scholarly journals Differential Role of p53 in Oligodendrocyte Survival in Response to Various Stresses: Experimental Autoimmune Encephalomyelitis, Cuprizone Intoxication or White Matter Stroke

2021 ◽  
Vol 22 (23) ◽  
pp. 12811
Author(s):  
Fucheng Luo ◽  
Zhen Zhang ◽  
Yu Luo
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
White Matter ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Brain Injuries ◽  
Motor Coordination ◽  
Subcortical White Matter ◽  
Loss Of Function ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Promoting oligodendrocyte viability has been proposed as a therapeutic strategy for alleviating many neuronal diseases, such as multiple sclerosis and stroke. However, molecular pathways critical for oligodendrocyte survival under various stresses are still not well known. p53 is a strong tumor suppressor and regulates cell cycle, DNA repair and cell death. Our previous studies have shown that p53 plays an important role in promoting neuronal survival after insults, but its specific role in oligodendrocyte survival is not known. Here, we constructed the mice with oligodendrocyte-specific p53 loss by crossing TRP53flox/flox mice and CNP-cre mice, and found that p53 was dispensable for oligodendrocyte differentiation and myelin formation under physiological condition. In the experimental autoimmune encephalomyelitis (EAE) model, p53 loss of function, specifically in oligodendrocytes, did not affect the EAE disease severity and had no effect on demyelination in the spinal cord of the mice. Interestingly, p53 deficiency in oligodendrocytes significantly attenuated the demyelination of corpus callosum and alleviated the functional impairment of motor coordination and spatial memory in the cuprizone demyelination model. Moreover, the oligodendrocyte-specific loss of p53 provided protection against subcortical white matter damage and mitigated recognition memory impairment in mice in the white matter stroke model. These results suggest that p53 plays different roles in the brain and spinal cord or in response to various stresses. Thus, p53 may be a therapeutic target for oligodendrocyte prevention in specific brain injuries, such as white matter stroke and multiple sclerosis.

Susceptibility-weighted imaging in the experimental autoimmune encephalomyelitis model of multiple sclerosis indicates elevated deoxyhemoglobin, iron deposition and demyelination

2012 ◽  
Vol 19 (6) ◽  
pp. 721-731 ◽  
Author(s):  
Nabeela Nathoo ◽  
Smriti Agrawal ◽  
Ying Wu ◽  
Sarah Haylock-Jacobs ◽  
V Wee Yong ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
White Matter ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Iron Deposition ◽  
Lumbar Spinal Cord ◽  
Susceptibility Weighted Imaging ◽  
Autoimmune Encephalomyelitis ◽  
Lumbar Spinal ◽  
Experimental Autoimmune

Background: Susceptibility-weighted imaging (SWI) is an iron-sensitive magnetic resonance imaging (MRI) method that has shown iron-related lesions in multiple sclerosis (MS) patients. The contribution of deoxyhemoglobin to the signals seen in SWI has not been well characterized in MS. Objectives: To determine if SWI lesions (seen as focal hypointensities) exist in the experimental autoimmune encephalomyelitis (EAE) animal model of MS, and to determine whether the lesions relate to iron deposits, inflammation, demyelination, and/or deoxyhemoglobin in the vasculature. Methods: We performed SWI on the lumbar spinal cord and cerebellum of EAE and control mice (both complete Freund’s adjuvant/pertussis toxin (CFA/PTX)-immunized and naive). We also performed SWI on mice before and after perfusion (to remove blood from vessels). SWI lesions were counted and their locations were compared to histology for iron, myelin and inflammation. Results: SWI lesions were found to exist in the EAE model. Many lesions seen by SWI were not present after perfusion, especially at the grey/white matter boundary of the lumbar spinal cord and in the cerebellum, indicating that these lesion signals were associated with deoxyhemoglobin present in the lumen of vessels. We also observed SWI lesions in the white matter of the lumbar spinal cord that corresponded to iron deposition, inflammation and demyelination. In the cerebellum, SWI lesions were present in white matter tracts, where we found histological evidence of inflammatory perivascular cuffs. Conclusions: SWI lesions exist in EAE mice. Many lesions seen in SWI were a result of deoxyhemoglobin in the blood, and so may indicate areas of hypoxia. A smaller number of SWI lesions coincided with parenchymal iron, demyelination, and/or inflammation.

scholarly journals Elevated Expression of Fractalkine (CX3CL1) and Fractalkine Receptor (CX3CR1) in the Dorsal Root Ganglia and Spinal Cord in Experimental Autoimmune Encephalomyelitis: Implications in Multiple Sclerosis-Induced Neuropathic Pain

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Wenjun Zhu ◽  
Crystal Acosta ◽  
Brian MacNeil ◽  
Claudia Cortes ◽  
Howard Intrater ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Protein Expression ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Autoimmune Encephalomyelitis ◽  
Receptor Cx3cr1 ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG /SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS.

scholarly journals Early Postnatal Tobacco Smoke Exposure Aggravates Experimental Autoimmune Encephalomyelitis in Adult Rats

2020 ◽  
Author(s):  
Zhaowei Wang ◽  
Liping Wang ◽  
Fangfang Zhong ◽  
Chenglong Wu ◽  
Sheng-Tao Hou
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Risk Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Tobacco Smoke ◽  
Early Life ◽  
Tobacco Smoke Exposure ◽  
Autoimmune Encephalomyelitis ◽  
Early Life Exposure ◽  
Experimental Autoimmune

