Genistein-3'-sodium sulfonate promotes brain functional rehabilitation in ischemic stroke rats by regulating astrocytes polarization through NF-κB signaling pathway.

The activation and polarization of astrocytes are involved in neuroinflammation and brain functional rehabilitation after ischemic stroke. Our previous studies display the neuroprotective effect of genistein-3'-sodium sulfonate (GSS) in the acute phase of cerebral ischemia-reperfusion injury (CI/RI). This study aimed to investigate the brain function improvement of GSS during the recovery period after CI/RI in rats and to explore the potential mechanism from the perspective of astrocyte activation and polarization. The transient middle cerebral artery occlusion (tMCAO) rats were treated with GSS (1 mg/kg) continuously for 28 days. The behavior tests were measured to assess neurological function. The mRNA and protein expression in affected cerebral cortex were detected on day 29 after tMCAO. Our results demonstrated that GSS treatment significantly improved the spatial and temporal gait parameters in the Catwalk gait test, prolonged the time on the stick and increased the rotation speed in the rotarod test, and decreased the time to find the hidden platform and increased the time in the target quadrant in the Morris water maze test. In addition, GFAP, GBP2, C3, IL-1ß protein expressions and Nos2A mRNA level were decreased, while Nrf2, BDNF, IL-10 protein expressions and Sphk1 and Nef2l2 mRNA levels increased after GSS treatment. Interestingly, GSS presented a strong binding affinity to TLR4 and suppressed the activation of NF-κB signaling. In conclusion, GSS can promote brain function recovery by inhibiting astrocyte activation and polarization to A1 phenotype, and enhancing astrocyte polarization to A2 phenotype via inactivating TLR4/NF-κB signaling, which provide a candidate compound for clinical rehabilitation therapy in the recovery period after ischemic stroke.

The role of neuroglial cells communication in ischemic stroke.

Ischemic stroke is one of the leading causes of death and disability globally, but its treatment options are limited due to therapeutic window and reperfusion injury constraints. Microglia, astrocytes, and oligodendrocytes are the major components of the neurovascular unit, and there is substantial evidence suggesting their contributions to maintaining homeostasis in the central nervous system. Neuroglial cells participate in neuronal physiological functions and the repair of damaged neurons through various communication methods, including gap junctions, chemical signaling, and extracellular vesicles, in conjunction with other components of the neurovascular unit. Ischemia-induced microglia and astrocytes polarize into "M1/M2" and "A1/A2" phenotypes and exert neurotoxic or neuroprotective effects by releasing soluble factors, secreting extracellular vesicles, and forming syncytia networks in the acute (<72 h), subacute (>72 h), and chronic phases (>6 weeks). Apoptosis of oligodendrocytes due to ischemic hypoxia leads to white matter injury, causing long-term cognitive dysfunction, and promoting oligodendrogenesis is a crucial direction for achieving functional recovery in ischemic stroke. In this article, we summarize the cellular interactions following cerebral ischemia, analyze the roles of neuroglial cells through gap junctions, chemical signaling, and extracellular vesicles in different stages of ischemic stroke, and further explore strategies for intervening in ischemic stroke.