Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis.

Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines ( Il1ß, Tnfα, and Ifnγ) and glial cell markers ( Gfap and Cd68) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

Comparison between stem cell therapy and stem cell derived exosomes on induced multiple sclerosis in dogs.

BACKGROUND: Multiple sclerosis (MS) is a chronic condition that primarily manifests as demyelination of neuronal axons in the central nervous system, due to the loss or attack of oligodendroglia cells that form myelin. Stem cell therapy has shown promising results for the treatment of MS due to its capability to halt the immune attack, stop apoptosis and axonal degeneration, and differentiate into oligodendrocytes. Stem cell-derived Exosomes (Exosomes) have shown great capabilities for neuronal diseases as they have growth factors, complex sets of miRNA, enzymes, proteins, major peptides, lipids, and macromolecules with anti-inflammatory, angiogenesis, and neurogenesis activities. METHODS: This study aimed to compare the healing properties of stem cells, against Exosomes for the treatment of an experimentally induced MS dog model. Dog models of MS received either a single treatment of stem cells or a single treatment of Exosomes intrathecally and the treatment process was evaluated clinically, radiologically, histopathologically, and electron microscopy and cerebrospinal fluid analysis. RESULTS: showed marked amelioration of the clinical signs in both treated groups compared to the control one, magnetic resonance scans showed the resolution of the hyperintense lesions at the end of the study period, the histopathology and electron microscopy showed marked healing properties and remyelination in treated groups with superiority of the stem cells compared to Exosomes. CONCLUSIONS: Although stem cell results were superior to Exosomes therapy; Exosomes have proven to be effective and safe important actors in myelin regeneration, and their use in diseases like MS helps to stimulate remyelination.

An early clinical phenotype of necrotizing meningoencephalitis in the Pug reveals similarities to multiple sclerosis in humans.

Necrotizing meningoencephalitis (NME) is a fatal neuroinflammatory disease that previously carried a uniformly grave prognosis. Our recent identification of a novel early form of NME in Pugs suggests that disease onset and progression are likely more insidious than previously recognized and provides new hope that early therapeutic intervention may halt disease progression and ultimately prevent or cure NME. This novel perspective also sheds new light on the clinical similarities to multiple sclerosis (MS) in humans and provides a rationale for cross-species translation. The history of recent scientific discoveries in NME and new parallels between MS and NME will be reviewed.

L-Theanine Improves Locomotor Function in a Model of Multiple Sclerosis Mice.

This study designed to investigate the protective effects of L-theanine on experimental Multiple sclerosis in mice. Frothy Male C57BL/6 mice were allocated into 4 experimental groups: control no treatment received a regular chew pellet, and the cuprizone (CPZ) group received a standard chew pellet containing 0.2% (w/w) CPZ. In group 3, mice were fed a regular diet and administered p.o. with L-theanine (50mg/kg). In group 4, mice received a diet containing CPZ and were administered p.o. with L-theanine (50mg/kg). Finally, reflexive motor behavior and serum antioxidant levels were determined. Based on findings, CPZ significantly decreased ambulation score, hind-limb suspension, front limb suspension, and grip strength (P<0.05). The CPZ + L-theanine reduced the adverse effect of the CPZ on ambulation score, hind-limb foot angle, surface righting, and negative geotaxis (P<0.05). The CPZ + L-theanine increased front and hind-limb suspension, grip strength, number of the cross, and duration of a stay on the rotarod compared to the control animal (P<0.05). CPZ administration significantly elevated serum malondialdehyde (MDA) while superoxide dismutase (SOD) and glutathione peroxidase (GPx) and total antioxidant status (TAS) levels decreased compared to control mice (P<0.05). The CPZ + L-theanine leads to the cessation of MDA production while increasing SOD, GPx, and TAS levels (P<0.05). These results suggested L-theanine has a protective effect against CPZ-induced MS in mice.

Blocking the VISTA pathway enhances disease progression in (NZB × NZW) F1 female mice.

V-domain Ig suppressor of T-cell activation (VISTA) is a critical negative checkpoint molecule involved in regulating the immune response. Targeting the pathway with an antagonist anti-VISTA antibody designated 13F3 has been shown to enhance disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. To determine if VISTA plays a role in murine lupus, New Zealand Black × New Zealand White (BWF1) mice were treated with 13F3 or control hamster Ig and disease monitored. Onset of proteinuria was earlier and renal damage more profound in mice treated with 13F3. Cell subset analysis showed an increase of activated splenic T cells and inflammatory splenic myeloid cells, but no effect on B cells, in mice receiving 13F3. Examination of the kidney showed an increase in inflammatory myeloid cell infiltration with 13F3 treatment. This study along with previous EAE data, suggests that interventions that enhance VISTA regulatory activity may be effective for the treatment of autoimmune disease.

