Ghrelin-attenuated cognitive dysfunction in streptozotocin-induced diabetic rats.

Diabetic encephalopathy is clinically characterized by acquired behavior and cognitive dysfunction but its pathogenesis is not clear. This study aimed to explore the pathogenesis of diabetic encephalopathy and the mechanisms of ghrelin to ameliorate cognitive dysfunction in diabetic rats. Thirty-six streptozotocin diabetic rat models were established; 12 weeks later, all the rats were randomly divided into 3 groups [diabetic model group (D), ghrelin treatment group (T1), and ghrelin and D-lys-3-GHRP-6 treatment group (T2)] of 12 each. Twelve normoglycemic rats were classified in the normal group (N). Learning and memory behaviors were measured using a spatial version of the Morris water maze test. The brain-derived neurotrophic factor (BDNF), cAMP responsive element binding protein (CREB), phosphorylated CREB (p-CREB), phosphorylated ERK1/2 (p-ERK1/2), caspase-3, and Bcl-xl protein expressions in the hippocampi of all the rats were detected using immunohistochemistry. The mRNA expressions of BDNF, CREB, and caspase-3 were examined using reverse transcription-polymerase chain reaction. The hippocampus neuronal apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling method. We found that learning and memory level in the ghrelin treatment group improved significantly, expression of Bcl-xl, BDNF, CREB, p-CREB, and p-ERK1/2 in the hippocampus was increased in the ghrelin treatment group, and the number of apoptotic neurons in the hippocampus decreased remarkably. Our results showed that the changes of BDNF, CREB, and hippocampus neuronal apoptosis might be involved in the pathogenesis of diabetic encephalopathy. We suggested that ghrelin improved cognitive ability in streptozotocin-induced diabetic rats by improving the expressions of BDNF and CREB and by attenuating hippocampus neuronal apoptosis. The effects of ghrelin depend on the receptor of ghrelin, GHSR-1a, and ERK1/2 pathway.