Arketamine alleviates cognitive impairments and demyelination in mice with postoperative cognitive dysfunction via TGF-β1 activation

Ting-Ting Zhu; Ming-Ming Zhao; Dan Xu; Yi Cai; Guilin Liu; Rumi Murayama; Yong Yue; Jian-Jun Yang; Kenji Hashimoto

doi:10.1016/j.pnpbp.2024.111228

Arketamine alleviates cognitive impairments and demyelination in mice with postoperative cognitive dysfunction via TGF-β1 activation

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Dec 22:111228. doi: 10.1016/j.pnpbp.2024.111228. Online ahead of print.

Authors

Ting-Ting Zhu¹, Ming-Ming Zhao¹, Dan Xu², Yi Cai³, Guilin Liu⁴, Rumi Murayama⁵, Yong Yue³, Jian-Jun Yang⁶, Kenji Hashimoto⁷

Affiliations

¹ Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
² Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
³ Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
⁴ Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao 266100, China.
⁵ Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
⁶ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China. Electronic address: yjyangjj@zzu.edu.cn.
⁷ Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: hashimoto@faculty.chiba-u.jp.

PMID: 39719219
DOI: 10.1016/j.pnpbp.2024.111228

Abstract

Postoperative cognitive dysfunction (POCD) is characterized by a decline in cognitive functions, including memory, attention, and executive abilities, following surgery, with no effective therapeutic drugs currently available. Arketamine, the (R)-enantiomer of ketamine, has shown promise in mitigating cognitive deficits in animal models. In this study, we investigated whether arketamine could ameliorate cognitive deficits in a mouse model of POCD, with a focus on the role of transforming growth factor (TGF)-β1 in its effects. POCD mice displayed cognitive impairments and demyelination in the corpus callosum. A single arketamine injection (10 mg/kg) significantly improved both cognitive function and demyelination in the corpus callosum of POCD mice. Notably, pretreatment with RepSox (10 mg/kg), a TGF-β receptor 1 inhibitor, significantly blocked the beneficial effects of arketamine on cognitive deficits and demyelination. Moreover, intranasal administration of TGF-β1 (3.0 μg/kg) markedly alleviated cognitive impairments and demyelination in POCD mice. These findings suggest that arketamine exerts its effects through a TGF-β1-dependent mechanism, positioning it as a potential therapeutic option for POCD.

Keywords: Arketamine; Demyelination; Postoperative cognitive dysfunction; Surgery; TGF-β1.