DL-3-n-butylphthalide (NBP) ameliorates cognitive deficits and CaMKII-mediated long-term potentiation impairment in the hippocampus of diabetic db/db mice

Objective: Diabetes-associated cognitive deficits is characterized by long-term potentiation (LTP) decline in the hippocampus. DL-3-n-butylphthalide (NBP) is a novel agent exerting protective effect against ischemic brain. However, the effects of NBP on diabetes-associated cognitive deficits and underlying mechanisms are not fully clear. This study was designed to evaluate the effects of NBP on the cognitive deficits through activating CaMKII-mediated LTP process and protecting neuron structure of hippocampus in diabetic db/db mice. Methods: Male db/db mice were randomly divided into db/db group (n = 8) and db/db+NBP group (n = 8, 120mg/Kg NBP by gavage). Male db/m mice (n = 8) were included as control group. All animals were treated for 6 weeks. Morris Water Maze test was carried out to evaluate cognitive function. Electrophysiological recordings were performed to test LTP level. HE-staining and electron microscopy of hippocampus were used to observe structure change of neurons and synapse. RT-PCR and Western blot were used to assess the expression of CaMKII, NR2B, and GluR1. Results: Type 2 diabetes mellitus caused LTP decline, and significantly decreased NR2B, CaMKII, and GluR1 expression. Histological analysis showed that disorganized pyramidal cells, as well as degraded neuron and synapse ultrastructure in db/db mice. NBP treatment restored LTP and its associated proteins in db/db mice. The structure changes of hippocampal cells were partly reversed by NBP intervention. Conclusion: These results suggest that NBP ameliorates cognitive deficits induced by type 2 diabetes mellitus through improving CaMKII-mediated LTP and cell ultrastructure in the hippocampus. NBP is a potential therapeutic agent for diabetes-associated cognitive deficits. Abbreviations: NBP: DL-3-n-butylphthalide; LTP: long-term potentiation; CaMKII: calcium/calmodulin-dependent protein kinase II; NR2B: N-methyl-D-aspartic acid receptor subtype 2B; GluR1: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1.