PLX5622 / Daiichi Sankyo - LARVOL DELTA

Negative feedback control of cough hypersensitivity by microglia in chronic cough (ERS 2026) - "PLX5622 were used to specifically eliminate microglia... microglia acted as a key homeostatic modulator, negatively regulating cough hypersensitivity in chronic cough."

Chronic Cough • Cough • Immunology • Respiratory Diseases • FOS • NTS

Sacral Nerve Modulation Alleviates Neuropathic Pelvic Pain Through Modulation of the Spinal Immune Microenvironment and Microglial Activation. (PubMed, J Neuroimmune Pharmacol) - "Exogenous CX3CL1, LPS, minocycline, and PLX5622 were employed to validate the roles of microglia and the CX3CL1-CX3CR1 axis in SNM-induced analgesia. SNM alleviates NPP by inhibiting CX3CL1-CX3CR1-mediated microglial activation and downstream inflammatory signaling, thereby remodeling the spinal cord immune microenvironment. This study provides new evidence for the central immunological mechanism underlying SNM in treating chronic pelvic pain and suggests the CX3CL1-CX3CR1 axis as a potential target for combined neuromodulation therapy."

Journal • Gynecology • Immunology • Inflammation • Musculoskeletal Pain • Pain • CX3CL1 • CX3CR1 • IL1B • IL6 • TNFA

Mismatch negativity matures in adolescence and without sensitivity to microglial depletion. (PubMed, Neuropsychopharmacology) - "We found that microglial depletion with PLX5622 in adolescence arrests the development of resting oscillations in frontal areas, but does not affect the development of deviance detection, other signatures of visual context processing, or prefrontal-visual functional connectivity. Our findings suggest (a) a key component of mismatch negativity develops in adolescence, a period of vulnerability to schizophrenia, and (b) the development underlying this component does not require robust microglia activity, clarifying the developmental role of microglia in higher-order visual processing."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Gestational inhibition of CSF1R signaling using PLX5622 drives musculoskeletal changes in postnatal offspring. (PubMed, Cells Dev) - "Combined, we observed significant disruptions to cranioskeletal and mandibular morphologies, and notable changes in the shape of the muscles of mastication and tongue in newly born pups exposed to the CSF1R inhibitor PLX5622 in utero. By assessing the craniofacial skeleton and associated musculature at birth, we provide a more direct view of how inhibition of CSF1R signaling across embryogenesis contributes to changes in musculoskeletal development during periods of craniofacial morphogenesis."

Journal • Musculoskeletal Diseases • CSF1R

Endothelial epigenetic senescence driven microglial activation mediates cardio-retinal neuroinflammation in heart failure. (PubMed, Theranostics) - "The functional relevance of TGFβ2 and microglia was tested using anti-TGFβ2 antibody administration and microglial depletion with PLX5622 treatment. TAC mice exhibited pronounced retinal thinning, diminished electroretinography (ERG) amplitudes, and reduced vascular density...Endothelial-specific disruption of TGFβ2 signaling is sufficient to protect the retina independently of primary cardiac recovery. Targeting the TGFβ2-endothelial-microglia axis may represent a promising therapeutic strategy for preventing retinal neurovascular degeneration associated with systemic cardiac disease."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • CDKN1A • EP300 • IL1B • IL6 • TGFB2 • TNFA

Microglia regulate sleep and thermoregulatory stability. (PubMed, Brain Behav Immun) - "Male and female C57BL/6J mice (n = 128) were implanted with telemetry devices for continuous core body temperature monitoring and maintained on either a control diet or diet containing the CSF1R-inhibitor PLX5622 (PLX) to pharmacologically deplete microglia...These findings collectively suggest that microglia contribute to thermoregulatory processes and sleep stability in a sex-dependent manner, supporting a role for microglia in coordinating physiological homeostasis. Together, our results support a neuroimmune framework in which microglia may help coordinate thermoregulation and sleep, as microglial depletion was associated with dysregulation of both processes."

