PLX5622 / Daiichi Sankyo - LARVOL DELTA

Targeting CSF1R to overcome myeloid cell suppression in CART therapy (ASH 2025) - "Using lymphomamodels, B6 mice were engrafted with the luciferase+ CD19+ murine lymphoma cell line TBL-12 (1x106cells i.v. 1 day after 250 mg/kg cyclophosphamide)...When TSHR+ THJ529tumors reached approximately 100 mm3, mice were randomized by tumor volume and treated withCSF1R inhibitor PLX5622 (600mg/kg) or vehicle control, followed by either UTD or TSHR-CART cells5x106 i.v. Mice treated with TSHR-CART + PLX5622 showed significantly improved tumor control vs TSHR-CART + vehicle control (p<0.0001) or UTD + PLX5622 (p<0.0001). Together, our results highlight immunosuppressive myeloid cells which express CSF1R as a major celltype limiting CART efficacy in both solid and liquid tumors. We also identified a strategy to overcomemyeloid-mediated suppression of CART cells by targeting CSF1R with antibody or small moleculeinhibitors."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • CSF1R

Astrocyte regulates neuroinflammation and myelination in BCCAO-Related cognitive impairment via the PIAS1-STAT1 pathway. (PubMed, Brain Res) - "Further intervention studies showed that the microglial depleter PLX5622 failed to effectively rescue myelin damage and cognitive impairment, while astrocytes remained persistently activated...In summary, the findings of this study demonstrate that reduced expression of PIAS1 in astrocytes following mild cerebral ischemia plays a crucial role in triggering secondary cognitive deficits and myelin degeneration. Furthermore, PIAS1 regulates astrocyte-mediated inflammatory responses via a STAT1-dependent pathway, offering new perspectives on the underlying mechanisms of VaD and potential therapeutic interventions."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Reperfusion Injury • PIAS4

Myeloid cell recruitment propels right ventricular dysfunction in HFpEF via sterile inflammation. (PubMed, bioRxiv) - "To test whether myeloid cells are causally involved in the development of RV remodeling in HFpEF, we additionally treated RV-HFpEF mice with the colony stimulating factor 1 receptor inhibitor PLX-5622 (PLX) to deplete myeloid cells...What is new: We explore myeloid cell dynamics in a novel three-hit experimental HFpEF mouse model with RV hypertrophy, RV end-systolic pressure and RV dysfunction.In this model, RV dysfunction was associated with macrophage expansion, monocyte recruitment and extracellular matrix deposition, whilst macrophage depletion partly reversed these changes and rescued RV hemodynamics.HFpEF patients with RV dilation or RV dysfunction exhibit unique leukocyte dynamics and inflammatory profiles when compared to HFpEF patients with normal RV function or diameters. Clinical implications: There exists a major clinical discrepancy between high incidence of RV dysfunction associated to HFpEF and a lack of targeted treatment strategies.Our novel three-hit..."

Journal • Cardiovascular • Fibrosis • Heart Failure • Inflammation • CX3CR1

Carboplatin impairs optic nerve myelination in Neurofibromatosis Type 1 (NF1) by reducing cholesterol levels and inducing oligodendrocyte loss (SNO 2025) - "Our findings revealed that carboplatin induces optic nerve oligodendroglial toxicity in the context of NF1, which can be rescued by clemastine, PLX5622, or dietary cholesterol."

Brain Cancer • Genetic Disorders • Glioma • Neurofibromatosis • Solid Tumor • NF1

Deciphering spatio-temporal trajectories of tissue adaptation after surgical resection of glioblastoma (SNO 2025) - "Similar reduction of tumor-neuron synaptic contacts was observed after depletion of microglia with PLX5622, supporting a co‑operative metabolic‑inflammatory-axis. Post-resection metabolic adaptation and tumor regrowth link was confirmed in vivo leveraging a LDH inhibitor or ROS scavenger demonstrating a significant decrease in tumor relapse. Our data delineate a narrow, druggable window immediately after surgery in which hypoxic‑inflammatory-reprogramming metabolically and synoptically primes glioblastoma for recurrence, nominating peri‑cavity lactate-shuttling or microglial activation as actionable adjuvant targets."

