Spinal Cord Brain Derived Neurotrophic Factor (BDNF) Responsive Cells in an Experimental Autoimmune Encephalomyelitis (EAE) Model of Multiple Sclerosis (MS): Implications in Myelin Repair

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.

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

10.1101/2020.07.28.224709 ◽

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1915141116 ◽

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.

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

Brain ◽

10.1093/brain/awaa385 ◽

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.

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

10.21203/rs.3.rs-114482/v3 ◽

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.

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Experimental autoimmune encephalomyelitis in the common marmoset: a translationally relevant model for the cause and course of multiple sclerosis

Primate Biology ◽

10.5194/pb-6-17-2019 ◽

2019 ◽

Vol 6 (1) ◽

pp. 17-58 ◽

Cited By ~ 4

Author(s):

Bert A. &apos;t Hart

Keyword(s):

Multiple Sclerosis ◽

Experimental Autoimmune Encephalomyelitis ◽

Common Marmoset ◽

Preclinical Research ◽

Autoimmune Encephalomyelitis ◽

Neuroinflammatory Disease ◽

Mouse Experimental Autoimmune Encephalomyelitis ◽

Eae Model ◽

Experimental Treatments ◽

Experimental Autoimmune

Abstract. Aging Western societies are facing an increasing prevalence of chronic autoimmune-mediated inflammatory disorders (AIMIDs) for which treatments that are safe and effective are scarce. One of the main reasons for this situation is the lack of animal models, which accurately replicate clinical and pathological aspects of the human diseases. One important AIMID is the neuroinflammatory disease multiple sclerosis (MS), for which the mouse experimental autoimmune encephalomyelitis (EAE) model has been frequently used in preclinical research. Despite some successes, there is a long list of experimental treatments that have failed to reproduce promising effects observed in murine EAE models when they were tested in the clinic. This frustrating situation indicates a wide validity gap between mouse EAE and MS. This monography describes the development of an EAE model in nonhuman primates, which may help to bridge the gap.

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