Metabolic Brain Disease

, Volume 34, Issue 1, pp 309–318 | Cite as

L-3-n-butylphthalide attenuates cognitive deficits in db/db diabetic mice

  • Song-yun ZhangEmail author
  • Su-xiao Ji
  • Xiao-mei Bai
  • Fang Yuan
  • Li-hui Zhang
  • Jie Li
Original Article


Numerous epidemiological studies have shown that diabetes mellitus (DM) is associated with dementia and cognition decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The neuroprotective effect of L-3-n-butylphthalide (L-NBP) has been demonstrated in vascular dementia animal models. The purpose of this study was to determine whether L-NBP can ameliorate cognitive deficits in db/db mice, a model of obesity and type 2 diabetes. The mice were administered with vehicle or L-NBP (120 mg/kg) by gavage daily for 6 weeks. Then, Morris water maze tasks were performed, and hippocampal LTP was recorded in vivo. Next, the synaptic structure of the CA1 hippocampus region was investigated via electron microscopy. Finally, the expression levels of MDA, SOD, 8-OHdG, and NADPH oxidase subunits gp91 and p67, as well as the expression of NF-κB p65, TNF-α, IL-1β and caspase-3 were measured by Western blot, RT-PCR and ELISA. Treatment with L-NBP significantly attenuated the learning and memory deficits in db/db mice. Concomitantly, L-NBP also increased hippocampus synaptic plasticity, characterized by an enhanced in vivo LTP, and suppressed oxidative stress, as indicated by increased SOD activity and decreased MDA, 8-OHdG, and NADPH oxidase subunits p67 and gp91. L-NBP also significantly decreased NF-κB p65, TNF-α, IL-1βand caspase-3 levels in the hippocampus. L-NBP significantly ameliorated cognitive decline in type 2 diabetic mice, and this effect was accompanied by an improvement in hippocampal plasticity and an amelioration of oxidative stress, inflammation and apoptosis cascades. Thus, L-NBP may be a promising therapeutic agent against DM-mediated cognitive dysfunction.


L-3-n-butylphthalide Diabetes Cognitive dysfunction LTP Oxidative stress Inflammation Apoptosis 



Alzheimer’s disease


Advanced glycation end-product


Diabetes mellitus


Enzyme-linked immunosorbent assay




Long-term potentiation






Population spikes


Reverse transcription-polymerase chain reaction


Superoxide dismutase





This research was supported by the Natural Science Foundation of Hebei Province. We gratefully acknowledge Di Wen, PhD, for his support and encouragement of this project, and Zheng Yong, PhD, and Shuzhuo Zhang, PhD, for their advice on the hippocampus LTP test.


This study was funded by the Natural Science Foundation of Hebei Province (Grant NO.H2014206390; recipient, ZHANG Song-yun).

Compliance with ethical standards

Disclosure of conflicts of interest



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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople’s Republic of China
  2. 2.Department of EndocrinologyHandan First HospitalHandanChina
  3. 3.Department of PathophysiologyHebei Medical UniversityShijiazhuangChina

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