Re-entraining the broken rhythm: electroacupuncture and suvorexant in ischemia-associated perioperative neurocognitive dysfunction – an experimental study

Background: Perioperative neurocognitive disorder (PND), particularly under ischemic conditions in older adults, is closely associated with circadian rhythm disruption and aberrant orexin-A (OxA) signaling. This study aimed to investigate the therapeutic potential and mechanistic underpinnings of electroacupuncture (EA) and suvorexant (SUV), individually and in combination, in a rat model of ischemia-associated PND (iPND). Methods: A randomized, controlled preclinical study was conducted using late-adult Sprague–Dawley rats subjected to bilateral common carotid artery occlusion to establish the iPND model. Animals received 28 days of EA, SUV, or EA + SUV treatment. Behavioral assessments included circadian rhythm analysis, novel object recognition, and Morris water maze tests. Transcriptomic profiling, qPCR, western blotting, immunofluorescence, and ultrastructural imaging were used to explore molecular and cellular mechanisms, with a focus on OxA, circadian clock genes (Bmal1–Per/Cry axis), and Aβ accumulation. Results: EA and SUV each significantly improved cognitive performance, normalized circadian rhythmicity, and reduced Aβ deposition in the hippocampus. Notably, combined EA + SUV therapy produced greater improvements in escape latency ( P < 0.01) and cognitive flexibility than either monotherapy. Two-way ANOVA confirmed a significant interaction effect between EA and SUV on cognitive outcomes ( P = 0.005), supporting a synergistic tendency. EA and SUV also suppressed hippocampal OxA, Bmal1, and Aβ expression, restored cAMP/pCREB signaling, and preserved mitochondrial synaptic integrity. Double immunostaining further revealed reduced co-localization of OxA and Aβ following treatment. Conclusions: EA and SUV exert complementary effects in alleviating iPND through modulation of the OxA/circadian axis and inhibition of Aβ pathology. Their combination offers enhanced neuroprotection, supporting a multimodal therapeutic strategy targeting both circadian and neurodegenerative mechanisms. These findings provide a rationale for integrative approaches in perioperative cognitive care and merit further translational investigation. Graphical abstract available at: http://links.lww.com/JS9/H337