Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo

Liu, Yiting; Given, Katherine S.; Dickson, Erin L.; Owens, Gregory P.; Macklin, Wendy B.; Bennett, Jeffrey L.

doi:10.1016/j.expneurol.2019.04.011

Cited by 65 publications

(55 citation statements)

References 26 publications

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“…Similarly, our past study using a clinically relevant irradiation paradigm did not show adverse physiological effects of PLX5622 treatment on the control animals [4]. Moreover, no adverse impact of PLX5622 treatment on neural stem and oligo-progenitor cell proliferation and differentiation was observed [36, 38]. Therefore, we posit that PLX5622 treatment-mediated reduction in microglia and neuroinflammation contributed significantly to restoring cognitive function.…”

Section: Discussionsupporting

confidence: 61%

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Allen

Apodaca

Syage

et al. 2019

acta neuropathol commun

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Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4–6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.

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Section: Discussionsupporting

confidence: 61%

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Allen

Apodaca

Syage

et al. 2019

acta neuropathol commun

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“…For example, sustained microglia elimination for the period of seven months in the 5xFAD mouse prevented plaque formation whereas re-population of microglia upon CSF1R inhibitor withdrawal led to robust plaque formation [69]. No adverse effects of PLX5622 treatment were observed on neural stem and oligo-progenitor cell proliferation and differentiation [70,71]. Moreover, treatment with PLX5622 showed neurocognitive benefits and attenuation of neuroinflammation in a chemobrain model [72].…”

Section: Discussionmentioning

confidence: 99%

Mitigation of helium irradiation-induced brain injury by microglia depletion

Allen

Syage

Maroso

et al. 2020

J Neuroinflammation

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Background: Cosmic radiation exposures have been found to elicit cognitive impairments involving a wide-range of underlying neuropathology including elevated oxidative stress, neural stem cell loss, and compromised neuronal architecture. Cognitive impairments have also been associated with sustained microglia activation following low dose exposure to helium ions. Space-relevant charged particles elicit neuroinflammation that persists long-term post-irradiation. Here, we investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions. Methods: Adult mice were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia 2 weeks after whole body helium irradiation (4 He, 30 cGy, 400 MeV/n). Cohorts of mice maintained on a normal and PLX5622 diet were tested for cognitive function using seven independent behavioral tasks, microglial activation, hippocampal neuronal morphology, spine density, and electrophysiology properties 4-6 weeks later. Results: PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiated animals on normal diet exhibited a range of behavioral deficits involving the medial prefrontal cortex and hippocampus and increased microglial activation. Animals on PLX5622 diet exhibited no radiation-induced cognitive deficits, and expression of resting and activated microglia were almost completely abolished, without any effects on the oligodendrocyte progenitors, throughout the brain. While PLX5622 treatment was found to attenuate radiation-induced increases in post-synaptic density protein 95 (PSD-95) puncta and to preserve mushroom type spine densities, other morphologic features of neurons and electrophysiologic measures of intrinsic excitability were relatively unaffected. Conclusions: Our data suggest that microglia play a critical role in cosmic radiation-induced cognitive deficits in mice and, that approaches targeting microglial function are poised to provide considerable benefit to the brain exposed to charged particles.

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“…Since Csf1R expression, the only receptor for Csf1, is prominent in microglia throughout the brain, Csf1R-/-mice have a more severe phenotype than the Csf1-/-, however, they exhibit increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes and substantially poorer viability [67]. Numerous Csf1R inhibitors (e.g., PLX3397, PLX5622, and AFS98) have been developed as a novel strategy for experimental depletion of microglia in rodents [73,74], however, upon treatment cessation residual microglia rapidly repopulate the CNS [75].…”

Section: Discussionmentioning

confidence: 99%

Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination

Wylot

Mieczkowski

Niedziółka

et al. 2019

Cells

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Remyelination, a highly efficient central nervous system (CNS) regenerative process, is performed by oligodendrocyte progenitor cells (OPCs), which are recruited to the demyelination sites and differentiate into mature oligodendrocytes to form a new myelin sheath. Microglia, the specialized CNS-resident phagocytes, were shown to support remyelination through secretion of factors stimulating OPC recruitment and differentiation, and their pharmacological depletion impaired remyelination. Macrophage colony-stimulating factor (Csf1) has been implicated in the control of recruitment and polarization of microglia/macrophages in injury-induced CNS inflammation. However, it remains unclear how Csf1 regulates a glial inflammatory response to demyelination as well as axonal survival and new myelin formation. Here, we have investigated the effects of the inherent Csf1 deficiency in a murine model of remyelination. We showed that remyelination was severely impaired in Csf1-/- mutant mice despite the fact that reduction in monocyte/microglia accumulation affects neither the number of OPCs recruited to the demyelinating lesion nor their differentiation. We identified a specific inflammatory gene expression signature and found aberrant astrocyte activation in Csf1-/- mice. We conclude that Csf1-dependent microglia activity is essential for supporting the equilibrium between microglia and astrocyte pro-inflammatory vs. regenerative activation, demyelinated axons integration and, ultimately, reconstruction of damaged white matter.

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Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo

Cited by 65 publications

References 26 publications

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Mitigation of helium irradiation-induced brain injury by microglia depletion

Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination

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