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

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Abstract

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.

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Abbreviations

AD :

Alzheimer’s disease

AGE :

Advanced glycation end-product

DM :

Diabetes mellitus

ELISA :

Enzyme-linked immunosorbent assay

HFS :

High-frequencystimulation

LTP :

Long-term potentiation

L-NBP :

L-3-n-Butylphthalide

MDA :

Malondialdehyde

PS :

Population spikes

RT-PCR :

Reverse transcription-polymerase chain reaction

SOD :

Superoxide dismutase

8-OHdG :

8-hydroxy-deoxyguanosine

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Acknowledgments

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.

Funding

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

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Authors and Affiliations

  1. Department of Endocrinology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road Xinhua District, Shijiazhuang, 050000, People’s Republic of China

    Song-yun Zhang, Su-xiao Ji, Xiao-mei Bai, Li-hui Zhang & Jie Li

  2. Department of Endocrinology, Handan First Hospital, Handan, China

    Su-xiao Ji

  3. Department of Pathophysiology, Hebei Medical University, Shijiazhuang, Hebei, China

    Fang Yuan

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  1. Song-yun Zhang
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Correspondence to Song-yun Zhang.

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Zhang, Sy., Ji, Sx., Bai, Xm. et al. L-3-n-butylphthalide attenuates cognitive deficits in db/db diabetic mice. Metab Brain Dis 34, 309–318 (2019). https://doi.org/10.1007/s11011-018-0356-6

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  • DOI: https://doi.org/10.1007/s11011-018-0356-6

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