Electroacupuncture May Ease Early Postoperative Cognitive Decline by Targeting Brain Inflammation

Postoperative neurocognitive disorders, encompassing postoperative delirium, delayed neurocognitive recovery, and postoperative cognitive dysfunction, represent common complications among older surgical patients. These conditions are linked with prolonged hospital stays, impaired recovery, compromised quality of life, and increased postoperative mortality. In a comprehensive review published in Chinese Medicine, researchers Shirong Wei, Huadong Ni, and colleagues evaluate current mechanistic findings and clinical trials investigating electroacupuncture as a minimally invasive neuromodulatory therapy for perioperative cognitive decline. Surgical trauma and anesthesia disrupt central nervous system homeostasis by triggering complex cascades of tissue trauma, neuroinflammation, and metabolic strain. Because conventional management remains largely supportive, effective targeted pharmacological therapies are still lacking. Conventional single-target drugs frequently struggle against this multifactorial pathophysiology, establishing a strong rationale for exploring non-pharmacological interventions with multimodal regulatory capabilities. Electroacupuncture, which delivers low-intensity electrical currents to specific neuroanatomical acupoints, offers a promising approach to modulate central neural pathways and attenuate postoperative cognitive decline.

The clinical burden of perioperative cognitive complications is substantial across major surgical specialties and vulnerable patient populations. Reported incidences of postoperative delirium range from 16.4 to 50 percent following cardiac surgery, while postoperative cognitive dysfunction persists in 9.9 to 12.7 percent of older non-cardiac patients at three months post-surgery. Pathophysiologically, perioperative surgical trauma and anesthetic exposure inflict tissue damage and compromise cell membrane integrity. Damaged somatic cells release substantial quantities of damage-associated molecular patterns, prominently high mobility group box 1, adenosine triphosphate, and uric acid, into the peripheral circulation. These released mediators trigger systemic inflammatory cascades that destabilize blood-brain barrier integrity. Endothelial tight junction proteins, including claudin-5, occludin, and zonula occludens-1, undergo downregulation alongside elevated matrix metalloproteinase activity, permitting circulating inflammatory cytokines to enter central nervous compartments. Within the brain, these invading mediators activate pattern recognition receptors, specifically Toll-like receptors TLR2 and TLR4 and the receptor for advanced glycation end products, initiating downstream inflammatory signaling pathways.

Direct experimental evidence from animal models confirms that electroacupuncture can effectively restrain central neuroinflammatory signaling networks. In aged rodent models subjected to surgical trauma, electroacupuncture applied to Baihui (GV20) and Dazhui (GV14) attenuated neuroinflammation and cognitive impairment by downregulating hippocampal TLR2 and TLR4 expression. This receptor suppression curtailed microglial overactivation and significantly decreased local tissue concentrations of pro-inflammatory cytokines, including interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. Beyond Toll-like receptor inhibition, electroacupuncture exerts targeted control over the hippocampal NLRP3 inflammasome. In postoperative models, electrical stimulation at Zusanli (ST36) and Baihui (GV20) inhibited both priming and activation phases of the NLRP3 inflammasome by downregulating NLRP3, ASC, and caspase-1. Furthermore, recent work by Ma and colleagues revealed that electroacupuncture at GV20, PC6, and ST36 in aged rats following sevoflurane anesthesia and splenectomy suppressed hippocampal neuronal cGAS-STING signaling and downstream NF-κB and IRF3 activation, thereby preserving postoperative cognitive performance.

Preclinical investigations also reveal that electroacupuncture orchestrates neuroimmune phenotypic switching while actively regulating peripheral-central communication axes. In animal models of postoperative cognitive dysfunction, Liu and colleagues demonstrated that electroacupuncture applied at Baihui (GV20), Neiguan (PC6), and Hegu (LI4) reduced astrocytic activation, suppressed microglial reactivity, and shifted microglial polarization away from the pro-inflammatory M1 phenotype toward the neuroprotective M2 phenotype. In orthopedic fracture models, electroacupuncture limited hippocampal mast cell degranulation and relieved cognitive deficits through alpha-7 nicotinic acetylcholine receptor signaling pathways. Concurrently, electroacupuncture modulates the microbiota-gut-brain axis, which is frequently disrupted when surgical trauma, anesthetic exposure, and postoperative pain induce intestinal dysbiosis and impair barrier integrity. Findings by Zhu and colleagues demonstrated that electroacupuncture remodeled gut microbiota dysbiosis in surgical mice by enriching beneficial taxa like Coprococcus and suppressing pathogenic taxa like Helicobacteraceae. This remodeling restored intestinal and blood-brain barrier integrity, ultimately attenuating hippocampal neuroinflammation and reducing postoperative cognitive impairment.

