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Updated: Jun 5, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive
Alessandra Pistolesi1, Giuseppe Ranieri1, Maura Calvani2
1Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Abstract:
Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.
Insights
Myeloperoxidase (MPO) inhibition with verdiperstat did not slow progressive multiple sclerosis (MS) in mice. Targeting microglia activation alone is insufficient to halt MS progression, suggesting immune-independent factors drive neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) lacks effective disease-modifying drugs.
- Myeloperoxidase (MPO), an enzyme in neutrophils and microglia, is implicated in neurodegeneration.
- MPO inhibitors are being tested for other neurological diseases, but not MS.
Purpose of the Study:
- To investigate the efficacy of the MPO inhibitor verdiperstat (AZD3241) in a mouse model of progressive MS (PMS).
- To assess the drug's impact on functional, immune, and mitochondrial parameters during disease progression.
Main Methods:
- Utilized the NOD mouse model of progressive MS.
- Administered daily treatment with verdiperstat.
- Evaluated functional outcomes, immune cell infiltration, and mitochondrial parameters in the spinal cord.
Main Results:
- Verdiperstat treatment did not alter disease progression or survival rates.
- The drug successfully reduced mitochondrial reactive oxygen species and microglia activation in the spinal cord.
- Adaptive immunity, neutrophil invasion, and mitochondrial damage remained unaffected.
Conclusions:
- Microglia suppression via MPO inhibition is insufficient to prevent disease progression in this MS model.
- These findings support the hypothesis that immune-independent mechanisms drive neurodegeneration in progressive MS.
