PLX-5622

JOURNAL/nrgr/04.03/01300535-202606000-00077/figure1/v/2026-02-11T151048Z/r/image-tiffGerminal matrix hemorrhage in preterm neonates often leads to white matter injury, contributing to long-term neurodevelopmental impairments. As resident brain immune cells, microglia play a complex role in injury response, including inflammation and repair. Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia, their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored. Here, we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice, and intraperitoneally administered PLX5622 72 hours post–germinal matrix hemorrhage to achieve targeted, temporary microglial depletion during the peak injury response. We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation, white matter integrity, and neurobehavioral outcomes. Additionally, RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions. RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post–germinal matrix hemorrhage, thus pinpointing the critical response phases for potential interventions. Delayed PLX5622 treatment effectively depleted activated microglia, protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions. Moreover, magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice. Behaviorally, PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice. These findings suggest that, when timed to avoid interference with initial oligodendrocyte lineage cell proliferation, targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage. The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.

Retinitis pigmentosa (RP) is an inherited retinal degenerative disorder characterized by the progressive loss of retinal pigment epithelial cells and rod and cone photoreceptors and irreversible vision loss, with no effective therapies currently available. Microglia, the resident immune cells in the retina, are known to aggravate neurodegeneration when chronically activated. Here, we investigated the impact of temporally controlled microglial depletion and repopulation on retinal degeneration in rd10 mice. Using the CSF1R inhibitor PLX5622, we achieved efficient microglial depletion during the peak of degeneration (P21), followed by spontaneous microglial repopulation. Short-term-repopulated microglia displayed a ramified morphology and homeostatic transcriptomic signatures, including the downregulation of disease-associated microglia (DAM) genes and suppression of neurodegeneration-related pathways, effects that were correlated with preserved visual function and photoreceptor survival. However, long-term repopulated microglia progressively exhibited DAM phenotypes, which coincided with diminished therapeutic efficacy and exacerbated neurodegeneration. Single-cell RNA sequencing confirmed the dynamic transcriptional transitions of repopulated microglia, their altered regulon activity, and their functional association with other immune cells. 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.