Journal • CNS Disorders • Sleep Disorder

Ouabain Relieves Sleep Deprivation-Induced Anxiety-Like Behavior in Mice by Suppressing Hippocampal Neuroinflammation and Oxidative Stress. (PubMed, Brain Behav) - "Collectively, these findings suggest that low-dose ouabain mitigates acute SD-induced anxiety-like behavior, at least in part by suppressing hippocampal neuroinflammation and oxidative stress, and identify a potential signaling axis for further investigation."

Journal • Preclinical • CNS Disorders • Inflammation • Mood Disorders • Psychiatry • IL10 • IL1B • IL4 • TNFA

CSF1R+ Macrophages and Osteoclasts Are Essential for Limb Bone Development During Embryogenesis. (PubMed, J Dev Biol) - "Interestingly, strain-specific defects were observed in the heel, where most of the CD1 mice presented with absent talus and underdeveloped calcaneus bones, while the C57BL/6 mice presented with milder developmental disruptions in both bones. Taken together, our data demonstrate that PLX5622 effectively depletes CSF1R-expressing macrophages and osteoclasts in embryonic limbs and suggest an essential role for embryonic CSF1R+ cells in driving limb bone morphogenesis."

Journal • CNS Disorders • Developmental Disorders • Psychiatry • CSF1R

Carboplatin induces optic nerve oligodendrocyte loss and impairs myelin sheath microstructure in a mouse model of neurofibromatosis type 1 (NF1). (PubMed, Neuro Oncol) - "Our findings demonstrate that carboplatin induces oligodendroglial toxicity in Nf1-mutant optic nerves, which can be mitigated by clemastine, PLX5622, or dietary cholesterol following carboplatin exposure."

Journal • Preclinical • Brain Cancer • Genetic Disorders • Glioma • Neurofibromatosis • Oncology • Solid Tumor • NF1

Microglial Epigenetic Memory is Associated with Accelerated Resolution of Inflammatory Pain Induced by Prophylactic Macrophage-Derived Small Extracellular Vesicles. (PubMed, J Inflamm Res) - "Microglia were ablated using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 prior to sEV administration...These findings support a model in which sEVs establish a primed, memory-like state in spinal microglia, characterized by enhancer-associated chromatin changes that confer latent regulatory potential and enhance resolution of subsequent inflammatory pain. This work links extracellular vesicles to microglial epigenetic remodeling and suggests a potential strategy for non-addictive, preventive pain therapeutics."

Journal • Immunology • Inflammation • Pain • SETD7

Microglia-mediated neuroinflammation and demyelination contribute to pain and social behavioral deficits after spared nerve injury. (PubMed, Neuroscience) - "Importantly, pharmacological ablation of microglia via intraperitoneal administration of the CSF1R inhibitor PLX5622 markedly alleviated pain hypersensitivity, restored social novelty behavior, and rescued demyelination in both regions. Together, these findings identify microglia-driven central demyelination as a critical pathological mechanism linking peripheral nerve injury to sensory and social dysfunction, and highlight microglia-oligodendrocyte-myelin interactions as potential therapeutic targets for chronic pain."

Journal • Immunology • Inflammation • Neuralgia • Pain • Solid Tumor • IL10 • IL1B • TNFA

PLX3397 Reshapes Hepatic Lipid Metabolism Independent of Microglial Depletion. (PubMed, Neurosci Bull) - "Colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX5622 and PLX3397 (pexidartinib), are widely used for in vivo microglial depletion and for investigating microglial functions and therapeutic potential. By uncovering previously unrecognized peripheral effects of PLX3397, our findings identify brain-periphery interactions as a potential source of confounding in studies of microglial function. These results suggest that systemic metabolic effects should be carefully considered when interpreting neural or behavioral phenotypes in pharmacological microglia depletion paradigms."

