T817MA Regulates Mitochondrial Dynamics via Sirt1 and Arc Following Subarachnoid Hemorrhage

Wei-Wei Chen; Fu-Qiang Sun; Bo Wang; Xiao-Xiao Tian; Rong-Ping Zhang; Wen-Bo Liu

doi:10.1016/j.neuroscience.2023.06.020

T817MA Regulates Mitochondrial Dynamics via Sirt1 and Arc Following Subarachnoid Hemorrhage

Neuroscience. 2023 Nov 1:531:1-11. doi: 10.1016/j.neuroscience.2023.06.020. Epub 2023 Jun 28.

Authors

Wei-Wei Chen¹, Fu-Qiang Sun², Bo Wang², Xiao-Xiao Tian³, Rong-Ping Zhang⁴, Wen-Bo Liu⁵

Affiliations

¹ Central Laboratory, The First Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, Shandong 261000, China; Naval Medical Center of PLA, Naval Medical University of PLA, Shanghai 200052, China.
² Central Laboratory, The First Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, Shandong 261000, China.
³ Naval Medical Center of PLA, Naval Medical University of PLA, Shanghai 200052, China.
⁴ Department of Surgery, Shanghai Songjiang Sijing Hospital, Shanghai 200052, China.
⁵ Central Laboratory, The First Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, Shandong 261000, China. Electronic address: liuwb@wfmc.edu.cn.

PMID: 37385332
DOI: 10.1016/j.neuroscience.2023.06.020

Abstract

Spontaneous subarachnoid hemorrhage (SAH) is an acute neurologic emergency with poor outcomes, and mitochondrial dysfunction is known as one of the key pathological mechanisms underlying the SAH-induced early brain injury (EBI). 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate (T817MA) is a newly synthesized neurotrophic compound that has been demonstrated to exert protective effects against brain injury. Here, we investigated the effect of T817MA in neuronal injury following experimental SAH both in vitro and in vivo. Primary cultured cortical neurons were treated with oxyhemoglobin (OxyHb) to mimic SAH in vitro, and T817MA at concentrations higher than 0.1 μM reduced OxyHb-induced neuronal injury. T817MA treatment significantly inhibited lipid peroxidation, reduced neuronal apoptosis and attenuated mitochondrial fragmentation. The results of western blot showed that T817MA markedly reduced the expression of mitochondrial fission proteins, fission protein 1 (Fis-1) and dynamin-related GTPase-1 (Drp-1), but prolonged the expression of the postsynaptic protein activity-regulated cytoskeleton-associated protein (Arc). In addition, T817MA significantly increased the expression of sirtuin 1 (Sirt1), which was accompanied by preserved enzymatic of isocitrate dehydrogenase (IDH2) and superoxide dismutase (SOD). Knockdown of Sirt1 and Arc via small interfere RNA (siRNA) transfection partially prevented the T817MA-induced protection in cortical neurons. Furthermore, treatment with T817MA in vivo significantly reduced brain damage and preserved neurological function in rats. The decreased expression of Fis-1 and Drp-1, as well as the increased expression of Arc and Sirt1 were also observed in vivo. Taken together, these data indicate that the neuroprotective agent T817MA protects against SAH-induced brain injury via Sirt1- and Arc-mediated regulation of mitochondrial dynamics.

Keywords: Arc; SAH; Sirt1; T817MA; mitochondrial dynamics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Brain Injuries* / pathology
Mitochondrial Dynamics
Neuroprotective Agents* / pharmacology
Rats
Rats, Sprague-Dawley
Sirtuin 1 / metabolism
Subarachnoid Hemorrhage* / drug therapy
Subarachnoid Hemorrhage* / metabolism

Substances

Sirtuin 1
Neuroprotective Agents
Sirt1 protein, rat