Effects of Preoperative Electroacupuncture on Remifentanil-Induced Post-Infusion Hyperalgesia in Patients Undergoing Thyroidectomy: A Double-Blind Randomized Controlled Trial.

Objective: Electroacupuncture (EA) delivered one day before surgery could reduce postoperative pain. Remifentanil-induced post-infusion hyperalgesia (RPH) was occurred after exposure to high-dose remifentanil. This study aimed to investigate the effects of preoperative EA on RPH in patients undergoing thyroidectomy. Methods: A total of 80 patients who were scheduled to undergo elective thyroidectomy were randomly assigned to two groups: an EA group and a sham EA (SEA) group. EA was delivered at the Zusanli (ST36) and Neiguan (PC6) acupoints 24 h before the surgery. To ensure uniformity across all patients, remifentanil was administered at the same set rate (0.3 µg/kg/min) to all patients. Mechanical pain thresholds were recorded by an electronic von Frey device around the skin incision and on the arm before surgery as well as at 30 min and 6, 24, and 48 h after surgery. Results: At 30 min and 6 h after surgery, the EA group showed considerably greater mechanical pain thresholds surrounding the surgical site compared with the SEA group. At 30 min and 6 h after surgery, the patients in the SEA group showed a greater incidence of postoperative hyperalgesia surrounding the surgical site than those in the EA group. At 24 and 48 h after surgery, no significant differences were found between the two groups, although the pain intensity of the EA group was less than that of the SEA group. There were also no substantial differences between the two groups in the frequency of postoperative adverse reactions and rescue analgesia needed. Conclusion: EA administered 24 h before surgery could alleviate RPH in patients undergoing thyroidectomy.

Electroacupuncture Ameliorates Tibial Fracture-Induced Cognitive Dysfunction by Elevating α7nAChR Expression and Suppressing Mast Cell Degranulation in the Hippocampus of Rats.

Intracerebral neuroinflammation, closely related to brain mast cell (MC) activation, performs an integral function in the pathogenic process of postoperative cognitive dysfunction (POCD). In addition to regulating cognitive activities, the alpha-7-nicotinic acetylcholine receptor (α7nAChR) engages in the progression of cognitive deficiency. In this research, we aimed to investigate how electroacupuncture (EA) affects the cognitive function in rats after tibial fracture surgery to determine whether the underlying mechanism involves the inhibition of hippocampal MC degranulation via α7nAChR. A rat model of tibial fracture surgery for inducing POCD was developed and subjected to treatment with EA or the α7nAChR antagonist α-bungarotoxin (α-BGT) and the α7nAChR agonist PHA-543613. The spatial memory tasks in the Morris Water Maze (MWM) test showed that both EA and PHA-543613-treated rats performed significantly better than untreated rats, with reduced escape latency and increased frequency of passage through the platform. However, EA and PHA-543613 intervention decreased the protein and mRNA levels of High-mobility group box-1(HMGB-1) and proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) in the serum and hippocampus, respectively, by upregulating α7nAChR in the hippocampus. Furthermore, EA and PHA-543613 pretreatment reduced the number of activated MCs and suppressed neuronal apoptosis after tibial fracture surgery in the hippocampal CA1 regions, which was reversed by α-BGT. The findings indicated that EA pretreatment ameliorated POCD after tibial fracture surgery in rats by inhibiting brain MC activation and neuroinflammation mediated by the α7nAChR-dependent cholinergic anti-inflammatory system.

Electroacupuncture Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury by Regulating Mitophagy via mTOR-ULK1/FUNDC1 Axis in Rats.

OBJECTIVE: Electroacupuncture (EA) pretreatment has been shown to alleviate cerebral ischemia-reperfusion (I/R) injury; however, the underlying mechanism remains unclear. To investigate the involvement of mTOR signaling in the protective role of EA in I/R-induced brain damage and mitochondrial injury. METHODS: Sprague-Dawley male rats were pretreated with vehicle, EA (at Baihui and Shuigou acupoints), or rapamycin + EA for 30 min daily for 5 consecutive days, followed by the middle cerebral artery occlusion to induce I/R injury. The neurological functions of the rats were assessed using the Longa neurological deficit scores. The rats were sacrificed immediately after neurological function assessment. The brains were obtained for the measurements of cerebral infarct area. The mitochondrial structural alterations were observed under transmission electron microscopy. The mitochondrial membrane potential changes were detected by JC-1 staining. The alterations in autophagy-related protein expression were examined using Western blot analysis. RESULTS: Compared with untreated I/R rats, EA-pretreated rats exhibited significantly decreased neurological deficit scores and cerebral infarct volumes. EA pretreatment also reversed I/R-induced mitochondrial structural abnormalities and loss of mitochondrial membrane potential. Furthermore, EA pretreatment downregulated the protein expression of LC3-II, p-ULK1, and FUNDC1 while upregulating the protein expression of p-mTORC1 and LC3-I. Rapamycin effectively blocked the above-mentioned effects of EA. CONCLUSION: EA pretreatment at Baihui and Shuigou alleviates cerebral I/R injury and mitochondrial impairment in rats through activating the mTORC1 signaling. The suppression of autophagy-related p-ULK1/FUNDC1 pathway is involved in the neuroprotective effects of EA.

