Repurposing of pexidartinib for microglia depletion and renewal.

Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other members of the platelet derived growth factor receptor family. It is approved for treatment of tenosynovial giant cell tumors (TGCT). CSF1R is highly expressed by microglia, which are macrophages of the central nervous system (CNS) that defend the CNS against injury and pathogens and contribute to synapse development and plasticity. Challenged by pathogens, apoptotic cells, debris, or inflammatory molecules they adopt a responsive state to propagate the inflammation and eventually return to a homeostatic state. The phenotypic switch may fail, and disease-associated microglia contribute to the pathophysiology in neurodegenerative or neuropsychiatric diseases or long-lasting detrimental brain inflammation after brain, spinal cord or nerve injury or ischemia/hemorrhage. Microglia also contribute to the growth permissive tumor microenvironment of glioblastoma (GBM). In rodents, continuous treatment for 1-2 weeks via pexidartinib food pellets leads to a depletion of microglia and subsequent repopulation from the remaining fraction, which is aided by peripheral monocytes that search empty niches for engraftment. The putative therapeutic benefit of such microglia depletion or forced renewal has been assessed in almost any rodent model of CNS disease or injury or GBM with heterogeneous outcomes, but a tendency of partial beneficial effects. So far, microglia monitoring e.g. via positron emission imaging is not standard of care for patients receiving Pexidartinib (e.g. for TGCT), so that the depletion and repopulation efficiency in humans is still largely unknown. Considering the virtuous functions of microglia, continuous depletion is likely no therapeutic option but short-lasting transient partial depletion to stimulate microglia renewal or replace microglia in genetic disease in combination with e.g. stem cell transplantation or as part of a multimodal concept in treatment of glioblastoma appears feasible. The present review provides an overview of the preclinical evidence pro and contra microglia depletion as a therapeutic approach.

Repetitive and compulsive behavior after Early-Life-Pain associated with reduced long-chain sphingolipid species.

BACKGROUND: Pain in early life may impact on development and risk of chronic pain. We developed an optogenetic Cre/loxP mouse model of "early-life-pain" (ELP) using mice with transgenic expression of channelrhodopsin-2 (ChR2) under control of the Advillin (Avil) promoter, which drives expression of transgenes predominantly in isolectin B4 positive non-peptidergic nociceptors in postnatal mice. Avil-ChR2 (Cre +) and ChR2-flfl control mice were exposed to blue light in a chamber once daily from P1-P5 together with their Cre-negative mother. RESULTS: ELP caused cortical hyperexcitability at P8-9 as assessed via multi-electrode array recordings that coincided with reduced expression of synaptic genes (RNAseq) including Grin2b, neurexins, piccolo and voltage gated calcium and sodium channels. Young adult (8-16 wks) Avil-ChR2 mice presented with nociceptive hypersensitivity upon heat or mechanical stimulation, which did not resolve up until one year of age. The persistent hypersensitivy to nociceptive stimuli was reflected by increased calcium fluxes in primary sensory neurons of aged mice (1 year) upon capsaicin stimulation. Avil-ChR2 mice behaved like controls in maze tests of anxiety, social interaction, and spatial memory but IntelliCage behavioral studies revealed repetitive nosepokes and corner visits and compulsive lickings. Compulsiveness at the behavioral level was associated with a reduction of sphingomyelin species in brain and plasma lipidomic studies. Behavioral studies were done with female mice. CONCLUSION: The results suggest that ELP may predispose to chronic "pain" and compulsive psychopathology in part mediated by alterations of sphingolipid metabolism, which have been previously described in the context of addiction and psychiatric diseases.