Electroacupuncture of the trigeminal nerve causes N-methyl-D-aspartate receptors to mediate blood-brain barrier opening and induces neuronal excitatory changes.

The blood-brain barrier (BBB) is an important structure for maintaining environmental stability in the central nervous system (CNS). Our previous study showed that specific parameters of electroacupuncture (EA) at the head points Shuigou (GV26) and Baihui (GV20) can open the BBB; however, the mechanism by which stimulation of body surface acupuncture points on the head results in peripheral stimulation and affects the status of the central BBB and the neuronal excitatory changes has not been elucidated. We used laser spectroscopy, the In Vivo Imaging System (IVIS), immunofluorescence and immunoblotting to verified the role of the trigeminal nerve in BBB opening during EA, and we applied the central N-methyl-D-aspartate (NMDA) receptors blocker MK-801 to verify the mediating role of NMDA receptors in EA-induced BBB opening. Next, electroencephalogram (EEG) and in vivo calcium imaging techniques were applied to verify the possible electrical patterns of BBB opening promoted by different intensities of EA stimulation. The results showed that the trigeminal nerve plays an important role in the alteration of BBB permeability promoted by EA stimulation of the head acupoints. Brain NMDA receptors play a mediating role in promoting BBB permeability during EA of the trigeminal nerve, which may affect the expression of the TJ protein occludin, and thus alter BBB permeability. The analysis of the electrical mechanism showed that there was no significant change in the rhythm of local field potentials (LFP) in different brain regions across frequency bands immediately after EA of the trigeminal nerve at different intensities. However, the local primary somatosensory (S1BF) area corresponding to the trigeminal nerve showed a transient reduction in the delta rhythm of LFP with no change in the high-frequency band, and the action potential (spike) with short inter spike interval (ISI) varied with EA intensity. Meanwhile, EA of the trigeminal nerve resulted in rhythmic changes in calcium waves in the S1BF region, which were influenced by different EA intensities. This study provides a research perspective and a technical approach to further explore the mechanism of EA-induced BBB opening and its potential clinical applications.

Multicenter, randomized, double-blind, controlled trial of transcutaneous electrical nerve stimulation for pancreatic cancer related pain.

BACKGROUND: Up to 80% of patients with pancreatic cancer experience abdominal and back pain. Although pharmacologic medications provide some relief, many report inadequate analgesia and adverse effects. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive physical modality and had been widely applied for pain relieving, yet no study has investigated the effectiveness of TENS for pain in pancreatic cancer. METHODS: Eligible patients were randomly assigned in a 1:1 ratio to TENS group or control group. The primary outcome was percentage change of numerous rating scale (NRS) after treatment. Secondary outcomes included percentage change of analgesic medication consumption and effect on constipation and poor appetite. RESULTS: One hundred seventy-one patients were recruited (84 to control group and 87 to TENS group). NRS in TENS group has been largely decreased 77.9% right after treatment and 27.1% in 2 hours, before applying any analgesic medication, while that in control group was slightly downregulated right after treatment but gave a trend to increase at 1, 2, and 3 hours. When comparing both groups, pain was significantly well controlled without analgesic medication supplement in TENS group at 0 hour (difference in mean percent change in NRS = 50.0 [95% CI, 50-51.4], P < .01) and 3 hours (difference in mean percent change in NRS = 134.0 [95% CI, 130.0-142.7], P < .01) after treatment, and this analgesic effect last to 3 weeks after treatment cycle (difference in mean percent change in NRS = 22.5 [95% CI, 17.6-27.3], P < .01) without increase of analgesic medication consumption. CONCLUSIONS: TENS reduces pain without increase analgesic medication consumption in patients with pancreatic cancer pain. It provides an alternative therapy for pain in pancreatic cancer. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT03331055.

Specific Frequency Electroacupuncture Stimulation Transiently Enhances the Permeability of the Blood-Brain Barrier and Induces Tight Junction Changes.