Amelioration of Neuropathic Pain and Attenuation of Neuroinflammation Responses by Tetrahydropalmatine Through the p38MAPK/NF-κB/iNOS Signaling Pathways in Animal and Cellular Models.

Neuropathic pain (NP) treatment remains a challenge because the pathomechanism is not yet fully understood. Because of low treatment efficacy, there is an important unmet need in neuropathic pain patients, and the development of a more effective pharmacotherapy is urgently required. Neuroinflammation induced by oxidative stress-mediated activation of nuclear factor-kappa B (NF-κB) plays an important role in NP. In this study, we aimed to investigate the protective properties of tetrahydropalmatine (THP) on a spared nerve injury (SNI) model of neuropathic pain in mice in in vivo and also in in vitro experiments. THP decreased mechanical hyperalgesia and cold allodynia compared with the SNI group. A microarray was applied to analyze differentially expressed of mRNA among different groups, and THP noticeably changed the expression of MAPK-related proteins compared with the SNI groups. H&E staining showed that the THP changed the inflammation after the spared nerve injury, with decreased NO expression in the THP group as compared to the SNI group. In addition, SNI-induced pain was reversed by intraperitoneal administration of THP, and further results indicated that THP suppressed inducible nitric oxide synthase (iNOS, pro-nociceptive mediators), phosphorylated MAPKs, and p65 in the dorsal root ganglions and sciatic nerve, while the serum levels of the pro-inflammatory cytokines IL-1ß were significantly higher in the SNI group as compared to the THP group. To identify the molecular mechanism of the antineuropathic activity of THP, sodium nitroprusside (SNP)-induced neuro-2a (N2a) cells, LPS-induced BV2 cells, and LTA-induced astrocytes were further investigated in signaling pathways. In vitro experiments indicated that THP suppressed the expression of IL-1ß, iNOS, phosphorylated MAPKs, and p65, which were assayed using western blotting, and immunofluorescence.

Electroacupuncture attenuates spared nerve injury-induced neuropathic pain possibly by promoting the progression of AMPK/mTOR-mediated autophagy in spinal microglia.

Background: Neuropathic pain (NP) is a syndrome that arises from central or peripheral nerve injury, which manifests primarily as hyperalgesia, spontaneous pain, and allodynia. The recent trend has exhibited a shift towards the development of therapies for managing NP. Activation of autophagy is involved in the function of the glial cells, which may be implicated further to attenuate pain. Methods: In this study, the analgesic effects of electroacupuncture (EA) were evaluated among NP rats developed using spared nerve injury (SNI). Acupuncture treatment or EA was carried out after 7 days of SNI at two acupoints, i.e., the Zusanli (ST36) and Huantiao (GB30). Results: The application of EA was found to attenuate mechanical hyperalgesia. The marker protein for microglial cells (CD11b) alone, without either the astrocyte marker or neuronal marker, was co-expressed with the autophagy indicator p62, as illustrated with immunofluorescence staining. Western blotting demonstrated that the expression levels of p62, Beclin-1, and LC3-II/LC3-I were elevated in the spinal cords of rats in the SNI group compared to the control levels. EA treatment resulted in reduced expression of p62, while the expressions of Beclin-1 and LC3-II/LC3-I were increased. The electron microscopy results indicated that EA could induce autophagy progression in the microglia of the spinal dorsal horn in SNI rats. Furthermore, we explored the causal relationship between EA-induced inhibition of NP and increased autophagic levels in microglia using the AMPK inhibitor compound C, and found that the mechanism of EA-induced analgesia may contribute to the promotion of AMPK/mTOR-mediated autophagy in spinal microglia. Conclusions: Our work showed that the analgesic impact of EA is partly related to AMPK/mTOR pathway activation and autophagy induction in microglial cells, providing a potential therapeutic target for NP.

Electroacupuncture Pretreatment against Cerebral Ischemia/Reperfusion Injury through Mitophagy.

Cerebral ischemia/reperfusion (I/R) injury can induce the mitophagy of neurons in the ischemic brain. Electroacupuncture (EA) pretreatment has a protective effect on cerebral ischemia/reperfusion injury. However, its internal mechanism still needs to be further studied. The present study's purpose is to investigate whether mitophagy is involved in neuroprotection elicited by EA pretreatment in a rat model of cerebral ischemia/reperfusion injury. The rats were pretreated with vehicle, EA at the Baihui (GV20) and Shuigou (GV26) acupoints 30 min daily, for 5 days consecutively prior to the focal cerebral ischemia injury induced by the middle cerebral artery occlusion (MCAO) model. Compared to the sham group, the neurological scores, infarction volume, number of autophagosomes, FUNDC1, p62, and the ratio of LC3-II/I were significantly increased but mitochondrial membrane potential and autophagy-related protein p-mTORC1 significantly decreased in the I/R group. However, EA pretreatment significantly reversed these trends. Overall, the results of this study demonstrated that EA pretreatment protected the cerebral ischemia/reperfusion injury which maybe correlated with mitophagy.

