Central nervous system demyelinating diseases and increased release of cholesterol into the urinary system of rats

The question of what happens to cholesterol in the adult central nervous system during its slow turnover has been addressed using rats with brain and spinal cord labeled with [4-¹⁴C]cholesterol upon intracerebral injection of labeled cholesterol into rats at 10–12 days of age. At six months after injection,¹⁴C was found only in the brain and spinal cord and was slowly releasedvia the rat's urine. When labeled rats were given demyelinating agents (triethyl tin chloride, hexachlorophene, sodium cyanide) and when experimental allergic encephalomyelitis was induced, a measurable increase in urinary¹⁴C label above control levels was found. It was concluded that there is a direct relationship between the experimental demyelination induced and the increased release of cholesterol metabolites into urine. The study suggests that a clinical method could be developed to determine the rate of central nervous system demyelination by measuring the amount of urinary cholesterol metabolites.     

EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model

The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases.     

One Raft to Guide Them All,and in Axon Regeneration Inhibit Them

Central nervous system damage caused by traumatic injuries, iatrogenicity due to surgical interventions, stroke and neurodegenerative diseases is one of the most prevalent reasons for physical disability worldwide. During development, axons must elongate from the neuronal cell body to contact their precise target cell and establish functional connections. However, the capacity of the adult nervous system to restore its functionality after injury is limited. Given the inefficacy of the nervous system to heal and regenerate after damage, new therapies are under investigation to enhance axonal regeneration. Axon guidance cues and receptors, as well as the molecular machinery activated after nervous system damage, are organized into lipid raft microdomains, a term typically used to describe nanoscale membrane domains enriched in cholesterol and glycosphingolipids that act as signaling platforms for certain transmembrane proteins. Here, we systematically review the most recent findings that link the stability of lipid rafts and their composition with the capacity of axons to regenerate and rebuild functional neural circuits after damage.     

Fatty Acid Synthesis in Glial Cells of the CNS

Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing to brain pathologies such Alzheimer’s disease or multiple sclerosis. Intervention strategies targeting FA synthesis in glia represents a potential therapeutic opportunity for several CNS diseases.     

Cholesterol turnover in the central nervous system

Immature rat brains were examined for a metabolite of cholesterol which could conceivably form in the central nervous system as a result of cholesterol turnover. A basic assumption was made that an acidic product would be formed, preferentially by oxidative degradation of the cholesterol side chain. Chemical fractionation of brain tissue and thin-layer chromatography of an appropriate acidic fraction indicated the presence of a monohydroxy steroidal acid(s) which remains to be positively identified. Preliminary tracer experiments did not clarify the origin of the unidentified metabolite.     

Protein Tyrosine Phosphatase Receptor Type Z in Central Nervous System Disease

Gliomas are among the most common tumors of the central nervous system and include highly malignant subtypes, such as glioblastoma, which are associated with poor prognosis. Effective treatments are therefore urgently needed. Despite the recent advances in neuroimaging technologies, differentiating gliomas from other brain diseases such as multiple sclerosis remains challenging in some patients, and often requires invasive brain biopsy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is a heavily glycosylated membrane protein that is highly expressed in the central nervous system. Several reports analyzing mouse tumor models suggest that PTPRZ may have potential as a therapeutic target for gliomas. A soluble cleaved form of PTPRZ (sPTPRZ) in the cerebrospinal fluid is markedly upregulated in glioma patients, making it another promising diagnostic biomarker. Intriguingly, PTPRZ is also involved in the process of remyelination in multiple sclerosis. Indeed, lowered PTPRZ glycosylation by deletion of the glycosyltransferase gene leads to reduced astrogliosis and enhanced remyelination in mouse models of demyelination. Here, we review the expression, molecular structure, and biological roles of PTPRZ. We also discuss glioma and demyelinating diseases, as well as the pathological role of PTPRZ and its application as a diagnostic marker and therapeutic target.     

