DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress

• Published in: Acta pharmacologica Sinica Vol. 42; no. 3; pp. 347 - 360
• Main Authors: Wang, Bei-ni, Wu, Cheng-biao, Chen, Zi-miao, Zheng, Pei-pei, Liu, Ya-qian, Xiong, Jun, Xu, Jing-yu, Li, Pei-feng, Mamun, Abdullah Al, Ye, Li-bing, Zheng, Zhi-long, Wu, Yan-qing, Xiao, Jian, Wang, Jian
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.03.2021; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Benzofurans - therapeutic use; Biomedical and Life Sciences; Biomedicine; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cognitive ability; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - etiology; Cyclic AMP response element-binding protein; Dementia disorders; Dendrites - drug effects; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Hippocampus; Hippocampus - drug effects; Immunology; Inflammation; Internal Medicine; Ischemia; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Morphology; Morris Water Maze Test - drug effects; Neuroprotection; Neuroprotective Agents - therapeutic use; Oral administration; Oxidative stress; Oxidative Stress - drug effects; PC12 Cells; Pharmacology/Toxicology; Pheochromocytoma cells; Phosphatidylinositol 3-Kinases - metabolism; Postsynaptic density proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Seeds; Signal Transduction - drug effects; Synapses - drug effects; Synapsin; Synaptophysin; Vaccine; Vascular dementia; cognitive function; diabetes-associated cognitive decline; hippocampus; BDNF; neuroprotection; DL-3-n-butylphthalide; oxidative stress
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00583-3

DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg· kg −1 · d −1 ) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.