Oxovanadium Complex Intervention On Learning And Memory Damage Of Diabetic Mice And Caveolin-1 Expression

Diabetes mellitus, a common metabolic disease with rising global prevalence, is associated with long-term complications of peripheral nervous system and central nervous system. Numerous studies have focused on the damage of cognitive function of diabetic mice. However, to date there is still no convincing empirical evidence on the pathogenesis of this disorder.Vanadium, a required trace element of human body, has been proved to have insulin-like function. Vanadium complex not only could improve the hyperglycaemia, but also can be involved in the treatment of diabetic complication. Recently, vanadium complex was reported to ameliorate the antioxidation ability, protect diabetic rats from oxidative damage and ameliorate learning and memory damage of diabetic rats induced by streptozotocin (STZ). Caveolin-1 (Cav-1) is a resident protein of Caveolae, a subset of membrane microdomains.Cav-1 has been proved to bind with many signal molecules such as growth associated protein-43 (GAP-43), synaptophysin (Syn) and synaptosomal-associated protein 25 (SNAP25) through Caveolin binding domain. Many studies indicate that during the process of active axon growth and synapse formation, Cav-1 plays an important role in regulating the rebuilding of neuron membrane. In our previous study, Cav-1 expression showed distinctive features in different brain areas of different aged rats, which indicates that Cav-1 may be involved in the process of discrimination learning and memory.In present study, we aim to study on the relationship between Cav-1 and diabetic learning and memory damage, as well as to investigate the mechanism of the effects of oxovanadium complex on learning and memory of diabetes, expecting to provide basis for elucidating the mechanism of the roles of Cav-1 in regulating neural plasticity.Firstly, learning and memory ability of diabetic mice was observed by Morris water maze and Western blot was performed to detect expressions of Cav-1 and related signal proteins in hippocampus of diabetic mice. And then, a new oxovanadium complex with relatively lower toxicity synthesized by previous study, VO(HB(3,5-Me2pz)3)(3,5-Me2pzH)(SCN)(SCNH)2, was used and its intervention effects on cognitive function and protein expressions in hippocampus of diabetic mice were observed. Further, PC12 cells were used as neuron model to be treated with methyl-β-cyclodextrin (MβCD) to down-regulate Cav-1 expression. After that, we detected the effects of Cav-1 down-regulation on the expression of GAP-43, which is an internal determinant of neuron development and regeneration.The results showed that (1) the latency was longer and the percent of time in target quadrant was lower in diabetes group compared with that in control group. Also, diabetic mice showed no bias character to targete quadrant. Oxovanadium complex intervention could reduce the latency and increase the percent of time in target quadrant of diabetic mice. However, it showed no significant effect on the aspect of bias character of diabetic mice. These suggested that diabetic mice had a certain of learning and memory damage and oxovanadium complex could ameliorate the learning ability but had no significant effect on the impaired spatial memory retention of diabetic mice; (2) compared with those in control group, Cav-1 and phospho-MAPK expressions were remarkably lower and CREB2 expression was remarkbly higher in diabetic hippocampus. Oxovanadium complex dramatically increased Cav-1 expression and phosphorylation level of MAPK in diabetic hippocampus. But it had subtle effect on CREB2 expression of diabetic mice. These suggested that the pathogenesis of diabetic learning and memory damage and the mechanism of the effects of oxovanadium complex might be involved in Caveolin-MAPK-CREB pathway; (3) Cav-1 expression was down-regulated by MβCD treatment in PC12 cells, with a concomitant drop in GAP-43 expression, which suggested that Cav-1 might be involved in the regulation of GAP-43 expression and play an important role in the process of neuron development and regeneration.Conclusions:1. Depression of Caveolin-MAPK-CREB pathway in hippocampus and the following inhibition of neuron development and regeneration may be an possible pathogenesis of diabetic learning and memory damage.2. The mechanism of the effects of oxovanadium complex on learning and memory of diabetes may be involved in the activation of Caveolin-MAPK-CREB pathway in hippocampus and the following inhibition of neuron development and regeneration.