Salidroside Inhibits Inflammation Through PI3K/Akt/HIF Signaling After Focal Cerebral Ischemia in Rats

Abstract

Salidroside is being investigated for its therapeutic potential in stroke because it is neuroprotective over an extended therapeutic window of time. In the present study, we investigated the mechanisms underlying the anti-inflammatory effects of salidroside (50 mg/kg intraperitoneally) in rats, given 1 h after reperfusion of a middle cerebral artery that had been occluded for 2 h. After 24 h, we found that salidroside increased the neuronal nuclear protein NeuN and reduced the marker of microglia and macrophages CD11b in the peri-infarct area of the brain. Salidroside also decreased IL-6, IL-1β, TNF-α, CD14, CD44, and iNOs mRNAs. At the same time, salidroside increased the ratio of phosphorylated protein kinase B (p-Akt) to total Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 prevented this increase in p-Akt and reversed the inhibitory effects of salidroside on CD11b and inflammatory mediators. Salidroside also elevated the protein levels of hypoxia-inducible factor (HIF) subunits HIF1α, HIF2α, HIF3α, and of erythropoietin (EPO). The stimulatory effects of salidroside on HIFα subunits were blocked by LY294002. Moreover, YC-1, a HIF inhibitor, abolished salidroside-mediated increase of HIF1α and prevented the inhibitory effects of salidroside on CD11b and inflammatory mediators. Taken together, our results provide evidence for the first time that all three HIFα subunits and EPO can be regulated by PI3K/Akt in cerebral tissue, and that salidroside entrains this signaling pathway to induce production of HIFα subunits and EPO, one or more of which mediate the anti-inflammatory effects of salidroside after cerebral IRI.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…In addition, AKT activation induces the expression of high levels of HIF-1, an important regulator of angiogenesis that can upregulate the expression of VEGF and other angiogenic factors, thereby promoting angiogenesis. HIF-1 affects vascular endothelial cells through the following mechanisms of action: (1) promoting the migration and proliferation of endothelial cells; (2) increasing vascular permeability, plasma protein exosmosis, and cellulose scaffold formation to help vascular endothelial cells migrate and provide support for vascular growth; and (3) activating the proteolytic enzyme system, degrading the extracellular matrix and promoting angiogenesis [109][110][111][112].…”

Salidroside Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis by Inhibiting the Hypoxia-Inducible Factor-1α Expression Through Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

“…PI3K/Akt signaling pathway has been shown to positively affect the translational as well as transcriptional initiation of the HIF-1α gene [17]. Interestingly, a research conducted by Wei et al [19] demonstrated that salidroside inhibits inflammation through PI3K/Akt/HIF signaling after focal cerebral ischemia in rats, in which indicates that SAL might attenuates Adriamycin-induced FSGS via targeting PI3K/AKT pathway. In our study, when treated with Adriamycin, the PI3K/AKT pathway was activated, which is confirmed by the high levels of PI3K and pAKt.…”

“…All of these papers indicated the tight relationship between PI3K/AKT and HIF-1α. Interestingly, a research conducted by Wei et al [19] demonstrated that SAL inhibits inflammation through PI3K/ Akt/HIF signaling after focal cerebral ischemia in rats. Based on these findings, we believe SAL may attenuate Adriamycin-induced FSGS through inhibiting HIF-1αvia targeting PI3K/AKT pathway, which finally attenuated inflammatory response and oxidative stress.…”

HIF‐1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa

“…DMOG also prevented microglial and glial activation (Iba‐1 and GFAP immunolabeling). Although we have not evaluated it, other researchers have shown that HIF‐1α and its targets (e.g., erythropoietin) can exert antiapoptotic and anti‐inflammatory effects through ERK‐1/2 signaling and activation of PKB pathway (55–58). Further studies are needed to clarify the molecular mechanisms underlying the neuroprotective effect of DMOG.…”