The attenuation effect of potassium 2-(1-hydroxypentyl)-benzoate in a mouse model of diabetes-associated cognitive decline: The protein expression in the brain

dl-PHPB (potassium 2-(1-hydroxypentyl)-benzoate) has been shown to have neuroprotective effects against acute cerebral ischemia, vascular dementia, and Alzheimer's disease. The aim of this study was to investigate the effects of dl-PHPB on memory deficits and preliminarily explore the underlying molecular mechanism.

These results indicate that dl-PHPB may play a potential role in diabetes-associated cognitive impairment through PI3K/Akt/GSK-3β signaling pathway and the differentially expressed proteins may become putative therapeutic targets.

Blood glucose and behavioral performance were evaluated in the KK-Ay diabetic mouse model before and after dl-PHPB administration. Two-dimensional difference gel electrophoresis (2D-DIGE)-based proteomics was used to identify differentially expressed proteins in brain tissue. Western blotting was used to study the molecular mechanism of the related signaling pathways.

Three-month-old KK-Ay mice were given 150 mg/kg dl-PHPB by oral gavage for 2 months, which produced no effect on the level of serum glucose. In the Morris water maze test, KK-Ay mice treated with dl-PHPB showed significant improvements in spatial learning and memory deficits compared with vehicle-treated KK-Ay mice. Additionally, we performed 2D-DIGE to compare brain proteomes of 5-month KK-Ay mice treated with and without dl-PHPB. We found 14 altered proteins in the cortex and 11 in the hippocampus; two of the 25 altered proteins and another four proteins that were identified in a previous study on KK-Ay mice were then validated by western blot to further confirm whether dl-PHPB can reverse the expression levels of these proteins. The phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase-3β (PI3K/Akt/GSK-3β) signaling pathway was also changed in KK-Ay mice and dl-PHPB treatment could reverse it. Conclusions: These results indicate that dl-PHPB may play a potential role in diabetes-associated cognitive impairment through PI3K/Akt/GSK-3β signaling pathway and the differentially expressed proteins may become putative therapeutic targets.