Danggui-Shaoyao San Promotes Microglia-Mediated Oligodendrocyte Maturation and White Matter Repair After Stroke

Ischemic stroke is a leading cause of long-term disability, yet effective therapies that promote white matter repair and remyelination during the recovery phase remain limited. Danggui-Shaoyao-San (DSS) has demonstrated neuroprotective effects, but its mechanisms during the recovery phase are unclear. Here, we tested whether delayed DSS treatment improves long-term outcomes after transient focal ischemia by reprogramming microglia to support oligodendroglial differentiation and remyelination. In a mouse model of transient middle cerebral artery occlusion, DSS starting 30 min after reperfusion and continued throughout the recovery period produced sustained improvements in neurological function. These benefits were accompanied by preserved myelin-axon coupling, improved myelin ultrastructure in peri-infarct white matter, and enhanced progression of oligodendrocyte lineage cells toward a mature myelin-forming state. DSS reduced pro-inflammatory microglial activation while increasing repair associated microglial markers across the subacute period. Mechanistically, DSS enhanced microglial estrogen receptor ERα and ERβ signaling, increased expression of the ER associated corepressor CtBP, and suppressed NF-κB activation. In BV2 microglia, DSS containing serum dampened LPS-induced inflammatory gene expression programs and promoted repair associated markers, and pharmacological ER blockade reversed DSS-driven microglial polarization. Importantly, conditioned medium from DSS-treated microglia rather than direct exposure to DSS promoted oligodendroglial differentiation and induced pro-regenerative gene expression in oligodendrocyte lineage cells, supporting a paracrine signaling mechanism from microglia to oligodendroglia. Together, our findings identify DSS as a delayed recovery phase intervention that improves long term outcomes after ischemic stroke and suggest that ER dependent microglial reprogramming is a tractable upstream target for promoting remyelination and white matter repair.