without CNS (n=57, median=0.08, range 0–0.91). Similarly, lower expression values of IL-15 were found in B-cell precursor (BCP)-ALL (P=0.015) as well as in the subtype of common ALL (p=0.013) with CNS+, as compared to cases without CNS-. In CNS+ ALL, patients with BCR–ABL+–BCP–ALL (n=9) had lower IL-15 expression compared to patients with BCR–ABL–BCP–ALL (n=21, P=0.017). In contrast to CNS– patients, no statistically significant difference was found regarding IL-15 expression between BCR–ABL+- and BCR–ABL–BCP–ALL. Furthermore, the expression of IL-15 was more than 5-fold higher in T–lineage ALL (n=23) than in BCP-ALL (n=72, p<0.001). Among T-lineage-ALLs, CD1+ cortical-T-ALL strongly expressed IL-15 as compared with pre-T or mature T-ALLs. The expression of both spliced variants of long signal peptide (LSP)-IL-15 and short signal peptide (SSP)-IL-15 did not differ between CNS+ and CNS– of all cases. Interestingly, the expression of LSP-IL-15 and SSP-IL-15 is higher in common or pre-B than in pro-B-leukemic cells, whereas high LSP-IL-15 was found in cortical T-ALL, but not in pre-T or mature T-ALL. In conclusion, lower expression of IL-15 in adult BCP-ALL at diagnosis was associated with CNS involvement. This unexpected difference in IL-15 expression between adult and childhood ALL may reflect differences in biologic features of leukemic cells and/or inflammation processes in the pathogenesis of CNS disease. Furthermore, the expression of IL-15 and its spilced variants was correlated with lineage commitment and differentiation status of leukemic cells in B-lineage-ALL as well as in T-ALL. It remains to be evaluated whether these prognostic and biologic findings of distinct expression pattern of IL-15 in adult ALL subtypes will have therapeutical implications for the future antileukemic strategies.