retinal-ganglion-cell-quantification-for-evaluating-neurodegeneration

Retinal Ganglion Cell Quantification for Evaluating Neurodegeneration in Mouse Models of Multiple Sclerosis&#8203;

Quantification of retinal ganglion cell (RGC) loss provides a sensitive and reproducible measure of neurodegeneration in mouse models of ...

Johns Hopkins University School of Medicine

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). In people with MS, impaired remyelination and axonal loss lead to debilitating long-term neurologic deficits. Current MS disease-modifying drugs mainly target peripheral immune cells and have demonstrated little efficacy for neuroprotection or promoting repair. To elucidate the pathological mechanisms and test therapeutic interventions, multiple animal models have been developed to recapitulate specific aspects of MS pathology, particularly the acute inflammatory stage. However, there are few animal models that facilitate the study of remyelination in the presence of inflammation, and none fully replicate the biology of chronic demyelination in MS. In this review, we describe the animal models that have provided insight into the mechanisms underlying demyelination, myelin repair, and potential therapeutic targets for remyelination. We highlight the limitations of studying remyelination in toxin-based demyelination models and discuss the combinatorial models that recapitulate the inflammatory microenvironment, which is now recognized to be a major inhibitor of remyelination mechanisms. These models may be useful in identifying novel therapeutics that promote CNS remyelination in inflammatory diseases such as MS.

Animal models to investigate the effects of inflammation on remyelination in multiple sclerosis.

Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2PDGFRa) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2CC1 cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the mice with NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelination of the corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.

The Effects of NLY01, a Novel Glucagon-Like Peptide-1 Receptor Agonist, on Cuprizone-Induced Demyelination and Remyelination: Challenges and Future Perspectives.

Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS).

Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis.

Central nervous system inflammation is implicated in neurodegeneration across several disorders, including multiple sclerosis (MS). While marked therapeutic progress has been made in preventing relapses in MS, primary neuroprotection in this disease remains elusive. This, in part, is due to an incomplete understanding of the molecular pathways involved in immune-mediated neuronal death. Here we show that parthanatos, a recently described caspase-independent and DNA damage-induced cell death program, contributes to neuron death in the experimental autoimmune encephalomyelitis (EAE) mouse model of autoimmune neuroinflammation. We reveal that DNA damage increases in neurons during EAE, and that neurons are progressively lost over the disease course. Neurons in affected areas display intracellular hallmarks of the parthanatos cascade. Genetic or pharmacologic blockade of the final step in parthanatos, genomic fragmentation by macrophage migration inhibitory factor (MIF) nuclease, reduces neuron loss and disease severity. Transcriptomic characterization of neurons with and without MIF nuclease activity reveals parthanatos-dependent differences in response to EAE. Together, this work establishes parthanatos as a key mechanism of neuron cell death during neuroinflammation.

Autoimmune neuroinflammation leads to neuronal death via MIF nuclease-mediated parthanatos.

Author Correction: Autoimmune neuroinflammation leads to neuronal death via MIF nuclease-mediated parthanatos.

Multiple sclerosis (MS) is characterized by peripheral immune cell infiltration into the central nervous system (CNS) and associated reactive gliosis, demyelination, and neuroaxonal degeneration. Existing therapies broadly target adaptive immune cells and treat acute inflammation but are not effective in halting chronic neurodegeneration that occurs in progressive MS. High-efficacy precision therapies that target pathways in the CNS known to contribute to MS pathophysiology are lacking. Several MS studies have identified prominent dysregulation of macrophage migration inhibitory factor (MIF), a multifunctional protein with both cytokine and enzyme activity, in inflammatory diseases. MIF is elevated in the CSF of people with MS and MIF gene variants have been linked with progressive MS, but its precise contributions to the pathophysiologic underpinnings of MS remain unclear. MIF has extracellular signaling capacity through CD74. MIF also has 2 discrete and endogenous enzymatic functions as a tautomerase and nuclease.

Article	Year
Animal models to investigate the effects of inflammation on remyelination in multiple sclerosis. Frontiers in molecular neuroscience\| PubMed ID: 36407761	2022
The Effects of NLY01, a Novel Glucagon-Like Peptide-1 Receptor Agonist, on Cuprizone-Induced Demyelination and Remyelination: Challenges and Future Perspectives. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics\| PubMed ID: 37296356	2023
Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England)\| PubMed ID: 37982154	2024
Autoimmune neuroinflammation leads to neuronal death via MIF nuclease-mediated parthanatos. Nature neuroscience\| PubMed ID: 41703302	2026
Author Correction: Autoimmune neuroinflammation leads to neuronal death via MIF nuclease-mediated parthanatos. Nature neuroscience\| PubMed ID: 41807848	2026
MIF Tautomerase Inhibition Protects Neurons From Immune-Mediated Cell Death. Neurology(R) neuroimmunology & neuroinflammation\| PubMed ID: 42018964	2026

Jackson W. Mace

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