PLX5622 / Daiichi Sankyo - LARVOL DELTA

Targeted CSR1R inhibition via PLX5622 adversely affects clinical outcome in experimental pneumococcal meningitis (ESCMID Global 2026) - No abstract available

Clinical • Clinical data • CNS Disorders • Infectious Disease • Pneumococcal Infections

The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer's and Parkinson's disease: a systematic review and meta-analysis. (PubMed, Front Aging Neurosci) - "This systematic review and meta-analysis aim to evaluate the effects of microglial depletion using colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX3397 and PLX5622, in preclinical models of AD and PD. Further studies are needed, particularly those assessing post-onset intervention, sex-specific effects, and broader behavioral and pathological endpoints to better understand the therapeutic potential of microglial modulation. https://www.crd.york.ac.uk/prospero/, identifier CRD420251075163."

Journal • Preclinical • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy. (PubMed, Acta Pharmacol Sin) - "Notably, the benefits of FPR2/ALX stimulation were attenuated in mice with autoimmune astrocytopathy after microglial depletion using the CSF1R inhibitor PLX5622 or natural killer (NK) cell depletion using an anti-NK1.1 monoclonal antibody. Additionally, the protective effects of FPR2/ALX stimulation were diminished in mice with autoimmune astrocytopathy that received the SYK inhibitor R406...FPR2/ALX stimulation suppresses autoimmune astrocytopathy: Using a mouse model of autoimmune astrocytopathy, we demonstrated that FPR2/ALX stimulation with the small molecule Quin-C1 reduces the CNS infiltration of lymphocytes and augments the anti-inflammatory activity of microglia, leading to attenuated astrocyte pathology induced by AQP4-IgG and complement-mediated attacks. Mechanistically, the benefits of FPR2/ALX stimulation using Quin-C1 involve microglia, natural killer (NK) cells, and SYK-AKT signaling."

Journal • Immunology • Inflammation • FPR2 • SYK

Microglia on Leave: PLX5622 Reveals Immune Neuronal Crosstalk in Epilepsy and Behavioral Comorbidities. (PubMed, Epilepsy Curr) - No abstract available

Journal • CNS Disorders • Epilepsy

High-dose polystyrene nanoparticles trigger aberrant activation of the MAPK pathway in spinal cord and pain hypersensitivity. (PubMed, J Nanobiotechnology) - "Notably, the PS NPs-induced hypersensitivity was reversed by microglial depletion (PLX5622) and inhibition of the MAPK pathway. Collectively, our findings delineate PS NPs-triggered sensory pathophysiology and establish a proof-of-concept mechanistic nexus between environmental pollutants and aberrant somatosensation."

Journal • Immunology • Pain

Colony-stimulating factor 1 receptor inhibition is neuroprotective to photoreceptors in retinal detachment. (PubMed, Cell Death Dis) - "Using PLX5622, a selective CSF1R inhibitor, we examined the local and systemic immune effects in RD in a novel experimental model with specific MG and Mø labeling...These findings highlight that CSF1R inhibition could create a therapeutic window to mitigate early inflammatory damage. Targeting CSF1R may represent a promising therapeutic strategy for neuroprotection in RD."

Journal • CNS Disorders • Inflammation • Retinal Disorders

More than microglial depletion: PLX5622 activates the hepatic constitutive androstane receptor to alter anesthesia and addiction. (PubMed, Neuron) - "Inactivation of CAR abolished these effects of PLX5622, indicating that the impact of PLX5622 treatment cannot be attributed exclusively to microglial depletion. Our findings raise awareness in evaluating consequences of PLX5622 treatment and provide insights into the design of specific CSF1R inhibitors."