Journal • Anesthesia • CNS Disorders • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry

Endothelial TGFβ signaling modulates choroidal neovascularization severity via myeloid-endothelial cell interaction. (PubMed, Front Immunol) - "In this study, we used a laser-induced CNV model in mice with endothelial-specific Tgfbr2 deletion and concomitant MP depletion via PLX5622...Transcriptome and RNA localization of CNV lesions identified fibrinogen alpha chain (Fga) as a MP-derived factor that is exclusively upregulated in mice without endothelial TGFβ signaling. These findings suggest a novel TGFβ-dependent interaction between endothelial cells and MP that promotes angiogenesis through microglia derived Fga expression."

Journal • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • FGA • TGFBR2

BRAINatomy: mechanisms and image-defined loci of cognitive and endocrine damage after therapeutic childhood brain irradiation (ISPNO 2026) - "Preclinical studies are assessing the cognitive effects of hypothalamic irradiation, microglial depletion and endocrine replacement: CSF1R inhibitor PLX5622 effectively depletes microglia, revealing sex-specific responses (82% depletion females vs. 54% males), and novel collimators achieve hypothalamic irradiation. BRAINatomy identified critical putative neuroprotection targets. Ongoing validation, mechanistic preclinical studies and clinical trials will inform next-generation RT treatment to optimize cognitive outcomes for childhood brain tumour survivors."

Clinical • Brain Cancer • Endocrine Disorders • Growth Hormone Deficiency • Medulloblastoma • Solid Tumor

Characterizing the Reactive Metabolites of Colony-Stimulating Factor 1 Receptor Inhibitor PLX5622 in Liver Microsomes and Mice. (PubMed, Chem Res Toxicol) - "Reduced glutathione (GSH) and methoxyamine (NH2OMe) were used to capture reactive intermediates. These insights into the metabolic pathways of PLX5622 are valuable for further study of its safety and potential drug interactions of CYP3A. Future studies using human primary hepatocytes or physiologically human-relevant models such as liver-on-a-chip systems are warranted to confirm clinical relevance and better predict in vivo outcomes."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology

Modulating Microglial Dynamics Through CSF1R Inhibition Impacts Cognitive Performance In A FTD- TDP43 Mouse Model (ENCALS 2026) - "Using the CSF-1R inhibitor PLX5622, we implemented two complementary strategies: (i) sustained microglial depletion during the disease progression stages and (ii) transient depletion followed by endogenous repopulation before the end stage, to assess effects on cognition, neuronal survival, and neuroinflammatory profiles in an FTD-TDP-43 mouse model...In the early repopulation paradigm, mice undergoing microglial repopulation also showed improved cognitive performance compared with untreated FTD-TDP43 animals. In both cases, these effects were accompanied by changes in neuroinflammatory marker profiles, consistent with a modified inflammatory environment following microglial turnover.Conclusion These findings underscore the relevance of microglial phenotypic remodeling in FTD and highlight CSF-1R inhibition as a promising strategy to modulate neuroinflammation and preserve neuronal function."

Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Inflammation • Proteinopathy • TARDBP

Timed microglia depletion promotes functional network reorganization and motor recovery after stroke. (PubMed, Brain Commun) - "Microglia were depleted between days 3 and 7 post-stroke using PLX5622, a colony-stimulating factor 1 receptor inhibitor...Following repopulation, microglial cells showed altered morphology and gene expression profiles. These findings reveal that transient microglial modulation during the subacute phase after stroke promotes cortical network reorganization and motor recovery."

Journal • Cardiovascular • Ischemic stroke

Microglia modulate concussion biomarkers and cognitive recovery in male mice. (PubMed, bioRxiv) - "Using PLX5622 to deplete microglia in a preclinical model, we observed opposing cognitive effects: depletion rescues deficits from concussion alone but eliminates preconditioning-induced protection...Together, these results demonstrate a dual, context-dependent role for microglia in concussion outcomes and establish brain-derived EVs as a powerful tool for surveilling neuroinflammatory processes governing recovery. Microglial state during concussion affects cognitive recovery and neuron-enriched extracellular vesicle biomarkers."

