Mechanisms of Polygalasaponin F Against Brain Ischemia-Reperfusion Injury by Targeting NKCC1-data
Description
Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) is a Na⁺, K⁺, 2Cl⁻ cotransporter protein expressed widely in the nervous system. The elevated expression of NKCC1 following a stroke can result in brain edema and disruption of the blood-brain barrier (BBB), pointing out that NKCC1 may become a potential therapeutic target for improving stroke outcomes. Polygalasaponin F (PGSF) is a triterpenoid saponin isolated from Polygala japonica Houtt, which in previous studies has demonstrated neuroprotective effects by shielding neurons from excitotoxicity and exerting immunomodulatory actions, suggesting its potential as a treatment for stroke. This study aimed to observe the protective effects of PGSF on cerebral ischemia-reperfusion injury (CIRI) in rats and elucidate its positive role in CIRI through targeting NKCC1. The research findings demonstrated that rats exhibited neurological deficits and extensive cerebral infarction after cerebral ischemia-reperfusion, accompanied by elevated levels of NKCC1 mRNA and protein in brain tissue. Treatment with PGSF significantly reduced neuronal damage, infarct volume, and brain edema in rats. Both high-dose PGSF (PGSF-H) and medium-dose PGSF (PGSF-M) markedly decreased the expression levels of NKCC1 mRNA and protein. Furthermore, pharmacological modulation with 5-Aza-2-deoxycytidine (5-Aza-CDR) coupled with methylation sequencing analysis revealed that PGSF may regulated NKCC1 expression through methylation changes. Additionally, Western blotting and Evans blue extravasation experiments supported the significant inhibitory effect of PGSF on the damage of BBB. In conclusion, PGSF protected rats from the effects of CIRI, and its mechanism of action may involved PGSF-mediated DNA methylation to reduce NKCC1 gene and protein expression levels in brain tissue.