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Inhibition of mTOR Alleviates Early Brain Injury After Subarachnoid Hemorrhage Via Relieving Excessive Mitochondrial Fission

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A Correction to this article was published on 22 April 2024

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Abstract

The mammalian target of rapamycin (mTOR) was reported to regulate cell autophagy and outcomes of several neurological diseases. Mitochondria, which serve as critical organelles in neurons. are also involved in the pathology of neurological diseases. However, the role of mTOR in mitochondrial morphology has not been clarified especially in subarachnoid hemorrhage (SAH). In this study, we established SAH models both in vivo and in vitro. Rapamycin and 3-methyl adenine (3-MA) were then administered to alter mTOR activity. Post-SAH assessment included SAH grading, neurological evaluation, blood–brain barrier (BBB) permeability, brain water content, mitochondrial membrane potential (MMP), mitochondrial morphology, ATP content, cell viability, cytotoxicity, and expression of proteins related to apoptosis and mitochondrial fission. The results showed that (1) neurological deficits, BBB permeability, and brain edema were increased after SAH and that cell viability was exacerbated in brain tissue. (2) Excessive mitochondrial fission was evident based on changes in mitochondrial morphology, while MMP and ATP content were decreased in neurons after SAH. (3) Administration of rapamycin improved the excessive mitochondrial fission and restored mitochondrial function, which subsequently reduced apoptosis. (4) 3-MA showed an adverse effect on mitochondria and aggravated excessive mitochondrial fission and dysfunction in SAH. Neurological deficits and neuronal viability were also exacerbated following the administration of 3-MA. Therefore, our study suggests that mTOR inhibition has neuroprotective effects against neuronal injury after SAH via alleviating excessive mitochondrial fission.

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Abbreviations

BBB:

Blood–brain barrier

CCA:

Common carotid artery

Cyt C:

Cytochrome c

DMSO:

Dimethylsulfoxide

Drp1:

Dynamin-related protein 1

EBI:

Early brain injury

ECA:

External carotid artery

GTP:

Guanosine-5′-triphosphate

Hb:

Oxyhemoglobin

ICA:

Internal carotid artery

MMP:

Mitochondrial membrane potential

mTOR:

Mammalian target of rapamycin

PBS:

Phosphate-buffered saline

ROS:

Reactive oxidative species

SAH:

Subarachnoid hemorrhage

TEM:

Transmission electron microscope

3-MA:

3-Methyl adenine

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Acknowledgements

This work is supported by Natural Science Foundation of Heilongjiang Province, China (ZD2018018) and Innovation Fund of Harbin Medical University, China (YTSKYCX2018-38HYD).

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  1. Yuchen Li and Pei Wu equally contributed to this study.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, Heilongjiang, China

    Yuchen Li, Pei Wu, Jiaxing Dai, Tongyu Zhang, Chunlei Wang, Yao Liu & Huaizhang Shi

  2. Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, 45435, USA

    Yuchen Li & Ji Bihl

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  1. Yuchen Li
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Li, Y., Wu, P., Dai, J. et al. Inhibition of mTOR Alleviates Early Brain Injury After Subarachnoid Hemorrhage Via Relieving Excessive Mitochondrial Fission. Cell Mol Neurobiol 40, 629–642 (2020). https://doi.org/10.1007/s10571-019-00760-x

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