Abstract: Objective To investigate the effects of exogenous hydrogen sulfide (H2S) on cognitive function and intestinal barrier function through nuclear factor E2 related factor 2/antioxidant response element/heme oxidase 1 (Nrf2/ARE/ HO-1) pathway in schizophrenic rats. Methods Forty SD rats were randomly divided into the control group, the model group, the H2S intervention group (intraperitoneal injection of 10 mg/kg H2S donor GYY4137), the Nrf2 inhibitor group (intraperitoneal injection of 10 mg/kg Nrf2 inhibitor ATRA) and the H2S+Nrf2 inhibitor group (intraperitoneal injection of GYY4137, ATRA), with eight in each group. Except for the control group, the other groups were injected intraperitoneally with 0.2 mg/kg of MK-801 to construct the schizophrenic rat model. After the model was successfully constructed, intervention was carried out according to the administration method of each group. The model group and the control group were replaced with normal saline, continuous intervention for 7 days. Morris water maze test was used to measure the cognitive function of rats. Hematoxylin-eosin staining (HE) was used to observe the pathological changes of hippocampus and intestine tissue. TUNEL was used to detect the apoptosis of intestinal mucosal cells in rats. Enzyme-linked immunosorbent (ELISA) kit was used to determine the levels of H2S, D-lactic acid, intestinal tissue superoxide dismutase (SOD), MDA, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in rat plasma. Western blot assay was used to detect the apoptosis of intestinal tissue and Nrf2/ARE/HO-1 pathway related proteins of rats. Results Compared with the control group, the injury of hippocampal tissue and intestinal tissue were aggravated in the model group. The incubation period, plasma D-lactic acid, intestinal mucosal cell apoptosis rate, intestinal Caspase-3, Bax protein, MDA, TNF-α, IL-6, Nrf2 and HO-1 were increased (P＜0.05). The number of puncture, the level of plasma H2S, the height of small intestinal villi, the depth of recess, the level of Bcl-2 protein and SOD decreased in intestinal tissue (P＜0.05). Compared with the model group, the injury of hippocampus and intestine was alleviated in the H2S intervention group. The incubation period, plasma D-lactic acid, intestinal mucosal cell apoptosis rate, intestinal tissue Caspase-3, Bax protein, MDA, TNF-α and IL-6 decreased (P＜ 0.05). The number of puncture, the level of plasma H2S, the height of small intestinal villi, the depth of recess, the levels of Bcl-2, Nrf2, HO-1 protein and SOD in intestinal tissue increased (P＜0.05). Nrf2 inhibitor can partially reverse the beneficial effects of H 2S on cognitive function, intestinal barrier and hippocampus of model rats. Conclusion Exogenous H 2S can significantly improve the cognitive function and intestinal barrier function of schizophrenic rats, which may be achieved by activating the Nrf2/ARE/HO-1 pathway.

Key words: hydrogen sulfide, schizophrenia, cognitive dysfunction, NF-E2-related factor 2, antioxidant response elements, heme oxygenase-1, intestinal barrier function