Brain Cancer • Cardiovascular • Glioblastoma • Solid Tumor • CXCL13 • HIF1A

Vessel-Associated Microglia Maintain Vascular Integrity and Prevent Early Hemorrhage in Glioblastoma (SNO 2025) - "To address this, we characterize vessel-associated myeloid cells in murine gliomas with high spatial and temporal resolution, leveraging in vivo two-photon imaging, MRI, and transgenic mouse lines.To investigate the role of microglia in glioma vasculature, we pretreated glioma-bearing mice with CSF1R inhibitors (PLX3397 & PLX5622) to ablate microglia prior to tumor inoculation. Using TMEM119CreER/+:R26tdTomato/+ mice, we confirmed these vessel-associated cells as brain-resident microglia, not infiltrating macrophages.Quantitatively, ~60% of peritumoral microglia were vessel-associated, compared to ~30% in naïve or contralateral hemispheres. These microglia displayed elongated somata and processes aligned with vessels or wrapping around vessels, which is a phenotype also observed following single-vessel photothrombosis, suggesting a response to impaired blood flow and BBB leakage.Our findings uncover a critical neurovascular role for vessel-associated microglia..."

Brain Cancer • Cerebral Hemorrhage • CNS Disorders • Glioblastoma • Glioma • Hematological Disorders • Solid Tumor • Thrombosis

Mismatch negativity develops in adolescence and independently of microglia. (PubMed, bioRxiv) - "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

Deciphering spatio-temporal trajectories of tissue adaptation after surgical resection of glioblastoma (WFNOS 2025) - P1 | "Similar reduction of tumor-neuron synaptic contacts was observed after depletion of microglia with PLX5622, supporting a co‑operative metabolic‑inflammatory-axis. Post-resection metabolic adaptation and tumor regrowth link was confirmed in vivo leveraging a LDH inhibitor or ROS scavenger demonstrating a significant decrease in tumor relapse. Our data delineate a narrow, druggable window immediately after surgery in which hypoxic‑inflammatory-reprogramming metabolically and synoptically primes glioblastoma for recurrence, nominating peri‑cavity lactate-shuttling or microglial activation as actionable adjuvant targets."

Brain Cancer • Cardiovascular • Glioblastoma • Solid Tumor • CXCL13 • HIF1A

Carboplatin impairs optic nerve myelination in Neurofibromatosis Type 1 (NF1) by reducing cholesterol levels and inducing oligodendrocyte loss (WFNOS 2025) - "Our findings revealed that carboplatin induces optic nerve oligodendroglial toxicity in the context of NF1, which can be rescued by clemastine, PLX5622, or dietary cholesterol."

Brain Cancer • Genetic Disorders • Glioma • Neurofibromatosis • Solid Tumor • NF1

Vessel-Associated Microglia Maintain Vascular Integrity and Prevent Early Hemorrhage in Glioblastoma (WFNOS 2025) - "To address this, we characterize vessel-associated myeloid cells in murine gliomas with high spatial and temporal resolution, leveraging in vivo two-photon imaging, MRI, and transgenic mouse lines.To investigate the role of microglia in glioma vasculature, we pretreated glioma-bearing mice with CSF1R inhibitors (PLX3397 & PLX5622) to ablate microglia prior to tumor inoculation. Using TMEM119CreER/+:R26tdTomato/+ mice, we confirmed these vessel-associated cells as brain-resident microglia, not infiltrating macrophages.Quantitatively, ~60% of peritumoral microglia were vessel-associated, compared to ~30% in naïve or contralateral hemispheres. These microglia displayed elongated somata and processes aligned with vessels or wrapping around vessels, which is a phenotype also observed following single-vessel photothrombosis, suggesting a response to impaired blood flow and BBB leakage.Our findings uncover a critical neurovascular role for vessel-associated microglia..."

Brain Cancer • Cerebral Hemorrhage • CNS Disorders • Glioblastoma • Glioma • Hematological Disorders • High Grade Glioma • Solid Tumor • Thrombosis

Early microglia-mediated neuroinflammation after status epilepticus causes behavioral dysfunction and neurocognitive deficits but not epilepsy in mice. (PubMed, Brain Behav Immun) - "Suppression of microgliosis with PLX eliminates the neuroinflammatory response after SE, and this is associated with prevention of long-term behavioral impairment. However, this intervention does not influence the development of epilepsy. These results demonstrate that acquired epilepsy and its behavioral comorbidities have different pathogenic mechanisms after SE, with early microglial driven neuroinflammation most relevant to the latter."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Epilepsy • Inflammation • Vascular Neurology • CSF1 • CX3CR1 • GFAP • MRC1

