Esketamine alleviates cognitive impairment signs induced by modified electroconvulsive therapy in a depression rat model via the KLF4/p38 MAPK pathway

作者：Xiaohui Zhou, Li Zhang, Weiwei Gao, Huili Li, Qiongmei Guo, Jiajia Dai, Fei Gao, Li Wang · 发表于：Journal of Affective Disorders · 年份：2025 · DOI：10.1016/j.jad.2025.02.012 · 被引用次数：6 · 研究领域：Kruppel-like factors research、Tryptophan and brain disorders、Neurogenesis and neuroplasticity mechanisms

BACKGROUND: Depression is a common and serious psychiatric disorder with significant impacts on individuals. Modified electroconvulsive therapy (MECT) is an established treatment for severe and treatment-resistant depression, but its cognitive side effects, particularly memory impairments, limit its use. Esketamine (ESK), an FDA-approved antidepressant, has shown neuroprotective effects. However, its role in mitigating MECT-induced cognitive deficits remains unexplored. This study investigates whether ESK could alleviate MECT-induced signs of cognitive impairments in a rat model of depression and explores the underlying mechanisms. METHODS: Male Sprague-Dawley rats were exposed to chronic unpredictable mild stress (CUMS) model to induce depressive-like behaviors. Rats were then subjected to MECT, ESK treatment, or both. Depression-like behaviors and cognitive functions were evaluated using various tests. Molecular and cellular assays were performed to assess hippocampal neuronal apoptosis, inflammation, and synaptic plasticity, with a focus on the Krüppel-like factor 4 (KLF4) and p38 MAPK signaling pathways. RESULTS: MECT treatment significantly alleviated depressive-like symptoms but exacerbated cognitive impairments, hippocampal neuronal apoptosis, and neuroinflammation. ESK co-treatment improved depressive behaviors while reversing MECT-induced cognitive deficits, reducing hippocampal apoptosis, and decreasing inflammatory cytokine levels. Furthermore, ESK enhanced synapti...