Abstract: Objective To investigate the effect of Zuogui Jiangtang Jieyu Decoction (ZJJ) on Shh signaling and self-renewal of neural stem cells in the hippocampal dentate gyrus of diabetic rats with depression. Methods Diabetic rat models with depression were randomly divided into model group, positive drug (metformin+ fluoxetine) group, and low-, medium-, and high-dose ZJJ groups (n=16), with normal SD rats as the control group. The positive drugs and ZJJ were administered by gavage, and the rats in the control and model groups were given distilled water. After the treatment, blood glucose level was detected using test strips, and behavioral changes of the rats were assessed by forced swimming test and water maze test. ELISA was used to examine the serum level of leptin; The expressions of nestin and Brdu proteins in the dentate gyrus of the rats were detected using immunofluorescence assay, and the expressions of self-renewal marker proteins and Shh signaling proteins were detected using Western blotting. Results The diabetic rats with depression showed significantly increased levels of blood glucose and leptin (P<0.01) and prolonged immobility time in forced swimming test (P<0.01) and increased stage climbing time with reduced stage seeking time and stage crossings in water maze test (P<0.01). The expressions of nestin and Brdu in the dentate gyrus, the expressions of cyclin D1, SOX2, Shh, Ptch1, Smo in the hippocampus and the nuclear expression of Gli-1 were decreased (P<0.01) while hippocampal Gli-3 expression was increased significantly (P<0.01) in the rat models. Treatment of rat models with high-dose ZJJ significantly reduced the blood glucose (P<0.01) and leptin level (P<0.05) and improved their performance in behavioral tests (P<0.01). The treatment also obviously increased the expressions of nestin, Brdu, cyclin D1, SOX2, Shh, Ptch1, and Smo and the nuclear expression of Gli-1 in the dentate gyrus (P<0.01) and reduced hippocampal expression of Gli-3 (P<0.05) in the rat models. Conclusion ZJJ can significantly improve the self-renewal ability of neural stem cells and activate Shh signaling in dentate gyrus of diabetic rats with depression.

Key words: Zuogui Jiangtang Jieyu Decoction; diabetes complicated with depression; neural stem cells; self-renewal; Shh signaling