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Intranasal insulin administration may be highly effective in improving cognitive function in mice with cognitive dysfunction by reversing brain insulin resistance

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Abstract

It is well known in clinical practice that Alzheimer’s disease (AD) is closely associated with brain insulin resistance, and the cerebral insulin pathway has been proven to play a critical role in the pathogenesis of AD. However, finding the most efficient way to improve brain insulin resistance remains challenging. Peripheral administration of insulin does not have the desired therapeutic effect and may induce adverse reactions, such as hyperinsulinemia, but intranasal administration may be an efficient way. In the present study, we established a brain insulin resistance model through an intraventricular injection of streptozotocin, accompanied by cognitive impairment. Following intranasal insulin treatment, the learning and memory functions of mice were significantly restored, the neurogenesis in the hippocampus was improved, the level of insulin in the brain increased, and the activation of the IRS-1-PI3K-Akt-GSK3β insulin signal pathway, but not the Ras-Raf-MEK-MAPK pathway, was markedly increased. The olfactory bulb–subventricular zone–subgranular zone (OB-SVZ-SGZ) axis might be the mechanism through which intranasal insulin regulates cognition in brain-insulin-resistant mice. Thus, intranasal insulin administration may be a highly efficient way to improve cognitive function by increasing cerebral insulin levels and reversing insulin resistance.

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Abbreviations

STZ:

Streptozotocin

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

IRS-1:

Insulin receptor substrate-1

PI3K:

PI-3 kinase

GSK3:

Glycogen synthase kinase-3β

IDE:

Insulin-degrading enzyme

IN:

Intranasal administration

IP:

Intraperitoneal administration

Ins:

Insulin

NS:

Normal saline

I.C.V.:

Intracerebroventricular

IRBS:

Insulin-resistant brain state

IHC:

Immunohistochemistry

IF:

Immunofluorescence

DCX:

Doublecortin

BrdU:

5-Bromo-2-deoxyuridine

GLUT2:

Glucose transporter 2

SVZ:

Subependymal ventricular zone

SGZ:

Subgranular zone

OB:

Olfactory bulb

RMS:

Rostral migratory stream

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant No. 81860244); Guangxi Natural Science Foundation (Grant No. 2018GXNSFAA281051); the Basic Ability Enhancement Program for Young and Middle-age Teachers of Guangxi (Grant No. 2017KY0516).

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Authors and Affiliations

  1. Youjiang Medical University for Nationalities, Chengxiang Avenue, Youjiang District, Baise, 533000, Guangxi, People’s Republic of China

    Hui Lv, Lingjiao Tang & Chongdong Jian

  2. Graduate College of Youjiang Medical University for Nationalities, Chengxiang Avenue, Youjiang District, Baise, 533000, Guangxi, People’s Republic of China

    Yongming Jiang, Ce Gao & Yifan Wang

  3. The 6th Hospital of Wu Han, Wuhan, 430015, Hubei, People’s Republic of China

    Canshou Guo

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  1. Hui Lv
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  2. Lingjiao Tang
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  3. Canshou Guo
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  5. Ce Gao
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Contributions

CDJ designed experiments. HL, LJT, CSG, YMJ, CG and YFM performed experiments. CSG, QTL and XLM contributed to the statistical analyses and interpretation. HL drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chongdong Jian.

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Lv, H., Tang, L., Guo, C. et al. Intranasal insulin administration may be highly effective in improving cognitive function in mice with cognitive dysfunction by reversing brain insulin resistance. Cogn Neurodyn 14, 323–338 (2020). https://doi.org/10.1007/s11571-020-09571-z

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