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

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

  • Acta Pharmacol Sin. 2021 Mar;42(3):347-360. doi: 10.1038/s41401-020-00583-3.
Bei-Ni Wang  # 1 2,  Cheng-Biao Wu  # 3,  Zi-Miao Chen  # 1,  Pei-Pei Zheng 2,  Ya-Qian Liu 2,  Jun Xiong 2,  Jing-Yu Xu 4,  Pei-Feng Li 1,  Abdullah Al Mamun 2,  Li-Bing Ye 2,  Zhi-Long Zheng 2,  Yan-Qing Wu 5,  Jian Xiao 6 7,  Jian Wang 8
Affiliations

Affiliations

  • 1 Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China.
  • 3 Research Center, Affiliated Xiangshan Hospital, Wenzhou Medical University, Ningbo, 315700, China.
  • 4 The Institute of Life Sciences, Engineering Laboratory of Zhejiang province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, 325035, China.
  • 5 The Institute of Life Sciences, Engineering Laboratory of Zhejiang province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, 325035, China. yqwu220946@yeah.net.
  • 6 Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. xfxj2000@126.com.
  • 7 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China. xfxj2000@126.com.
  • 8 Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. jianwang0516@126.com.
  • # Contributed equally.
PMID: 33462377 DOI: 10.1038/s41401-020-00583-3
Abstract

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.

Keywords

BDNF; DL-3-n-butylphthalide; cognitive function; diabetes-associated cognitive decline; hippocampus; neuroprotection; oxidative stress.

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