Deciphering spatio-temporal trajectories of tissue adaptation after surgical resection of glioblastoma (WFNOS 2025) - "Similar reduction of tumor-neuron synaptic contacts was observed after depletion of microglia with PLX5622, supporting a co‑operative metabolic‑inflammatory-axis. Post-resection metabolic adaptation and tumor regrowth link was confirmed in vivo leveraging a LDH inhibitor or ROS scavenger demonstrating a significant decrease in tumor relapse. Our data delineate a narrow, druggable window immediately after surgery in which hypoxic‑inflammatory-reprogramming metabolically and synoptically primes glioblastoma for recurrence, nominating peri‑cavity lactate-shuttling or microglial activation as actionable adjuvant targets."

Brain Cancer • Cardiovascular • Glioblastoma • Solid Tumor • CXCL13 • HIF1A

The involvement of microglia and the CXCL16-CXCR6 axis in the recruitment of CD8+ T cells to an amyloidogenic mouse brain. (PubMed, Sci Rep) - "Although we demonstrated a strong association between microglial Cxcl16 and AD pathology, PLX5622-sensitive microglia are dispensable in the recruitment of Cxcr6+CD8+ T cells to the brain of APP/PS1 mice. Future in vivo analysis will help to dissect the mechanism of CD8+ T cell recruitment to the brain."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • CD8 • CXCL16 • CXCR6

Microglia-mediated Perineuronal nets loss contributes to social memory deficit in male mice after repeated neonatal sevoflurane exposure. (PubMed, Brain Behav Immun) - "Our findings reveal microglia-dependent PNN degradation as a key mechanism underlying early-life sevoflurane exposure-induced social memory impairments in male mice. Targeting microglial activity or preserving PNNs may offer new strategies to prevent anesthesia-induced neurodevelopmental impairments."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • CNS Disorders

Traumatic brain injury exacerbates alcohol consumption and neuroinflammation with decline in cognition and cholinergic activity. (PubMed, Transl Psychiatry) - "Notably, depleting microglial cells by systemic PLX 5622 administration enhanced cholinergic activity, as measured by electrophysiology and acetylcholine biosensing. These findings suggest that TBI promotes alcohol consumption and impairs cognitive abilities through microglia activation and reduced cholinergic function. This research provides critical insight into the mechanisms linking TBI with increased alcohol use and cognitive deficits, potentially guiding future therapeutic strategies."

Journal • CNS Disorders • Cognitive Disorders • Inflammation • Vascular Neurology

Diet gel-based oral drug delivery system for controlled dosing of small molecules for microglia depletion and inducible Cre recombination in mice. (PubMed, Lab Anim (NY)) - "This study demonstrates that a diet gel-based drug delivery system offers a minimally invasive alternative to current drug application methods for PLX5622 and tamoxifen. This approach could be useful for other drugs or tissues beyond the retina."

Journal • Preclinical • Ophthalmology • CX3CR1

Astrocyte-microglia crosstalk in the hippocampus mediates cognitive impairments induced by chronic intermittent hypoxia. (PubMed, Neurobiol Dis) - "Pharmacological depletion of microglia using PLX5622 ameliorated these CIH-induced impairments...Notably, blocking C3aR with SB290157 attenuated microglial overactivation, reduced aberrant synaptic engulfment, and improved cognitive performance in CIH-exposed mice. Collectively, these findings demonstrate that C3/C3aR-mediated astrocyte-microglia crosstalk contributes to CIH-induced cognitive dysfunction by activating microglia to excessive phagocytosis of synapses."

Journal • Alzheimer's Disease • Cognitive Disorders • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Evaluating the Optic Nerve Crush Model to Understand the Function of Microglia in Glaucoma Neuroprotection. (PubMed, Invest Ophthalmol Vis Sci) - "Microglial function was examined by depleting microglia with the CSF1R inhibitor PLX5622 and using Trem2-deficient mice with dampened microglial activation...This finding challenges the utility of the ONC model for evaluating microglia-based glaucoma treatments. Additionally, the study reaffirms the value of combining fluorescent reporter mouse lines with noninvasive ocular imaging for streamlining future research."

