Keap1-Nrf2/ARE signal pathway activated by butylphthalide in the treatment of ischemic stroke

To analyze the clinical efficacy and possible mechanism of butylphthalide in treatment of acute ischemic stroke.

In this retrospective study, 127 patients with ischemic stroke, hospitalized during Jan. 2019 to Jan. 2021, were enrolled and as assigned to observation group (n=65) and control group (n=62) according to treatment methods. The control group received routine treatment, and the observation group was treated with butylphthalide injection in addition to conventional cure. The treatments lasted for 2 weeks in both groups. Subsequently, the recovery of neurological deficits (NIHSS) and Barthel index (BI) of the two groups of patients, cerebrovascular vascular reserve function (CVR) values and pulsation index (PI) before and after treatment, and the levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and recombinant basic fibroblast growth factor (bFGF) were detected. The expression of Keap1-Nrf2/ARE signaling pathway related molecules was detected by ELISA.

The overall response rate (ORR) of observation group was remarkably superior to that of control group (P<0.05). NIHSS score obviously decreased while BI remarkably increased in both groups after treatment (all P<0.05); and the observation group showed an significantly higher BI score but significantly lower NIHSS score compared with the control group (all P<0.05). The CVR of the two groups of patients after treatment was significantly higher than that before treatment (P<0.05), while PI was significantly lower than before treatment (P<0.05); The CVR of observation-group after treatment was substantially higher than that of control-group (P<0.05), while PI was lower than control-group (P<0.05). Serum Keap1 levels of the two groups of patients after treatment were significantly higher than that before treatment (P<0.05), while serum levels of NQO1, Nrf2, and ARE were significantly lower than that before treatment (P<0.05). The serum level of Keap1 in the observation group was remarkably higher than that of the control group (P<0.05), while the serum levels of NQO1, Nrf2 and ARE were evidently lower than those in the control group (P<0.05). The two groups had insignificant difference in incidence of adverse reactions (P>0.05).

The butylphthalide can effectively improve the clinical efficacy of acute ischemic stroke, and promote patients' neurological function and activities of daily living. The mechanism may be that butylphthalide improves the CVR of patients, enhances the establishment of collateral compensatory vessels, and changes the expression of the Keap1-Nrf2/ARE signaling pathway, thereby exerting the neuroprotective effect. Clinically, butylphthalide may have good safety in adjuvant therapy of acute ischemic stroke.