AbstractAlthough substantial evidence supports smoking as a risk factor for the development of multiple sclerosis (MS) in adulthood, it remains controversial as to whether early-life exposure to environmental tobacco smoke (ETS) increases the risk of MS later in life. Here, using experimental autoimmune encephalomyelitis (EAE) as an animal model for MS, we show that exposing neonatal rats during the 1st week (ETS1-EAE), but not the 2nd week (ETS2-EAE) and the 3rd week (ETS3-EAE) after birth, increased the severity of EAE in adulthood in comparison to pups exposed to filtered compressed air (AIR-EAE). The EST1-EAE rats showed a worse neurological deficit score and a significant increase in CD4+ cell infiltration, demyelination, and axonal injury in the spinal cord compared to AIR-EAE, ETS2-EAE, and ETS3-EAE groups. Flow cytometry analysis showed that the ETS1 group had decreased numbers of regulatory T (Treg) cells and increased effector T (Teff) cells in the brain and spinal cord. The expressions of Treg upstream regulator Foxp3 and downstream cytokines such as IL-10 were also altered accordingly. Together, these findings demonstrate that neonatal ETS exposure suppresses Treg functions and aggravates the severity of EAE, confirming early-life exposure to EST as a potential risk factor for multiple sclerosis in adulthood.

scholarly journals Aged hind-limb clasping experimental autoimmune encephalomyelitis models aspects of the neurodegenerative process seen in multiple sclerosis

2019 ◽  
Vol 116 (45) ◽  
pp. 22710-22720
Author(s):  
Lindsay S. Cahill ◽  
Monan Angela Zhang ◽  
Valeria Ramaglia ◽  
Heather Whetstone ◽  
Melika Pahlevan Sabbagh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Hind Limb ◽  
Histopathological Analysis ◽  
Autoimmune Encephalomyelitis ◽  
Axon Injury ◽  
Relapsing Remitting ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.

scholarly journals Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis

Brain ◽  
2020 ◽  
Author(s):  
Hardeep Kataria ◽  
Christopher G Hart ◽  
Arsalan Alizadeh ◽  
Michael Cossoy ◽  
Deepak K Kaushik ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Encephalomyelitis ◽  
Spinal Cord Lesions ◽  
Neuregulin 1 ◽  
Chondroitin Sulphate Proteoglycans ◽  
New Findings ◽  
Experimental Autoimmune

Abstract Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1β1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1β1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1β1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1β1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1β1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1β1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1β1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1β1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1β1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2021 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2020 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities.Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

Quantitative Evaluation of Leukocyte Infiltration into the Spinal Cord in a Model of Experimental Autoimmune Encephalomyelitis: Statistical-Analytical Techniques for Use in Evaluating Drugs

1998 ◽  
Vol 11 (3) ◽  
pp. 117-137 ◽  
Author(s):  
D. L. Chapman ◽  
S. M. Vroegop ◽  
L. A. Galinet ◽  
K. A. Ready ◽  
C. J. Dunn ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Monoclonal Antibody ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Negative Binomial ◽  
Clinical Signs ◽  
Clinical Disease ◽  
Leukocyte Infiltration ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is considered a useful animal model for preclinical development of drugs to treat human multiple sclerosis. The relationship between clinical disease signs and leukocyte infiltration into the lower spinal cord was studied in EAE in order to assess analytical and statistical methods for evaluating drug candidates. As expected, the degree of clinical disease was correlated with the amount of leukocyte infiltration into the lower spinal cord. Additionally, we were able to distinguish patterns of clinical signs and leukocyte infiltration for classes of recurring-remitting and progressive forms of the disease. The distributions of leukocyte infiltration sites correspond to negative binomial distributions, and the parameters calculated from the respective distributions differ significantly among disease classes. We determined the sensitivity of histological measures of the leukocyte infiltration and calculated the magnitude of differences required in order to observe statistically significant changes in leukocyte infiltration. Using immunohistochemistry to assess cell surface markers of leukocytes in the lower spinal cord, we measured the infiltration of CD4+ and CD8+ lymphocytes and cells of the macrophage/microglial lineage stained with the monoclonal antibody, F4/80. Treatment with an anti-4 integrin monoclonal antibody, PS/2, served as an indicator of how we may expect to measure the effects of new pharmaceutical agents tested using our particular model of EAE. PS/2 treatment affected clinical signs of disease only when administered very early in the time course of the disease, despite a marked statistically significant decline in CD4+ cells regardless of when the PS/2 was administered. The analytical and statistical techniques applied here may be used to design efficient and sensitive assays for the evaluation of new drugs that may prove useful in the treatment of multiple sclerosis.

scholarly journals Reduced spinal cord parenchymal cerebrospinal fluid circulation in experimental autoimmune encephalomyelitis

2018 ◽  
Vol 39 (7) ◽  
pp. 1258-1265 ◽  
Author(s):  
Antoine P Fournier ◽  
Maxime Gauberti ◽  
Aurélien Quenault ◽  
Denis Vivien ◽  
Richard Macrez ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Fluid Circulation ◽  
Autoimmune Encephalomyelitis ◽  
Cerebrospinal Fluid Circulation ◽  
Csf Circulation ◽  
The Brain ◽  
Experimental Autoimmune

An alteration of parenchymal cerebrospinal fluid circulation (CSF) has been proposed to take part in the pathophysiology of multiple sclerosis. By using an intragate T1-weighted high-resolution MRI of the spinal cord of freely breathing mice injected with a gadolinium chelate in the cisterna magna, we show that a parenchymal CSF circulation exists in the spinal cord, in addition to that originally described in the brain. In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, we show a reduction of parenchymal CSF circulation specifically in the spinal cord but not in the brain.

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