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

• Published in: Cellular and molecular neurobiology 2020-05, Vol.40 (4), p.629-642
• Main Authors: Li, Yuchen, Wu, Pei, Dai, Jiaxing, Zhang, Tongyu, Bihl, Ji, Wang, Chunlei, Liu, Yao, Shi, Huaizhang
• Format: Article
• Language: English
• Subjects: Adenine; Aneurysms; Animals; Apoptosis; Apoptosis - drug effects; Autophagy; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - pathology; Brain Edema - complications; Brain Edema - pathology; Brain Injuries - drug therapy; Brain Injuries - etiology; Brain Injuries - pathology; Brain injury; Cell Biology; Cell viability; Cytology; Cytotoxicity; Edema; Male; Membrane permeability; Membrane potential; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Dynamics - drug effects; Morphology; Neurobiology; Neurological diseases; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neurosciences; Organelles; Original Research; Permeability; Phagocytosis; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rapamycin; Rats, Wistar; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - complications; Subarachnoid Hemorrhage - drug therapy; Subarachnoid Hemorrhage - pathology; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Water content
• ISSN: 0272-4340; 1573-6830; 1573-6830
• DOI: 10.1007/s10571-019-00760-x

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.