Journal • Preclinical

Enhancing the specificity of microglia genetic targeting using a CSF1R inhibitor. (PubMed, Cell Rep) - "To overcome this limitation, we combined tamoxifen induction in Cx3cr1CreERT2 mice with PLX5622 treatment to accelerate peripheral macrophage turnover. In a brain infection model, this strategy increased the specificity of gene deletion in microglia in Cx3cr1CreERT2 mice and eliminated confounding contributions from peripheral macrophages. In sum, the use of a CSF1R inhibitor provides a solution to enhance the precision of microglial genetic manipulation using a common Cre line."

Journal • Infectious Disease • CX3CR1

Microglia depletion alleviates the disruptions in circadian rhythms and anxiety caused by bmal1 deficiency. (PubMed, Brain Behav Immun Health) - "Furthermore, we observed a normalization of proinflammatory cytokine levels (IL-1β and TNF-α) upon PLX5622 treatment, indicating a potential link between microglial modulation and neuroinflammation. Our findings highlight the intricate interplay between circadian rhythms, microglia, and neuronal health, offering insights into potential therapeutic interventions for circadian-related and neuroinflammatory disorders."

Journal • Inflammation • Mood Disorders • Psychiatry • ARNTL • BMAL1 • IL1B • TNFA

Expression and Role of Colony Stimulating Factor 1 Receptor During Odontogenesis. (PubMed, J Dev Biol) - "Here, we examined the spatiotemporal expression of CSF1R during tooth development and inhibited CSF1R pharmacologically in utero using PLX5622 during early stages of tooth morphogenesis...In contrast, postnatal CSF1R inhibition did not affect the structure or continuous growth of adult incisors. Together, these findings demonstrate a temporally restricted, indirect role for CSF1R in odontogenesis that is independent of tooth eruption and associated with remodeling of the bony crypts surrounding developing teeth by CSF1R-dependent cells."

Journal • CSF1R

Radiosynthesis and initial in vivo evaluation of [18F]PLX5622 for imaging Colony Stimulating Factor 1 Receptor on microglia (SNMMI 2026) - "Preliminary imaging data with [18F]PLX5622 suggest reversible brain uptake in rodents. Further evaluation of [18F]PLX5622 as a potential PET radiotracer is planned, including autoradiography and in vivo blockade to confirm selective uptake, optimization of the radiosynthesis, and investigation of 11C-labeled analogs."

Preclinical • CNS Disorders • Gastrointestinal Disorder • CSF1R

Radiosynthesis and initial in vivo evaluation of [18F]PLX5622 for imaging Colony Stimulating Factor 1 Receptor on microglia (SNMMI 2026) - "Preliminary imaging data with [18F]PLX5622 suggest reversible brain uptake in rodents. Further evaluation of [18F]PLX5622 as a potential PET radiotracer is planned, including autoradiography and in vivo blockade to confirm selective uptake, optimization of the radiosynthesis, and investigation of 11C-labeled analogs."

Preclinical • CNS Disorders • Gastrointestinal Disorder • CSF1R

A Novel Role of the Perineurium: Evidence for an Essential Function for Macrophage Maintenance and Increase in Isolated Peripheral Nerves. (PubMed, J Peripher Nerv Syst) - "We identified a pivotal role of the perineurium in supporting macrophage maintenance and expansion. The perineurium may serve as a source of trophic factors and/or may form a barrier maintaining a critical concentration of trophic factors within the endoneurium. Additionally, macrophages may originate from a cell pool within the perineurium."

Journal

Enhanced engraftment of transplanted microglia through host microglia depletion in the embryonic brain. (PubMed, Neurosci Res) - "Pregnant mice were fed a diet containing a colony-stimulating factor 1 receptor inhibitor (PLX5622) in advance to reduce resident microglia in the embryos...Microglial transplantation significantly reduced the size of these cavities. These results suggest that transient depletion of host microglia enhances embryonic microglial transplantation and that transplanted microglia can partially restore structural abnormalities caused by microglial loss."

Journal • Transplantation • CX3CR1 • ITGAM