Human IPSC-Derived Model to Study Myelin Disruption

Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption.     

The functional role of sphingomyelin in cell membranes

Sphingomyelins (SM) constitute an important class of phospholipids in the membranes of most eukaryotic cells. In mammalian tissues, SM usually constitute 2–15% of the total organ phospholipid, but certain tissues such as brain, peripheral nervous tissue and ocular lenses have even higher SM contents. Typical properties of SM include their low degree of unsaturation, an asymmetric molecular structure, and their extensive hydrogen‐bonding properties. These features are all very important for the structural role of SM in biological membranes. SM interact favorably with cholesterol (and other sterols) and there is an established co‐localization of SM and cholesterol in the plasma membranes of cells and at the surface of lipoprotein particles. Together they form SM/sterol‐rich domains that often are more ordered than the surrounding phase in biological membranes. The growing body of evidence regarding their favorable interaction with sterols indicates that the functional role of SM per se is largely related to being a regulator of cholesterol distribution within cellular membranes and cholesterol homeostasis in cells. Together with other sphingolipids, SM also have an important functional role as precursors of sphingolipid signaling molecules, extensively reviewed elsewhere and not to be discussed here in more detail.     

The neuroprotective functions of transforming growth factor Beta proteins

Transforming growth factor beta (TGF-β) proteins are multifunctional cytokines whose neural functions are increasingly recognized. The machinery of TGF-β signaling, including the serine kinase type transmembrane receptors, is present in the central nervous system. However, the 3 mammalian TGF-β subtypes have distinct distributions in the brain suggesting different neural functions. Evidence of their involvement in the development and plasticity of the nervous system as well as their functions in peripheral organs suggested that they also exhibit neuroprotective functions. Indeed, TGF-β expression is induced following a variety of types of brain tissue injury. The neuroprotective function of TGF-βs is most established following brain ischemia. Damage in experimental animal models of global and focal ischemia was shown to be attenuated by TGF-βs. In addition, support for their neuroprotective actions following trauma, sclerosis multiplex, neurodegenerative diseases, infections, and brain tumors is also accumulating. The review will also describe the potential mechanisms of neuroprotection exerted by TGF-βs including anti-inflammatory, -apoptotic, -excitotoxic actions as well as the promotion of scar formation, angiogenesis, and neuroregeneration. The participation of these mechanisms in the neuroprotective effects of TGF-βs during different brain lesions will also be discussed.     

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

Reticulons (RTNs) are crucial regulatory factors in the central nervous system (CNS) as well as immune system and play pleiotropic functions. In CNS, RTNs are transmembrane proteins mediating neuroanatomical plasticity and functional recovery after central nervous system injury or diseases. Moreover, RTNs, particularly RTN4 and RTN3, are involved in neurodegeneration and neuroinflammation processes. The crucial role of RTNs in the development of several neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neurological conditions such as brain injury or spinal cord injury, has attracted scientific interest. Reticulons, particularly RTN-4A (Nogo-A), could provide both an understanding of early pathogenesis of neurodegenerative disorders and be potential therapeutic targets which may offer effective treatment or inhibit disease progression. This review focuses on the molecular mechanisms and functions of RTNs and their potential usefulness in clinical practice as a diagnostic tool or therapeutic strategy.     

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.     

Kynurenines and Multiple Sclerosis: The Dialogue between the Immune System and the Central Nervous System

Multiple sclerosis is an inflammatory disease of the central nervous system, in which axonal transection takes place in parallel with acute inflammation to various, individual extents. The importance of the kynurenine pathway in the physiological functions and pathological processes of the nervous system has been extensively investigated, but it has additionally been implicated as having a regulatory function in the immune system. Alterations in the kynurenine pathway have been described in both preclinical and clinical investigations of multiple sclerosis. These observations led to the identification of potential therapeutic targets in multiple sclerosis, such as synthetic tryptophan analogs, endogenous tryptophan metabolites (e.g., cinnabarinic acid), structural analogs (laquinimod, teriflunomid, leflunomid and tranilast), indoleamine-2,3-dioxygenase inhibitors (1MT and berberine) and kynurenine-3-monooxygenase inhibitors (nicotinylalanine and Ro 61-8048). The kynurenine pathway is a promising novel target via which to influence the immune system and to achieve neuroprotection, and further research is therefore needed with the aim of developing novel drugs for the treatment of multiple sclerosis and other autoimmune diseases.     

Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.     

Fumaric Acid Esters Do Not Reduce Inflammatory NF-κB/p65 Nuclear Translocation,ICAM-1 Expression and T-Cell Adhesiveness of Human Brain Microvascular Endothelial Cells

Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 µM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.     

Notes on the Epidemiology of Multiple Sclerosis,with Special Reference to Dietary Habits

A hypothesis, based primarily on the occurrence of multiple sclerosis (MS) in the Faroe Islands and supported by numerous analytical epidemiological studies, is described. It proposes that MS is caused by the interaction of a virus disease with intestinal pathology, e.g., infectious mononucleosis, and application of smoked and nitrate/nitrite-cured meat products in the diet during circumscribed time intervals. The biological mechanisms might involve a break of tolerance by an alteration of self within the central nervous system, by nitrophenylated compounds conjugated to animal tissue, in particular to proteins occurring in the central nervous system. Further research is needed.     

新型口服多发性硬化症治疗药物

多发性硬化症（Multiple scslerosis,MS）是一种以中枢神经系统炎性脱髓鞘病变为主要特点的自身免疫性疾病,易发于年轻人身上。临床上常用免疫调节剂治疗,但这些治疗药需经皮下、肌肉或静脉等非肠胃途径给药,故亟需开发更为方便的口服治疗药。综述了有关口服MS药物及其在治疗方面的最新研究进展。     

What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI) and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting) and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects.     

Ferroptosis Mechanisms Involved in Hippocampal-Related Diseases

Ferroptosis is a newly recognized type of cell death that is different from traditional forms of cell death, such as apoptosis, autophagy, and necrosis. It is caused by the accumulation of intracellular iron, promoting lipid peroxidation and leading to cell death. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. An increased concentration of iron in the central nervous system has been associated with oxidative stress, lipid peroxidation of proteins, and cell death. The hippocampus is an important brain region for learning, memory, and emotional responses, and is also a sensitive part of the brain to the dysfunctional homeostasis of transition metals. Damage of hippocampal structure and function are intimately involved in the pathogenic mechanisms underlying neurodegenerative diseases. Currently, ferroptosis is playing an increasingly important role in treatment areas of central nervous system diseases. Thus, we provide an overview of ferroptosis regulatory mechanisms, such as lipid metabolism, glutathione metabolism, and iron metabolism in this review. We also highlight the role of ferroptosis in hippocampal-related diseases and investigate a theoretical basis for further research on the role of ferroptosis in nervous system disease treatment.     

Effect of PACAP in Central and Peripheral Nerve Injuries

Pituitary adenylate cyclase activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. In addition to its more classic role as a neuromodulator, PACAP functions as a neurotrophic factor. Several neurotrophic factors have been shown to play an important role in the endogenous response following both cerebral ischemia and traumatic brain injury and to be effective when given exogenously. A number of studies have shown the neuroprotective effect of PACAP in different models of ischemia, neurodegenerative diseases and retinal degeneration. The aim of this review is to summarize the findings on the neuroprotective potential of PACAP in models of different traumatic nerve injuries. Expression of endogenous PACAP and its specific PAC1 receptor is elevated in different parts of the central and peripheral nervous system after traumatic injuries. Some experiments demonstrate the protective effect of exogenous PACAP treatment in different traumatic brain injury models, in facial nerve and optic nerve trauma. The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in neuronal regeneration indicating that PACAP may also be a promising therapeutic agent in injuries of the nervous system.