Journal • Glaucoma • Ophthalmology • ITGAX

Repopulating Microglia Suppress Peripheral Immune Cell Infiltration to Promote Poststroke Recovery. (PubMed, CNS Neurosci Ther) - "Transient microglial depletion and repopulation via PLX5622 during the acute phase post stroke facilitate the recovery of neurological function. This immunomodulatory strategy offers a promising and clinically translationally relevant approach to enhance functional recovery following ischemic brain injury."

Journal • Cardiovascular • CNS Disorders • Immunology • Inflammation • Ischemic stroke • Vascular Neurology

Intraoperative application of an antioxidant nanoparticle-hydrogel targeting microglia regulates neuroinflammation in traumatic brain injury. (PubMed, J Nanobiotechnology) - "The colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 has shown promise in suppressing neuroinflammation by depleting microglia, but it lacks specificity in targeting microglia at the injury site...Together, these effects synergistically improved neurological function recovery in TBI mouse models. This innovative strategy offers a comprehensive and targeted approach to managing neuroinflammation after TBI, providing a promising avenue for advancing TBI therapies."

Journal • CNS Disorders • Inflammation • Vascular Neurology

Pro-Inflammatory Microglia Exacerbate High-Altitude-Induced Cognitive Impairment by Driving Lipid Droplet Accumulation in Astrocytes. (PubMed, Antioxidants (Basel)) - "Microglia were depleted using PLX5622, and mice were exposed to hypoxia or lipopolysaccharide (LPS) to validate microglia's role in driving astrocytic LD accumulation and cognitive decline. Minocycline effectively restores brain lipid homeostasis and mitigates cognitive impairment. This study provides novel insights into HACI mechanisms and suggests potential therapeutic strategies."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Inflammation • IL1B

HCAR2 Exerts Anti-Depressive Effects on Corticosterone-Induced Depression in Mice by Modulating Microglial Activity. (PubMed, Front Biosci (Landmark Ed)) - "Activation of HCAR2 can reduce depressive-like behaviors, neuronal injury, and neuroinflammation. Our findings suggest these neuroprotective effects are, at least in part, mediated through modulation of microglial activity by HCAR2."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Psychiatry

Macrophage Targeting Protects Nerve Structure and Improves Muscle Innervation in a Mouse Model of Charcot-Marie-Tooth 2J. (PubMed, Glia) - "Remarkably, treatment with PLX5622 not only ameliorated the peripheral neuropathy to an exceptionally high degree but also prevented distal axonal degeneration and denervation of neuromuscular junctions, leading to preserved motor function in CMT2J mice. These findings highlight macrophage-mediated inflammation as a treatment target in peripheral nerves not only in previously investigated demyelinating but also in axonal CMT neuropathies."

Journal • Preclinical • Genetic Disorders • Inflammation • Pain • CSF1R

Nanoparticles loaded with a CSF1R antagonist selectively depletes microglial cells and modulates inflammation in spinal cord injury. (PubMed, J Control Release) - "The colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 has been used to deplete microglia in the central nervous system...Furthermore, locally administered PLX NP downregulated proinflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β), increasing the M2/M1-like microglia ratio, thus reducing inflammation in a SCI contusion model. Our data support the hypothesis that local treatment with PLX NP, a formulation with a high translational value, reduces neuroinflammation and shifts the microglia population toward a pro-resolutive phenotype, with potential applications in SCI and central nervous system inflammatory diseases."

Journal • CNS Disorders • Inflammation • Orthopedics • IL1B • IL6 • TNFA

Microglia depletion in a mouse model of prenatal and postnatal immune activation. (PubMed, Brain Behav Immun) - "At weaning, offspring was exposed throughout adolescence (4 weeks) to either a diet containing Colony Stimulating Factor-1 receptor inhibitor (PLX 5622, PLX) to reduce microglia, or standard diet...Molecular data, beside a robust downregulation of microglia markers in PLX diet groups, also showed that EIA condition increased interleukin-6 (il-6) expression in EIA males in both mPFC and HP, and elevated il-1β levels in both sexes in mPFC and in male HP. Overall, these findings indicate that males have an increased vulnerability not only to the long-term behavioural and inflammatory effects of the EIA condition but also to effects of microglia depletion on behavioural outcomes."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Inflammation • Mood Disorders • Psychiatry • IL1B • IL6