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Intranasal Insulin Treatment Attenuates Metabolic Distress and Early Brain Injury After Subarachnoid Hemorrhage in Mice

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Abstract

Background

Intranasal administration of insulin to the brain bypasses the blood brain barrier (BBB) and can increase cerebral glucose uptake and prevent energy failure. Intranasal insulin treatment has shown neuroprotective effects in multiple central nervous system (CNS) lesions, but the effects of intranasal insulin on the metabolic and pathological process of subarachnoid hemorrhage (SAH) are not clear. This study is designed to explore the effects of intranasal insulin treatment on metabolic distress and early brain injury (EBI) after experimental SAH.

Methods

SAH model was built by endovascular filament perforation method in adult male C57BL/6J mice, and then, insulin was administrated via intranasal route at 0, 24, and 48 h post-SAH. EBI was assessed according to the neurological performance, BBB damage, brain edema, neuroinflammatory reaction, and neuronal apoptosis at each time point. To evaluate metabolic conditions, microdialysis was used to continuously monitor the real-time levels of glucose, pyruvate, and lactate in interstitial fluid (ISF) in living animals. The mRNA and protein expression of glucose transporter-1 and 3 (GLUT-1 and -3) were also tested by RT-PCR and Western blot in brain after SAH.

Results

Compared to vehicle, intranasal insulin treatment promoted the relative mRNA and protein levels of GLUT-1 in SAH brain (0.98 ± 0.020 vs 0.33 ± 0.016 at 24 h, 0.91 ± 0.25 vs 0.21 ± 0.013 at 48 h and 0.94 ± 0.025 vs 0.28 ± 0.015 at 72 h in mRNA/0.96 ± 0.023 vs 0.36 ± 0.015 at 24 h, 0.91 ± 0.022 vs 0.22 ± 0.011 at 48 h and 0.95 ± 0.024 vs 0.27 ± 0.014 at 72 h in protein, n = 8/Group, p < 0.001). Similar results were also observed in GLUT-3. Intranasal insulin reduced the lactate/pyruvate ratio (LPR) and increased ISF glucose level. It also improved neurological dysfunction, BBB damage, and brain edema and attenuated the levels of pro-inflammatory cytokines as well as neuronal apoptosis after SAH.

Conclusions

The intranasal insulin treatment protects brain from EBI possibly via improving metabolic distress after SAH.

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Funding

This work was supported by Zhejiang Provincial Natural Science Foundation (LY16H090014), Zhejiang Provincial Medical Health and Science and Technology Project Foundation (2020KY667, 2016KYB213, 2020PY018) and Science Planning Project from Science Technology Bureau of Shaoxing (2018C30150).

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Author notes

  1. Long-Biao Xu and Hua-Dong Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Zhuji People’s Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, China

    Long-Biao Xu & Ming Zhao

  2. Department of Neurosurgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China

    Hua-Dong Huang

  3. Department of Neurosurgery, First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, China

    Guo-Chong Zhu & Zhen Xu

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  1. Long-Biao Xu
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Correspondence to Zhen Xu.

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12028_2020_1011_MOESM1_ESM.tif

Supplementary Figure 1: Compared to the sham group, the mRNA and protein level of GLUT-3 significantly downregulated from 24 to 72 h after SAH (SUP Fig. 1A, B and C). Intranasal insulin treatment significantly promoted the mRNA and protein levels of GLUT-3 in brain (SUP Fig. 1A, B and C). Data were expressed as mean ± SEM (n = 8/Group, ***p < 0.001 versus sham, ###p < 0.001 versus vehicle). (TIFF 861 kb)

Supplementary Figure 2: Full Western blot gels of GLUT-1 and -3. (TIFF 4038 kb)

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Xu, LB., Huang, HD., Zhao, M. et al. Intranasal Insulin Treatment Attenuates Metabolic Distress and Early Brain Injury After Subarachnoid Hemorrhage in Mice. Neurocrit Care 34, 154–166 (2021). https://doi.org/10.1007/s12028-020-01011-4

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