Oxidative stress represents an equally destructive pathological contributor to perioperative neurocognitive disorders, occurring when excessive generation of reactive oxygen and nitrogen species outstrips endogenous antioxidant defenses. In the perioperative setting, surgical trauma induces ischemia-reperfusion injury and systemic inflammation, while anesthetic exposure impairs mitochondrial respiratory function. Because neuronal membrane polyunsaturated fatty acids are exceptionally vulnerable to reactive oxygen species, unchecked oxidative stress triggers widespread lipid peroxidation, destabilizing membranes and driving iron-dependent ferroptosis. Preclinical studies indicate that electroacupuncture counteracts ferroptotic injury by coordinating cellular iron handling and promoting antioxidant defenses. Chen and colleagues established that electroacupuncture downregulated transferrin receptor 1 and divalent metal transporter 1 while upregulating ferroportin to prevent intracellular iron overload. Additionally, evidence from Zhang and colleagues demonstrated that electroacupuncture activated the GRX1/GSK-3β/Nrf2 regulatory axis, driving nuclear translocation of Nrf2. This transcriptional activation upregulated glutathione peroxidase 4, an essential enzyme that neutralizes toxic lipid hydroperoxides and protects vulnerable hippocampal neurons against ferroptotic cell death.

Mitochondrial bioenergetic dysfunction is intimately intertwined with oxidative stress, functioning simultaneously as a major generator and a primary target of reactive oxygen species during surgery. Anesthetic agents and surgical trauma disrupt mitochondrial membrane potential, diminish adenosine triphosphate production, and induce mitochondrial permeability transition pore opening, causing cytochrome c leakage and downstream caspase activation. Preclinical evidence shows that electroacupuncture preserves mitochondrial integrity by limiting calcium overload, stabilizing membrane potential, and promoting mitochondrial translocation of telomerase reverse transcriptase. Simultaneously, electroacupuncture restores autophagic homeostasis across distinct phases of the degradation pathway. Surgical stress and neuroinflammation disturb autophagy initiation via AMPK and mTOR signaling while impairing lysosomal degradation, leading to abnormal accumulation of p62 and damaged organelles. Electroacupuncture modulates AMP-activated protein kinase and SIRT1/FOXO1 pathways, enhancing Beclin-1 expression while clearing p62 aggregates. Furthermore, electroacupuncture upregulates PINK1/Parkin-mediated mitophagy, facilitating selective clearance of damaged mitochondria, preserving neuronal ultrastructure, and mitigating postoperative spatial memory deficits in experimental models.

At the neurophysiological level, molecular and cellular injuries converge to disrupt hippocampal synaptic plasticity, neural electrical activity, and large-scale brain network connectivity. In perioperative neurocognitive disorders, neuroinflammation and mitochondrial failure impair long-term potentiation and alter functional connectivity across higher-order neural networks, including the default mode network and executive control network. Preclinical research demonstrates that electroacupuncture directly supports hippocampal synaptic plasticity signaling. In aged rats with surgery-induced cognitive decline, electroacupuncture pretreatment activated the ERK/MAPK/CREB pathway in the hippocampal CA1 subfield, improving cognitive performance. Furthermore, Cheng and colleagues showed that electroacupuncture applied at PC6, LI4, and ST36 in aged rats subjected to laparotomy under sevoflurane anesthesia restored CA1 neuronal morphology and elevated essential synaptic structural markers, including postsynaptic density protein 95 and synaptophysin. Mechanistically, electroacupuncture inhibited p38 mitogen-activated protein kinase phosphorylation, and pharmacological reactivation of p38 MAPK partially reversed these neuroprotective benefits, confirming that MAPK regulation plays a direct mechanistic role in electroacupuncture-mediated synaptic preservation.

