Therapeutic effect of gastrodin on neural injury in a rat model of hypertension with vascular dementia by regulating ferroptosis through the Nrf2/GPX4 signaling pathway
Objective To observe the therapeutic effect of gastrodin(GAS)on neural injury in hypertensive rats with vascular dementia(VaD)through the regulation of ferroptosis via the nuclear factor E2-related factor 2(Nrf2)/glutathione peroxidase 4(GPX4)signaling pathway.Methods Eight Wistar-Kyoto(WKY)rats were selected as the blank control group(WKY).Fifty spontaneously hypertensive rats(SHR)were used to establish a model of hypertension combined with VaD via a modified bilateral vascular occlusion method.Forty successfully modeled rats were randomly divided into five groups:model group,donepezil group,high-dose(GAS-H)group,medium-dose(GAS-M)group,and low-dose(GAS-L)group,with 8 rats in each group.The WKY group and model group were administered 1 mL of physiological saline per 100 g of body weight daily by gavage.The donepezil group received 0.45 mg/(kg·d)donepezil by gavage.The GAS-H,GAS-M,and GAS-L groups received GAS tablets in solutions at 100,50,and 25 mg/(kg·d),respectively.All treatments were given for 4 consecutive weeks.After 4 weeks of administration,tissue samples were collected.The morphological changes in hippocampal tissue,iron deposition,and levels of Fe2+,malondialdehyde(MDA),glutathione(GSH),and protein expression of Nrf2,GPX4,4-hydroxynonenal(4-HNE),and cyclooxygenase-2(COX-2)were compared across the groups.Results In the WKY group,the neurons were structurally normal,with abundant Nissl bodies.In the model group,neuronal necrosis was severe,with a significant decrease in Nissl bodies.In the donepezil group,neuronal necrosis was reduced and Nissl bodies increased.The GAS-H group showed significantly reduced neuronal necrosis and an increase in Nissl bodies.In the GAS-M and GAS-L groups,neuronal necrosis decreased to some extent,but the increase in Nissl bodies was not as pronounced.No blue iron deposition was observed in the WKY group,while significant iron deposition was found in the model group.Iron deposition was significantly reduced in the donepezil and GAS-H groups,while it decreased to a lesser extent in the GAS-M and GAS-L groups.Compared to the WKY group,the model group exhibited higher levels of Fe2+and MDA(P<0.01)and lower levels of GSH(P<0.05).Compared to the model group,the donepezil,GAS-H,GAS-M,and GAS-L groups had lower levels of Fe2+and MDA(P<0.05),and higher levels of GSH(P<0.05).The levels of Fe2+and MDA followed the order:GAS-H<donepezil<GAS-M<GAS-L(P<0.05).GSH levels followed the order:GAS-H>donepezil>GAS-M>GAS-L(P<0.05).The relative expression of Nrf2 and GPX4 proteins in the model group was significantly lower than that in the WKY group(P<0.01).The donepezil,GAS-H,and GAS-M groups showed higher expression of Nrf2 and GPX4 compared to the model group(P<0.01).The order of relative protein expression of Nrf2 and GPX4 was:GAS-H>donepezil>GAS-M>GAS-L(P<0.05).Compared to the WKY group,the relative expression of 4-HNE and COX-2 in the model group was significantly higher(P<0.01).In the donepezil,GAS-H,and GAS-M groups,the expression of 4-HNE and COX-2 was significantly lower than that in the model group(P<0.01),and in the GAS-L group,the expression of 4-HNE was significantly lower(P<0.05).The order of protein expression for 4-HNE and COX-2 was:GAS-H<donepezil<GAS-M<GAS-L(P<0.05).Conclusion GAS may improve hippocampal neuronal injury in hypertensive rats with VaD by activating the Nrf2/GPX4 signaling pathway,increasing GSH levels,reducing COX-2,MDA,and 4-HNE production,and decreasing iron deposition.
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