Journal • Anesthesia • CNS Disorders • Nicotine Addiction • Psychiatry

Depleting non-resolving neuroinflammation in chronic spinal cord injury attenuates thermal hypersensitivity. (PubMed, Exp Neurol) - "We administered a 2-week treatment of the CSF1-R antagonist, PLX-5622 (PLX), to deplete inflammatory microglia/macrophages (Iba-1+-cells) within and around chronic contusion SCI lesions starting after 9-weeks post-injury and evaluated changes in locomotor functions and thermal hypersensitivity...Our work identifies that non-resolving neuroinflammation plays an active role in producing neuropathic pain and impeding endogenous repair that can be ameliorated by depleting macrophages and microglia from the spinal cord at chronic timepoints. Our work provides a novel perspective on the nature of chronic neuroinflammation after SCI as it relates to ongoing motor and sensory functions as well as axon growth."

Journal • CNS Disorders • Immunology • Inflammation • Neuralgia • Orthopedics • Pain • CSF1

Temporal modulation of microglial repopulation attenuates retinal degeneration in retinitis pigmentosa. (PubMed, Neurobiol Dis) - "Using the CSF1R inhibitor PLX5622, we achieved efficient microglial depletion during the peak of degeneration (P21), followed by spontaneous microglial repopulation...To counteract microglial reactivation, we developed a sequential 2-round depletion-repopulation strategy, which restored microglial homeostasis, reduced the expression of the proinflammatory cytokine IL-1β, preserved outer nuclear layer thickness, and sustained visual function. Our findings highlight the time-dependent plasticity of microglial phenotypes and suggest that temporally optimized microglial modulation is a promising therapeutic strategy for retinal neurodegeneration in RP."

Journal • CNS Disorders • Genetic Disorders • Inflammation • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • CDKN1A • IL1B

Microglial epigenetic memory is associated with accelerated resolution of inflammatory pain induced by prophylactic macrophage-derived small extracellular vesicles. (PubMed, bioRxiv) - "To determine whether prophylactic sEVs could attenuate pain in the absence of microglia when administering sEVs, we ablated microglia using a colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622...Furthermore, inhibiting the H3K4 mono-methyltransferase SETD7 abolished sEV-induced pain attenuation. Our findings indicate that both microglia and its epigenetic reprogramming contribute to pain prophylaxis induced by macrophage-derived sEVs, providing novel insights into the development of non-addictive preventive analgesia."

Journal • Immunology • Pain • SETD7

The Role of Microglia in Sex Differences of Noise-Induced Hearing Loss (ARO 2026) - "Methods : Mice of both sexes were fed PLX5622 medicated chow for two weeks before the start of the experiments and throughout the rest of the study...Hearing assessments before and after noise exposure were performed via auditory brainstem response (ABR) and amplitude modulation following response (AMFR) measurements... Microglia depletion reduced sex differences in noise susceptibility in mice. This was due to a greater noise-susceptibility in microglia depleted female mice compared to controls. This indicates that female microglia serve a protective role in the auditory system after noise exposure."

Inflammation • Otorhinolaryngology

Immune Response in the Spiral Ganglion Following Kanamycin-Induced Hair Cell Loss (ARO 2026) - "We directly assessed the role of T cells in SGN death after deafening using T cell deficient RNU nude rats and found that T cells are not required for SGN death after hair cell loss. Using SRG rats, we found that lack of all lymphocytes improves SGN survival in the basal, but not apical, half of the cochlea, revealing regional differences in the role of immune cells in cochlear neurodegeneration. As we have previously reported, the increase in macrophage number and activation within the cochlea precedes significant neuronal death, implying that macrophages are not simply responding to increased need for phagocytosis of neuronal debris, but rather may be casual to the death of SGNs."

