Role of nuclear factor E2 related factor/heme oxygenase-1 pathway in hydrogen sulfide-induced reduction of blood brain barrier damage in rats with cardiac arrest

Abstract

Objective To investigate whether the nuclear factor E2 related factor/heme synthase-1(Nrf2/HO-1) pathway is involved in the mechanism of hydrogen sulfide-induced reduction of blood brain barrier(BBB) injury in rats with cardiac arrest and the possible mechanism involved in the effect. Methods Cardiac arrest was induced with transoesophageal cardiac pacing followed by cardiopulmonary resuscitation to establish the cardiac arrest model and the time of ischemia was 4 min. 140 adult male SD rats were randomly divided into five groups: sham operation group(Sham group, n=20), cardiac arrest model group (CPR group, n=30), sodium hydrogen sulfide(NaHS) group(n=30), NaHS+solvent group[NaHS+dimethyl sulfoxide(DMSO) group, n=30], NaHS+Nrf2 inhibitor retinoic acid(RA) group(NaHS+RA group, n=30). In Sham group, only anesthesia was performed, and the trachea was inserted through the mouth, and the catheters were performed via femoral artery and vein. The other four groups were all induced cardiac arrest by electrical stimulation. NaHS group and NaHS+RA group, rats received NaHS (0.5 mg/kg) at the start of CPR intravenously, followed by a continuous infusion of NaHS(1.5 mg·kg-1·h-1) for 3 h. NaHS+RA group, RA was given i.p. daily at 10 mg/kg for 1 week before experiment and immediately after recovery. NaHS+DMSO group was given the same amount of solvent daily for 1 week before experiment and immediately after recovery. CPR group was given the same amount of normal saline at the start of CPR intravenously. After recovery, 7 days were observed continuously and the survival condition was recorded, and neurological function were evaluated at 1, 3 d, and 7 d after recovery, brain water content, BBB permeability and Nrf2, HO-1, BBB tight junction protein occludin expression was detected at 24 h after resuscitation, and the expression of matrix metalloproteinase-9(MMP-9) was detected by immunohistochemical staining. Results The survival rates, neurologic deficit scores(NDS), Nrf2 and HO-1 expression, and occludin expression in NaHS group were higher than CPR group(P 0.05). Conclusions Hydrogen sulfide could reduce the BBB damage in rats with cardiac arrest, which may be related to the activation of Nrf2/HO-1 pathway, inhibiting the expression of MMP-9 and decreasing the loss of occludin protein. Key words: Nuclear factor E2 related factor/heme oxygenase-1 pathway; Blood-brain barrier; Hydrogen sulfide; Cardiac arrest; Cardiopulmonary resuscitation