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

IF 5.3 2区医学 Q1 CLINICAL NEUROLOGY Progress in Neuro-Psychopharmacology & Biological Psychiatry Pub Date : 2025-01-10 DOI:10.1016/j.pnpbp.2024.111228

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

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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.

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阿克他命通过TGF-β1激活减轻术后认知功能障碍小鼠的认知障碍和脱髓鞘。

术后认知功能障碍（POCD）的特点是手术后认知功能下降，包括记忆、注意力和执行能力，目前没有有效的治疗药物。阿克他命，氯胺酮的(R)-对映体，在动物模型中显示出减轻认知缺陷的希望。在本研究中，我们研究了阿克他明是否可以改善POCD小鼠模型的认知缺陷，重点研究了转化生长因子(TGF)-β1在其作用中的作用。POCD小鼠表现出认知障碍和胼胝体脱髓鞘。单次阿氯胺酮注射（10 mg/kg）可显著改善POCD小鼠的认知功能和胼胝体脱髓鞘。值得注意的是，TGF-β受体1抑制剂RepSox（10 mg/kg）预处理可显著阻断阿氯胺酮对认知缺陷和脱髓鞘的有益作用。此外，经鼻给药TGF-β1（3.0 μg/kg）可显著减轻POCD小鼠的认知障碍和脱髓鞘。这些发现表明，阿克他命通过TGF-β1依赖机制发挥其作用，将其定位为POCD的潜在治疗选择。

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来源期刊

Progress in Neuro-Psychopharmacology & Biological Psychiatry 医学-精神病学

CiteScore

12.00

自引率

1.80%

发文量

153

审稿时长

56 days

期刊介绍： Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international and multidisciplinary journal which aims to ensure the rapid publication of authoritative reviews and research papers dealing with experimental and clinical aspects of neuro-psychopharmacology and biological psychiatry. Issues of the journal are regularly devoted wholly in or in part to a topical subject. Progress in Neuro-Psychopharmacology & Biological Psychiatry does not publish work on the actions of biological extracts unless the pharmacological active molecular substrate and/or specific receptor binding properties of the extract compounds are elucidated.