Hydrogen-rich saline attenuates neuronal ischemia--reperfusion injury by protecting mitochondrial function in rats.

BACKGROUND: Hydrogen, a popular antioxidant gas, can selectively reduce cytotoxic oxygen radicals and has been found to protect against ischemia-reperfusion (I/R) injury of multiple organs. Acute neuronal death during I/R has been attributed to loss of mitochondrial permeability transition coupled with mitochondrial dysfunction. This study was designed to investigate the potential therapeutic effect of hydrogen-rich saline on neuronal mitochondrial injury from global cerebral I/R in rats. MATERIALS AND METHODS: We used a four-vessel occlusion model of global cerebral ischemia and reperfusion, with Sprague-Dawley rats. The rats were divided randomly into six groups (n = 90): sham (group S), I/R (group I/R), normal saline (group NS), atractyloside (group A), hydrogen-rich saline (group H), and hydrogen-rich saline + atractyloside (group HA). In groups H and HA, intraperitoneal hydrogen-rich saline (5 mL/kg) was injected immediately after reperfusion, whereas the equal volume of NS was injected in the other four groups. In groups A and HA, atractyloside (15 µL) was intracerebroventricularly injected 10 min before reperfusion, whereas groups NS and H received equal NS. The mitochondrial permeability transition pore opening and mitochondrial membrane potential were measured by spectrophotometry. Cytochrome c protein expression in the mitochondria and cytoplasm was detected by western blot. The hippocampus mitochondria ultrastructure was examined with transmission electron microscope. The histologic damage in hippocampus was assessed by hematoxylin and eosin staining. RESULTS: Hydrogen-rich saline treatment significantly improved the amount of surviving cells (P < 0.05). Furthermore, hydrogen-rich saline not only reduced tissue damage, the degree of mitochondrial swelling, and the loss of mitochondrial membrane potential but also preserved the mitochondrial cytochrome c content (P < 0.05). CONCLUSIONS: Our study showed that hydrogen-rich saline was able to attenuate neuronal I/R injury, probably by protecting mitochondrial function in rats.

[Effect of mild hypothermia on the expression of acid-sensing ion channels 1a and 2a following global cerebral ischemia-reperfusion in rats].

OBJECTIVE: To investigate the effects of mild hypothermia on the expression of ASIC1a and ASIC2a in the rat hippocampus following global cerebral ischemia-reperfusion, so as to speculate the underlying mechanisms of neuroresuscitation. METHODS: Ninety five male SD rats were randomly divided into five groups (n = 19): sham operation group (I), model group (II), mild hypothermia group (III), PcTX1 group (IV), mild hypothermia combined PcTX1 group (V). Transient (15 min) global cerebral ischemia was induced by the four-vessel occlusion. PcTX1 (500 ng/ml) 6 µl were injected into lateral cerebral ventricle immediately after reperfusion in group IV and V, while the equal volume of normal saline was injected into lateral cerebral ventricle immediately after reperfusion in the other three groups. At the same time, mild hypothermia after reperfusion was performed and lasted for 6 hours in group III and V, the rectal temperature was reduced to 32 - 33°C within 15 min, while it was maintained at 36 - 37°C by lamp in other three groups. Determination the expression of ASIC1a and ASIC2a protein at 6 h and 24 h of reperfusion, and the expression of ASIC1a and ASIC2a mRNA at 24 h of reperfusion. Observe the pathomorphological changes of hippocampal CA1 neurons at 24 h of reperfusion. Detect the brain water content at 72 h of reperfusion. RESULTS: The difference in the expression of ASIC1a mRNA and protein among the groups was not changed significantly (P > 0.05). Compared with group I, the expression of ASIC2a mRNA and ASIC2a protein was up-regulated in other groups (P < 0.05). It was significantly higher in group III and V than in group II and IV (P < 0.05). Compared to 6 h of reperfusion, the expression of ASIC2a protein was higher in group II, III, IV and V respectively after 24 h of reperfusion. Compared to group I, the number of pyramidal cells in CA1 region of hippocampus in group II, III, IV and V were decreased at 24 h of reperfusion (P < 0.01). Compared to group II, the number of pyramidal cells in CA1 region of hippocampus in group III, IV and V were increased at 24 h of reperfusion (P < 0.01); and compared to group III and IV, the number of pyramidal cells at 24 h of reperfusion in group V was significantly higher (P < 0.01). Compared to group I, the content of brain water in II, III and IV group were increased at 72 h of reperfusion (P < 0.01). Compared to group II, the content of brain water in group III, IV and V were decreased at 72 h of reperfusion (P < 0.01). Giving mild hypothermia or PcTX1 could alleviate the damage in CA1 region of hippocampus, with the best effect in group V, which administers PcTX1 combined mild hypothermia. CONCLUSION: Mild hypothermia attenuates global cerebral ischemia-reperfusion of rat, which may up-regulate the expression of ASIC2a mRNA and protein. Mild hypothermia combined by PcTX1 could induce neuroresuscitation.