Camk2d upregulation is associated with postoperative cognitive dysfunction in aged rats: pharmacological inhibition of CaMKII attenuates hippocampal neuroinflammation and neuronal apoptosis
- 1Department of Anesthesiology, The First Affiliated Hospital of Shihezi University, Shihezi, China
- 2School of Medicine, Shihezi University, Shihezi, China
Abstract
Background: Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients after major surgery. It delays postoperative recovery and increases the risk of neurodegenerative disorders. CaMKIIδ is a key calcium-signaling regulator of neuronal survival and neuroinflammation, yet its functional role in POCD remains poorly understood. This study aimed to identify injury-inducible calcium-signaling genes and to characterize the association of Camk2d, the gene encoding CaMKIIδ, with POCD progression in aged rats.
Methods: A POCD model was established in aged rats by sevoflurane anesthesia combined with splenectomy. Cognitive function was evaluated with the Morris water maze (MWM) and Y-maze tests. Hippocampal transcriptome profiling was performed using RNA sequencing and weighted gene co-expression network analysis (WGCNA). Key molecular and pathological alterations were validated by RT-qPCR, Western blotting, ELISA, and histological staining, and the pan-CaMKII inhibitor KN-93 was administered for functional validation. Serum inflammatory cytokines were measured in parallel to characterize peripheral-to-central inflammatory coupling.
Results: Cognitive performance was worst on postoperative day 3, which was therefore identified as the critical injury window of POCD. Hippocampal CaMKIIδ, phosphorylated NF-κB (p-NF-κB), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and pro-apoptotic Bax were markedly upregulated, whereas anti-apoptotic Bcl-2 reached its lowest level and neuronal apoptosis peaked on day 3. KN-93 treatment downregulated CaMKIIδ expression, suppressed neuroinflammation and neuronal apoptosis, and effectively rescued cognitive impairment in POCD rats.
Conclusion: Camk2d upregulation is closely associated with POCD pathogenesis, paralleling hippocampal neuroinflammation and neuronal apoptosis. Pharmacological inhibition of CaMKII by KN-93 alleviates POCD, supporting CaMKII signaling as a potential therapeutic target for perioperative cognitive protection.
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BibTeX
@article{wei2026camk2d,
title = {{Camk2d upregulation is associated with postoperative cognitive dysfunction in aged rats: pharmacological inhibition of CaMKII attenuates hippocampal neuroinflammation and neuronal apoptosis}},
author = {Kaihua Wei and Shiwen Fan and Yujia Zhao and Xiaobin Cai and Xinlei Qin and Jingwen Zhai and Liping Xie},
journal = {Frontiers in Aging Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnagi.2026.1975677},
url = {https://doi.org/10.3389/fnagi.2026.1975677},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Camk2d upregulation is associated with postoperative cognitive dysfunction in aged rats: pharmacological inhibition of CaMKII attenuates hippocampal neuroinflammation and neuronal apoptosis
AU - Kaihua Wei
AU - Shiwen Fan
AU - Yujia Zhao
AU - Xiaobin Cai
AU - Xinlei Qin
AU - Jingwen Zhai
AU - Liping Xie
PY - 2026
DA - 2026/10/12
JO - Frontiers in Aging Neuroscience
DO - 10.3389/fnagi.2026.1975677
UR - https://doi.org/10.3389/fnagi.2026.1975677
AB - Background: Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients after major surgery. It delays postoperative recovery and increases the risk of neurodegenerative disorders. CaMKIIδ is a key calcium-signaling regulator of neuronal survival and neuroinflammation, yet its functional role in POCD remains poorly understood. This study aimed to identify injury-inducible calcium-signaling genes and to characterize the association of Camk2d, the gene encoding CaMKIIδ, with POCD progression in aged rats. Methods: A POCD model was established in aged rats by sevoflurane anesthesia combined with splenectomy. Cognitive function was evaluated with the Morris water maze (MWM) and Y-maze tests. Hippocampal transcriptome profiling was performed using RNA sequencing and weighted gene co-expression network analysis (WGCNA). Key molecular and pathological alterations were validated by RT-qPCR, Western blotting, ELISA, and histological staining, and the pan-CaMKII inhibitor KN-93 was administered for functional validation. Serum inflammatory cytokines were measured in parallel to characterize peripheral-to-central inflammatory coupling. Results: Cognitive performance was worst on postoperative day 3, which was therefore identified as the critical injury window of POCD. Hippocampal CaMKIIδ, phosphorylated NF-κB (p-NF-κB), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and pro-apoptotic Bax were markedly upregulated, whereas anti-apoptotic Bcl-2 reached its lowest level and neuronal apoptosis peaked on day 3. KN-93 treatment downregulated CaMKIIδ expression, suppressed neuroinflammation and neuronal apoptosis, and effectively rescued cognitive impairment in POCD rats. Conclusion: Camk2d upregulation is closely associated with POCD pathogenesis, paralleling hippocampal neuroinflammation and neuronal apoptosis. Pharmacological inhibition of CaMKII by KN-93 alleviates POCD, supporting CaMKII signaling as a potential therapeutic target for perioperative cognitive protection.
SN - 1663-4365
ER -