Oligoclonal IgG bands synthesized in the central nervous system are present in rats with experimental autoimmune encephalomyelitis.

OBJECTIVE: Oligoclonal bands (OBs) in electrophoresis of cerebrospinal fluid (CSF) are present in multiple sclerosis and here is investigated whether these also occur in experimental autoimmune encephalomyelitis (EAE). MATERIAL AND METHODS: Experimental autoimmune encephalomyelitis was induced in 42 DA rats after immunization with rat spinal chord homogenate and the occurrence of OBs were detected by electrophoresis of both sera and CSF. The relationship between disease symptoms, antibody response against myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and appearance of OBs was studied. RESULTS: Development of CSF-specific OB was found to occur, 6 weeks after immunization, in seven of 42 rats. OB was detected in rats with an antibody response against MBP, whereas as a role no such bands were present in rats with an antibody response against MOG. Initially severe disease symptoms were correlated to a concomitant intense oligoclonal antibody response. CONCLUSION: Cerebrospinal fluid-specific OB occurs in EAE. It is present in rats with an anti-MBP, but not in rats with an anti-MOG antibody response. A severe disease results in an intense oligoclonal antibody response, which might have an anti-inflammatory effect.

A 40-cM region on chromosome 14 plays a critical role in the development of virus persistence, demyelination, brain pathology and neurologic deficits in a murine viral model of multiple sclerosis.

Theiler virus persists and induces immune-mediated demyelination in susceptible mice and serves as a model of multiple sclerosis. Previously, we identified 4 markers--D14Mit54, D14Mit60, D14Mit61, and D14Mit90--in a 40-cM region of chromosome 14 that are associated with demyelination in a cross between susceptible DBA/2 and resistant B10.D2 mice. We generated congenic-inbred mice to examine the contribution of this 40-cM region to disease. DBA Chr.14B10 mice, containing the chromosomal segment marked by the microsatellite polymorphisms, developed less spinal cord demyelination than did DBA/2 mice. More demyelination was found in the reciprocal congenic mouse B10.D2 Chr.14D2 than in the B10.D2 strain. Introduction of the DBA/2 chromosomal region onto the B10.D2 genetic background resulted in more severe disease in the striatum and cortex relative to B10.D2 mice. The importance of the marked region of chromosome 14 is indicated by the decrease in neurological performance using the Rotarod test during chronic disease in B10.D2 Chr.14D2 mice in comparison to B10.D2 mice. Viral replication was increased in B10.D2 Chr.14D2 mice as determined by quantitative real-time RT-PCR. These results indicate that the 40-cM region on chromosome 14 of DBA/2 mice contributes to viral persistence, subsequent demyelination, and loss of neurological function.

Defining and measuring exposure in epidemiologic studies of potential zoonoses.

Articles suggesting the zoonotic potential of certain human diseases (eg, multiple sclerosis, rheumatoid arthritis, and leukemia) periodically appear in the literature and frequently receive considerable attention in the popular press. Although various epidemiologic study designs have been utilized to test these hypotheses, defining and accurately measuring animal exposure has been a problem common to most of these studies and in some instances has limited their usefulness. The relative strengths and limitations of the definitions and measurements used most commonly by investigators evaluating potential zoonoses are discussed. In addition, several recommendations for assessing animal exposure in future studies are made.

Multiple sclerosis and infants fed on diets deficient in vitamin A or in selenium and vitamin E.

The characteristic features of multiple sclerosis (MS) include indications that its foundations are laid in early childhood as evidence by instances of the clustering of cases in particular localities by place of birth. Then there is the pattern of distribution in which the prevalence of MS among Caucasians progressively diminishes as the equator is approached, and the familial tendency of the disease to occur in close relatives of those who suffer from it. What is perhaps the most intriguing of all is the prevalence in the Orkney and Shetland Islands which is the highest in the world as far as is known. These and various other features, when considered in connection with the results of the research work which has been carried out on MS and on related subjects, provide reasonable grounds on which to base the hypothesis that the feeding of newborn infants over a period of approximately six months on diets containing insufficient vitamin A or selenium (Se) and to a lesser extent the vitamin E necessary to safeguard vitamin A against peroxidative degradation is a necessary condition but not a sufficient condition for the possible onset of the disease later in life.