Tetrahydrocoptisine alleviates postoperative delirium with sleep disturbances by modulating the TH/NLRP3 Inflammasome...

Postoperative delirium (POD) accompanied by sleep disturbances (SD) represents a significant concern in perioperative neurocognitive health. Emerging evidence indicates a potential bidirectional relationship between these conditions; however, their underlying mechanisms remain poorly elucidated, and effective therapeutic interventions are currently lacking. Rhizoma Corydalis (RC), a traditional Chinese medicinal herb recognized for its analgesic and anti-inflammatory properties, has not been previously investigated in the context of cognitive impairment and sleep regulation.

This study sought to elucidate the mechanisms by which RC and its bioactive compounds mitigate cognitive deficits and disrupted sleep architecture. This investigation was conducted through a combination of disease-target database mining, bioinformatics analysis, and validation in both in vivo and in vitro models of neuroinflammation.

POD and sleep disturbances were identified in subjects through tibial fracture surgery combined with electroencephalography/electromyography (EEG/EMG) monitoring of sleep architecture. These assessments were employed to preliminarily evaluate the effects of RC on cognitive function and sleep structure. Subsequently, a network pharmacology approach, integrated with LASSO regression analysis, was utilized to identify potential therapeutic targets and key bioactive compounds contributing to the effects of RC on surgery with SD. These findings were subsequently validated through in vivo experiments using the surgery + SD rat model and in vitro studies employing a primary glial cell inflammation model induced by sevoflurane exposure.

RC, particularly at higher doses, significantly ameliorated cognitive deficits (as shown by Morris water maze and novel object recognition tests) and restored sleep structure (as evidenced by EEG/EMG recordings) in surgery rats. Network pharmacology identified tyrosine hydroxylase (TH) as a key node and tetrahydrocoptisine (THC) as a principal active compound. RC and THC reduced interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS), elevated dopamine levels, and normalized the expression of TH, dopamine receptor D2, NLRP3, cleaved caspase-1, and gasdermin D N-terminal. These interventions also reversed rapid eye movement sleep reduction in surgery rats. In vitro analyses revealed that THC effectively suppressed inflammation in glial cells, with its effects negated by the TH inhibitor α-methyl-p-tyrosine (AMPT). Furthermore, siRNA-mediated knockdown of DRD2 abolished the anti-inflammatory and NLRP3-suppressing effects of THC, thereby confirming that THC exerts its protective action through the TH/DRD2 signaling pathway.

RC and its active compound THC significantly attenuate POD comorbid SD-induced cognitive impairment and sleep disturbances, likely through modulation of TH activity and inhibition of NLRP3 inflammasome activation. These findings provide mechanistic insight and preclinical evidence supporting the development of novel perioperative neuroprotective strategies targeting neuroinflammatory and neurotransmitter pathways.