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Background Currently, therapeutic hypothermia (TH) is the only intervention approved for the treatment of neonatal hypoxic-ischaemic encephalopathy (HIE), but the treatment window for TH is narrow (within 6 h after birth), and its efficacy is not ideal. Thus, alternative treatments are urgently needed., Our previous studies showed that Genistein-3′-sodium sulfonate (GSS), a derivative of genistein (Gen), has a strong neuroprotective effect in ischemia stroke rats, but its role in HIE is unclear. Methods The HI brain injury model was established in male Sprague-Dawley (SD) neonatal rats. Following treatment with GSS, cerebral infarction, neurological function, neuron damaged were assessed 24 h after reperfusion. RNA-Seq and bioinformatics analysis were used to explore differential expression genes (DEGs) and signals, which were validated by Western blotting subsequently. Results In this study, we found that GSS not only significantly reduced brain infarct size of rats with HIE and alleviated nerve damage, but also inhibited neuronal loss and degeneration in neonatal rats with HIE. A total of 2170 DEGs, of which 1102 were upregulated and 1068 were downregulated, were identified in the GSS group compared with the HI group. Downregulated DEGs significantly enriched in the Phagosome, NF-κB signalling pathway, Complement and coagulation cascades, and so on. Upregulated DEGs were significantly enriched in the Pathways of neurodegeneration, Glutamatergic synapse, Calcium signalling pathway, and so on. Conclusion These results indicate that GSS intervenes the process of HIE-induced brain injury by participating in multiple pathways, which provided drug candidates for the treatment of HIE.

BackgroundActivated microglia play a key role in initiating the in ammatory cascade following ischemic stroke and exert proin ammatory or anti-in ammatory effects depending on whether they are polarized toward the M1 or M2 phenotype. The present study investigated the regulatory effect of Icaritin (ICT) on microglial polarization in rats after cerebral ischemia/reperfusion injury (CI/RI) and explored the possible antiin ammatory mechanisms of ICT. MethodsA rat model of transient middle cerebral artery occlusion (tMCAO) was established. Following treatment with ICT, a G protein coupled estrogen receptor (GPER) inhibitor or an extracellular signal regulated kinase (ERK) inhibitor, the Garcia scale and rotarod test were used to assess neurological and locomotor function. 2,3,5-Triphenyltetrazolium chloride (TTC) and Fluoro-Jade C (FJC) staining were used to evaluate the infarct volume and neuronal death. The levels of in ammatory factors in the ischemic penumbra were evaluated by enzyme-linked immunosorbent assay (ELISA). In addition, Western blotting, immuno uorescence and quantitative PCR (qPCR) were used to measure the expression levels of markers of different microglial phenotypes and proteins related to the GPER-ERK-NF-κB signaling pathway. ResultsWe found that ICT treatment signi cantly decreased the cerebral infarct volume, brain water content and uorescence intensity of FJC; improved the Garcia score; increased the latency to fall and rotation speed in the rotarod test; inhibited the expression of IL-1β, TNF-α, Iba1, CD40, CD68 and p-P65-NF-κB; and increased the levels of CD206 and p-ERK. U0126 (an inhibitor of ERK) and G15 (a selective antagonist of GPER) antagonized these effects. ConclusionsThese ndings indicate that ICT plays roles in inhibiting the in ammatory response and achieving neuroprotection by regulating GPER-ERK-NF-κB signaling and then inhibits microglial activation and M1 polarization while promoting M2 polarization, which provides new therapeutic strategy against cerebral ischemia stroke.