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

Abstract

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. 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. 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. 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.