CNS Disorders • Inflammation • CD4 • CD8 • KLRB1

Electroacupuncture promotes BDNF-dependent neurogenesis via microglial reprogramming in a chronic stress model. (PubMed, Chin Med) - "Our findings demonstrate that EA exerts antidepressant effects by promoting a pro-neurogenic transformation of microglia. Mechanistically, these microglia enhance BDNF function via the PKA/MeCP2/BDNF pathway, thereby facilitating hippocampal neurogenesis and restoring synaptic plasticity, which collectively alleviate depressive symptoms."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • BDNF • NTRK2

Inhibiting H3K18 Lactylation in Microglia Aggravates White Matter Injury after Intracerebral Hemorrhage in Mice. (PubMed, Brain Res Bull) - "These results demonstrated that lactate-derived H3K18 lactylation (H3K18la), orchestrated by p300/CBP-mediated epigenetic reprogramming, serves as a critical endogenous neuroprotective axis of WMI following ICH. Microglia emerge as the cellular executors of this pathway. This lactate-p300/CBP-H3K18la axis thus represents a therapeutically targetable mechanism for enhancing post-hemorrhagic brain repair through microglia-guided myelin regeneration."

Journal • Preclinical • Alzheimer's Disease • Cerebral Hemorrhage • Cognitive Disorders • Hematological Disorders • Solid Tumor • MBP

BTLA-mediated regulation of neuroimmune responses enhances recovery after intracerebral hemorrhage. (PubMed, J Neuroinflammation) - "The agonistic anti-BTLA antibody significantly attenuates neuroinflammation and reduces brain injury following ICH, accompanied by enhanced neurological recovery. This protective effect appears to be mediated through microglia-dependent mechanisms. Our findings highlight BTLA may be a novel and promising immunomodulatory target for the treatment of ICH."

Journal • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Vascular Neurology • BTLA • CD8

Microglia and Retinal Vascularity: A Deeper Dive into Branching Dynamics. (PubMed, Curr Eye Res) - "In vitro, co-culture with microglia enhanced endothelial cell tube formation and sprouting. Our findings reveal a strong association between microglial distribution and vascular patterning, supporting the role of microglia in normal retinal vascular development and offering perspectives for future research."

Journal • CX3CR1

Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy. (PubMed, Brain Behav Immun) - "Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation

Model of selective neurodegeneration driven by a Ccp1 mutation leads to atypical microglia with an increased response to pathological stimuli. (PubMed, Brain Behav Immun) - "In vivo microglial depletion was achieved with the CSF1R inhibitor PLX5622...Consistent with this, animals showed altered motor behaviour, indicating functional consequences of microglial dysfunction. Together, these findings identify Ccp1 as a key regulator of microglial homeostasis and demonstrate how cytoskeletal disruption can reshape microglial responses in neurodegenerative environments, providing mechanistic insight and potential therapeutic targets."

Journal • CNS Disorders • Inflammation

NLRP3 facilitates α-synuclein-induced dopaminergic neuronal senescence in a mouse model of Parkinson's disease through SATB1/DNA damage/p21 signaling pathway. (PubMed, Acta Pharmacol Sin) - "Depletion of microglia by administration of the CSF1R inhibitor PLX5622 (1200 ppm) in diet for 1 week significantly attenuated α-synuclein aggregation, iron dysregulation and cellular senescence in the substantia nigra of PD mouse model...Moreover, genetic knockout of NLRP3 effectively mitigated α-syn-A53T-induced cellular senescence in these neurons by suppressing the SATB1/DNA damage/p21 signaling pathway. These results highlight the critical role of microglia in promoting dopaminergic neuronal senescence and suggest that NLRP3 may serve as a promising therapeutic target for early intervention in PD to mitigate neuronal senescence and subsequent neurodegeneration."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • CDKN1A • NLRP3 • SATB1

Activation of Wnt3a Signaling Rescues the Analgesic Efficacy of Morphine by Regulating Microglial Reactivation in the Spinal Cord. (PubMed, Glia) - "Ablation of the microglial population by PLX5622 revealed that microglial cells were required for Wnt3a to restore the analgesic efficacy of morphine. These findings demonstrate that Wnt3a signaling activation can rescue the analgesic effect of morphine and suppress morphine tolerance-induced neuroinflammation by regulating microglial reactivation in the spinal cord. This study provides mechanistic insights into the pathophysiology of morphine tolerance and potential therapeutic targets to control morphine-induced neuroinflammation."

Journal • Inflammation • Pain • STAT3 • WNT3A

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