Echinacoside targets the HIF-1α/LDHA axis to modulate A1/A2 astrocyte differentiation and promote glial scar repair following ischemic stroke.

Ethnopharmacological Relevance: Glial scar repair is an emerging approach to ischemic stroke (IS) management, and this process can be both positively and negatively influenced by astrocytes. As a phenylethanoid glycoside derived from Cistanche tubulosa (Schenk) Wight, echinacoside (ECH) exhibits an array of pharmacological effects. However, there has been little research specifically focused on the impact of ECH on glial scar repair following IS.

Aim Of The Study: To establish how ECH impacts glial scar repair following IS and to elucidate the underlying molecular mechanisms.

Materials And Methods: The ability of ECH to modulate pathological outcomes in a rat middle cerebral artery occlusion (MCAO) model and alter the apoptotic death of astrocytes subjected to oxygen-glucose deprivation (OGD) was assessed. Network pharmacology strategies and supporting approaches were also used to probe the effects of ECH on glial scar repair after IS.

Results: Relative to the model group, ECH significantly positively influenced neurological function following IS modeling in rates, contributing to reductions in cerebral infarct volume and neuronal apoptosis rates. Mechanistically, ECH modulated the differentiation of A1/A2 astrocytes through changes in C3/GFAP and S100A10/GFAP expression while also facilitating glial scar repair through the downregulation of phosphacan and neurocan. Network pharmacology analyses demonstrated that ECH-mediated IS treatment may be efficacious owing to mechanisms associated with HIF-1 signaling and glycolytic activity. ECH was also found to be capable of modulating glycolysis through the HIF-1α/LDHA axis, thereby affecting A1/A2 astrocyte differentiation and impacting glial scar repair following IS.

Conclusion: This is the first report describing the ability of ECH to promote glial scar repair following IS, offering a foundation for the design of drugs and therapeutic strategies aimed at treating IS by taking advantage of the ability of the HIF-1α/LDHA pathway to regulate A1/A2 astrocyte development.