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Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors
David Guenoun1,2, Nathan Blaise1, Alexandre Sellam1
1Inserm, NeuroDiderot, Université Paris-Cité, Paris, France.
Abstract:
A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.
Insights
Targeting colony-stimulating factor 1 receptor (CSF-1R) depletes microglia, the brain's immune cells. This strategy shows promise for treating neurodegenerative and neurodevelopmental diseases by reducing neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia, the central nervous system's immune cells, play a key role in neurological diseases.
- Colony-stimulating factor 1 receptor (CSF-1R) signaling is crucial for microglial function and can be pharmacologically targeted.
- Inhibiting CSF-1R leads to microglial depletion, with potential for repopulation upon treatment cessation.
Purpose of the Study:
- To compare three CSF-1R inhibitors (PLX3397, PLX5622, GW2580) for their efficacy in microglial depletion.
- To review the therapeutic potential of microglial depletion in adult neurodegenerative diseases.
- To explore the applicability of microglial depletion strategies in neurodevelopmental disorders.
Main Methods:
- Review of existing literature on CSF-1R inhibitors and microglial depletion.
- Comparative analysis of PLX3397, PLX5622, and GW2580.
- Examination of preclinical data from animal models of neurological diseases.
Main Results:
- Pharmacological CSF-1R inhibition effectively depletes microglia.
- Transitory microglial depletion has demonstrated neuroprotective effects and improved outcomes in models of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
- The potential benefits extend to neurodevelopmental diseases characterized by neuroinflammation.
Conclusions:
- Microglial depletion via CSF-1R inhibition is a promising therapeutic strategy for various neurological disorders.
- Further research is needed to understand the long-term effects of these strategies on other neural cell types (neurons, astrocytes, oligodendrocytes) in both adult and developing brains.
