Semi-synthetic sapogenin exerts neuroprotective effects by skewing the brain ischemia reperfusion transcriptome towards inflammatory resolution.

•RNA-sequencing and integrated pathway analysis reveal novel transcriptional mechanisms of neuronal damage in a rat model of transient experimental brain ischemia, involving increased differentiation of immune cells as well as reduced (cat)ion transport and synaptic activity.•The semi-synthetic sapogenin S15 reduces ischemic infarct size and neurological deficits, involving major transcriptional changes in inflammation-related pathways.•S15-dependent neuroprotection involves transcriptional modulation of phagosome specific resolution of tissue damage, chemotaxis and alternative anti-inflammatory activation of microglia.