Additional preclinical investigations have linked electroacupuncture with broader cellular survival mechanisms, particularly ferroptosis suppression, mitochondrial bioenergetics, and proteostatic control. In an aged mouse model of sevoflurane anesthesia paired with tibial fracture surgery, Du and colleagues demonstrated that electroacupuncture pretreatment improved postoperative cognitive performance and inhibited ferroptotic cell death through the SIRT1/NRF2/GPX4 signaling pathway. That study observed that electroacupuncture enhanced tissue ATP content, restored mitochondrial membrane potential, and improved mitochondrial ultrastructural morphology. While single-cell transcriptomic analyses by Suo and colleagues in postoperative models identified widespread protein dysmetabolism, mitochondrial abnormalities, and impaired neuroglial communication, direct electroacupuncture studies assessing the ubiquitin-proteasome system and wide-scale proteomic turnover remain scarce. The review authors emphasize that while classical apoptosis and proteasome dysfunction represent biologically plausible pathways, their regulation by electroacupuncture has not yet been directly demonstrated in perioperative models. Future investigations combining multi-omics technologies and proteomic profiling will be essential to establish whether electroacupuncture directly regulates global protein turnover in the perioperative brain.

At the clinical level, randomized controlled trials and meta-analyses provide growing evidence that perioperative electrical acupoint stimulation can mitigate early postoperative cognitive decline in older surgical patients. A comprehensive systematic review and meta-analysis conducted by Wu and colleagues, encompassing 26 randomized controlled trials with 2,309 elderly patients undergoing general anesthesia, revealed that perioperative electroacupuncture significantly reduced the incidence of perioperative neurocognitive disorders, improved postoperative Mini-Mental State Examination scores, and lowered circulating levels of interleukin-6, interleukin-1 beta, tumor necrosis factor-alpha, and S100 calcium-binding protein beta. Similar cognitive improvements have been observed across various surgical settings using either invasive electroacupuncture or transcutaneous electrical acupoint stimulation, a non-invasive modality delivering electrical currents via surface electrodes. In elderly patients undergoing hip fracture repair, gastrointestinal tumor resection, or video-assisted thoracoscopic surgery, electrical stimulation applied to core acupoints—most frequently Baihui (GV20), Neiguan (PC6), and Zusanli (ST36)—commencing thirty minutes prior to anesthesia induction and maintained through surgery, significantly reduced early cognitive dysfunction and improved cognitive assessment scores.

Despite these encouraging clinical observations and rich preclinical findings, the review authors emphasize substantial methodological limitations that necessitate a cautious interpretation of current evidence. Many existing clinical trials are single-center investigations with modest sample sizes conducted primarily in China, potentially limiting geographic generalizability. Furthermore, clinical trials exhibit significant methodological heterogeneity regarding acupoint prescriptions, stimulation waveforms, electrical frequencies, and intervention timing, with protocols applying preoperative, intraoperative, or repeated postoperative treatments. Most studies rely on basic screening scales such as the Mini-Mental State Examination or Montreal Cognitive Assessment rather than delirium-specific diagnostic tools, and long-term cognitive follow-up remains scarce. Rigorous ongoing protocols, such as Wei and colleagues’ multicenter, sham-controlled trial evaluating electroacupuncture for postoperative delirium with the 3D-CAM assessment in prostatectomy patients, illustrate an important methodological evolution toward standardized reporting and robust sham controls. The authors conclude that definitive confirmation of electroacupuncture as a standard clinical therapy requires large-scale, sham-controlled trials coupled with dynamic multi-omics and electrophysiological biomarkers to establish optimal stimulation protocols and substantiate long-term cognitive protection.

Subject of Research: Mechanisms and clinical evidence of electroacupuncture for perioperative neurocognitive disorders

Article Title: Advances in electroacupuncture for perioperative neurocognitive disorders: mechanisms and clinical evidence

Article References: Wei, S., Zhou, S., Tu, J., Zhi, T., Wang, Y., Shen, Q., Ni, C., Yao, M., & Ni, H. (2026). Advances in electroacupuncture for perioperative neurocognitive disorders: mechanisms and clinical evidence. Chinese Medicine, 21(1), Article 182. https://doi.org/10.1186/s13020-026-01466-1

Image Credits: AI Generated

DOI: 10.1186/s13020-026-01466-1

Keywords: electroacupuncture, perioperative neurocognitive disorders, postoperative cognitive dysfunction, postoperative delirium, neuroinflammation, NLRP3 inflammasome, cGAS-STING signaling, oxidative stress, ferroptosis, mitochondrial dysfunction, autophagic flux, synaptic plasticity, microbiota-gut-brain axis, transcutaneous electrical acupoint stimulation, hippocampal CA1, geriatric surgery, microglial polarization, biomarkers