Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer

Thompson, Michelle L.; Jiménez-Andrade, Juan Miguel; Chartier, Stephane; Tsai, James; Burton, Elizabeth A.; Habets, Gaston; Lin, Paul S.; West, Brian L.; Mantyh, Patrick W.

doi:10.1097/j.pain.0000000000000228

Cited by 26 publications

(14 citation statements)

References 93 publications

(107 reference statements)

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“…However, although these drugs are supposed to have a very high specificity for a cell type or a surface receptor, there might still be some receptor expression in other cell types, resulting in controversial outcomes of different studies like for instance in the case of the L-AAA-induced astrocyte ablation ( Saffran and Crutcher, 1987 ; Khurgel et al, 1996 ). The same becomes true for microglia: although there are no controversial reports about the application of PLX3397 to induce myeloid cell death, it is already known that the drug might cross-react with some other receptor-kinases like, e.g., the platelet-derived growth factor receptor (PDGFR) making also other cells expressing those susceptible to cell death ( Cornelis et al, 2005 ; Chitu et al, 2012 ; Thompson et al, 2015 ). For NG2-glia there are until now no cell specific drugs available, probably due to the lack of a unique promising target receptor on those cells.…”

Section: Discussion and Outlookmentioning

confidence: 99%

Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation

Jäkel

Dimou

2017

Front. Cell. Neurosci.

387

263

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Glial cells, consisting of microglia, astrocytes, and oligodendrocyte lineage cells as their major components, constitute a large fraction of the mammalian brain. Originally considered as purely non-functional glue for neurons, decades of research have highlighted the importance as well as further functions of glial cells. Although many aspects of these cells are well characterized nowadays, the functions of the different glial populations in the brain under both physiological and pathological conditions remain, at least to a certain extent, unresolved. To tackle these important questions, a broad range of depletion approaches have been developed in which microglia, astrocytes, or oligodendrocyte lineage cells (i.e., NG2-glia and oligodendrocytes) are specifically ablated from the adult brain network with a subsequent analysis of the consequences. As the different glial populations are very heterogeneous, it is imperative to specifically ablate single cell populations instead of inducing cell death in all glial cells in general. Thanks to modern genetic manipulation methods, the approaches can now directly be targeted to the cell type of interest making the ablation more specific compared to general cell ablation approaches that have been used earlier on. In this review, we will give a detailed summary on different glial ablation studies, focusing on the adult mouse central nervous system and the functional readouts. We will also provide an outlook on how these approaches could be further exploited in the future.

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Section: Discussion and Outlookmentioning

confidence: 99%

Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation

Jäkel

Dimou

2017

Front. Cell. Neurosci.

387

263

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“…PLX3397 (also known as Pexidartinib; MedChemExpress, NJ) inhibits the tyrosine protein kinase c‐Kit, CSF1R, and FMS‐related tyrosine kinase 3, resulting in substantial reductions in microglial population within the brain (Elmore et al, 2014; Rice et al, 2015; Spangenberg et al, 2016; Thompson et al, 2015). This compound was incorporated into standard rat chow at 1,200 mg/kg (TD.170153 formula, Envigo, Huntingdon, UK) to provide approximately 45 mg/kg of PLX3397 in the food.…”

Section: Methodsmentioning

confidence: 99%

Partial microglial depletion is associated with impaired hippocampal synaptic and cognitive function in young and aged rats

Yegla

Boles

Kumar

et al. 2021

Glia

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The role of microglia in mediating age‐related changes in cognition and hippocampal synaptic function was examined by microglial depletion and replenishment using PLX3397. We observed age‐related differences in microglial number and morphology, as well as increased Iba‐1 expression, indicating microglial activation. PLX3397 treatment decreased microglial number, with aged rats exhibiting the lowest density. Young rats exhibited increased expression of pro‐inflammatory cytokines during depletion and repopulation and maintenance of Iba‐1 levels despite reduced microglial number. For aged rats, several cytokines increased with depletion and recovered during repopulation; however, aged rats did not fully recover microglial cell number or Iba‐1 expression during repopulation, with a recovery comparable to young control levels rather than aged controls. Hippocampal CA3–CA1 synaptic transmission was impaired with age, and microglial depletion was associated with decreased total synaptic transmission in young and aged rats. A robust decline in N‐methyl‐d‐aspartate‐receptor‐mediated synaptic transmission arose in young depleted rats specifically. Microglial replenishment normalized depletion‐induced synaptic function to control levels; however, recovery of aged animals did not mirror young. Microglial depletion was associated with decreased context‐object discrimination memory in both age groups, which recovered with microglial repopulation. Aged rats displayed impaired contextual and cued fear memory, and microglial replenishment did not recover their memory to the level of young. The current study indicates that cognitive function and synaptic transmission benefit from the support of aged microglia and are hindered by removal of these cells. Replenishment of microglia in aging did not ameliorate age‐related cognitive impairments or senescent synaptic function.

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“…Furthermore, the BBB remains intact after treatment, as assessed by Evans Blue straining [10]. However, this inhibitor is not specific for CSF-1R, as it also inhibits three other kinases: FLT3, PDGFR, and KIT [49,50]. In addition, systemic treatment with CSF-1R inhibitor leads to broad myelosuppression, impacting macrophages, HSCs, osteoclasts, and mast cells [51].…”

Section: Genetic Deletion Models In Micementioning

confidence: 97%

Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems

Waisman¹,

Ginhoux²,

Greter³

et al. 2015

Trends in Immunology

166

147

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Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer

Cited by 26 publications

References 93 publications

Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation

Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation

Partial microglial depletion is associated with impaired hippocampal synaptic and cognitive function in young and aged rats

Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems

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