Cerebral ischemia/reperfusion injury (CIRI) seriously threatens human life and health. Scutellarin (Scu) exhibits neuroprotective effects, but little is known about its underlying mechanism. Therefore, we explored its protective effect on CIRI and the underlying mechanism. Our results demonstrated that Scu rescued HT22 cells from cytotoxicity induced by oxygen and glucose deprivation/reoxygenation (OGD/R). Scu also showed antioxidant activity by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, upregulating heme oxygenase-1 (HO-1) expression, increasing superoxide dismutase (SOD) activity, and inhibiting reactive oxygen species (ROS) generation in vitro. Additionally, Scu reduced nuclear factor-kappa B (NF-κB) activity and the levels of pro-inflammatory factors. Interestingly, these effects were abolished by Nrf2 inhibition. Furthermore, Scu reduced infarct volume and blood-brain barrier (BBB) permeability, improved sensorimotor functions and depressive behaviors, and alleviated oxidative stress and neuroinflammation in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Mechanistically, Scu-induced Nrf2 nuclear accumulation and inactivation of NF-κB were accompanied by an enhanced level of phosphorylated protein kinase B (p-AKT) both in vitro and in vivo. Pharmacologically inhibiting the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway blocked Scu-induced Nrf2 nuclear translocation and inactivation of NF-κB, as well as its antioxidant and anti-inflammatory activities. In summary, these results suggest that Scu exhibits antioxidant, anti-inflammatory, and neuroprotective effects in CIRI through Nrf2 activation mediated by the PI3K/Akt pathway.

Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).