Pioglitazone improves the ability of learning and memory via activating ERK1/2 signaling pathway in the hippocampus of T2DM rats

OBJECTIVE: To explore the correlation between effect of PIO (pioglitazone, PIO) on learning as well as memory and ERK1/2 (extracellular signal regulated kinase 1/2, ERK1/2) pathway in T2DM (type 2 diabetes mellitus, T2DM) rats, further to elucidate the potential mechanism of PIO in improvement of learning and memory. METHODS: 12-week-old male SD rats (number of 10 per group) were randomly divided into control group (CON), T2DM group (DM) and T2DM +PIO group (DM + PG). Rats in DM and DM + PG groups were given high fat diet for 20 weeks, then treated with Streptozotocin (27 mg/kg) by intraperitoneal injection at 2lweek. After 72 h, the FBG (fasting blood glucose, FBG) was greater than 7.0 mmol/L can considered T2DM rats. DM + PG group was treated with PIO (10 mg.kg(-1).d(-1)) by gavage daily. After Hyperinsulinemic-Euglycemic Clamp Study and Morris water maze test at 30-week, all of animals were sacrificed. The expressions of RKIP (Raf-1 kinase inhibitor protein, RKIP) and ERK1/2 in hippocampus were detected using Western Blot and real-time PCR. RESULTS: The FBG level: DM group (7.68 +/- 0.54 mmol/L) was higher than CON group (5.35 +/- 0.63 mmol/L) and DM + PG group (6.07 +/- 0.84 mmol/L), the differences were considered statistically significant (P < 0.05). Hyperinsulinemic-Euglycemic Clamp Studies: GIR (glucose infusion rate, GIR) of DM group (21.02 +/- 5.10 mg.kg(-1).d(-1)) was less than CON group (27.64 +/- 3.87 mg.kg(-1).d(-1)) and DM +PG group (26.04 +/- 5.41 mg.kg(-1)d(-1)), the differences were considered statistically significant (P <0.05). Morris water maze training: The escape latencies and searching platform performance of DM group (24.54 +/- 5.02s) decreased significantly compared with CON group (16.73 +/- 4.02s) and DM + PG group (18.05 +/- 4.12s) (P <0.05). Changes of RKIP, ERK, p-ERK protein relative content in rat hippocampus: Compared with CON groupand DM+ PG group, the relative content of RKIP in DM group remarkably increased (P < 0.01); ERK protein levels were not considered statistically significant among the three groups (P >0.05); The relative content of p-ERK1/2 protein in CON group and DM + PG group rats dorsal were higher than those in group DM, the difference was considered statistically significant (P < 0.01). Changes in hippocampus of rat RKIP and ERR gene relative content: Compared with CON group and DM+ PG group, levels of RKIP mRNA in DM group were significantly increased (P < 0.01); ERR mRNA levels were not considered statistically significant among the three groups (P>0.05). CONCLUSION: Activation of ERK1/2 signal transduction pathway via reducing RKIP in the hippocampus may be one of the mechanisms of PIO to improve the learning and memory of the T2DM rats. (C) 2017 Elsevier B.V. All rights reserved.