Frontiers in Aging Neuroscience · Oct 12, 2026

Camk2d upregulation is associated with postoperative cognitive dysfunction in aged rats: pharmacological inhibition of CaMKII attenuates hippocampal neuroinflammation and neuronal apoptosis

By Wei K, Fan S, Zhao Y et al.

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.

doi.org/10.3389/fnagi.2026.1975677 Open access PubMed 42935898 Mechanisms