The blood-brain barrier (BBB) plays an important role in both the physiological state and pharmacological state of the brain. Transiently enhancing the permeability of the BBB may allow the use of more types of medications for neuropsychiatric diseases. Our previous research revealed that electroacupuncture (EA) stimulation at certain parameters can enhance the permeability of the BBB in Sprague-Dawley rats, but this phenomenon is not well characterized. We propose that specific frequency EA can transiently open the BBB and may be related to the change of tight junctions (TJ). To find the best EA frequency among commonly used frequencies, preliminarily explore the mechanism, we detected BBB permeability by measuring the intensity of Evans Blue and 20 kDa FITC-dextran fluorescence in the cerebral cortex. Then, we used a laser spectrometer, immunofluorescence, western blotting, and transmission electron microscopy to detect the mechanism of BBB opening. Finally, measured brain water content, AQP4, GFAP, Iba1, and used the DeadEndTM Fluorometric TUNEL System to clear whether the stimulation caused obvious negative effects. The results show that EA stimulation at 2/100 Hz maximally increased BBB permeability, and the BBB closed within 12 h after EA stimulation was removed. EA stimulation increased blood perfusion, c-fos levels, and Substance P expression in the cerebral cortex, decreased ZO-1 and occludin levels and induced ultrastructural changes in TJ morphology. EA stimulation at specific parameters did not cause brain edema, activation of glial cells, or cell apoptosis. This study shows that EA stimulation induces a reversible, frequency-dependent alteration of BBB permeability and proposes a hypothetical mechanism of BBB opening related to vasodilation and TJ disruption. Transiently enhancing the permeability of the BBB with EA at specific parameters may be a new strategies for delivering therapeutics to the central nervous system. Further study of this technology is needed.

The Mechanism of MAPK Signal Transduction Pathway Involved with Electroacupuncture Treatment for Different Diseases.

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays an important role in the regulation of various diseases, such as cardiovascular and cerebrovascular diseases, and takes part in anti-inflammatory effects, analgesic effects, protection against injury, and maintenance of gastrointestinal functions. Electroacupuncture therapy is an external therapy used in traditional Chinese medicine. By adding external electrical stimulation to traditional acupuncture, the stimulus gets doubled and the therapeutic efficacy gets enhanced accordingly. It combines the benefits of both acupuncture and electrical stimulation. In recent years, some studies have explored the molecular mechanisms of MAPK signal pathways involved with electroacupuncture treatment. Based on these recent studies, this article summarizes the mechanisms of MAPK signal transduction pathways involved with electroacupuncture treatment. This adds great value to the studies of molecular mechanisms of electroacupuncture treatment and also provides an effective reference for its clinical use.

Electroacupuncture: a new approach to open the blood-brain barrier in rats recovering from middle cerebral artery occlusion.

OBJECTIVE: To examine for an opening effect on the blood-brain barrier (BBB) in intact rats and rats with experimental ischaemia-reperfusion (I/R) during the recovery period after various electroacupuncture (EA) treatments with different time courses, and to determine whether there is a time-dependent effect. An additional objective was to determine whether this method could induce the penetration of nerve growth factor (NGF) through the BBB. METHODS: A middle cerebral artery occlusion (MCAO) model was first established. We chose different stimulation time courses and observed the effects of EA treatment (100 Hz frequency; 2 mA intensity) at GV20 and GV26 on the BBB in rats recovering from MCAO 3 weeks after modelling. The rats were injected with 2% Evans blue (EB) saline. The brain water content was measured using a wet/dry weighing method. The degree of penetration of EB was detected using spectrophotometry and laser confocal microscopy. The rats were then injected with NGF, and the concentration of NGF in the brain tissues was measured using ELISA. RESULTS: The increase in the BBB permeability was most notable following the 8 min EA stimulation (P<0.05), which may be advantageous for the targeted delivery of drugs (such as NGF) into the brain. Additionally, this effect did not appear to cause brain oedema (P>0.05) in healthy or MCAO rats. CONCLUSIONS: EA treatment for a certain stimulation time at GV20 and GV26 in MCAO rats can increase BBB permeability.

Dengzhanxixin injection for cerebral infarction: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: No systematic review has been published in English of Dengzhanxixin (DZXX) injection for cerebral infarction. The aim of this systematic review was to assess the effects and safety of DZXX injection for cerebral infarction. METHODS: Eight databases were searched from their inception. Randomized controlled trials (RCTs) related to DZXX for cerebral infarction in English or Chinese without restrictions on the publication status were included. Neurological deficit, quality of life, and response rates were analyzed. Adverse events were also investigated. RESULTS: Twenty-three randomized controlled trials (RCTs) with 2291 participants were included. Meta-analysis showed that DZXX injection plus routine western therapy was better than routine western therapy alone for reducing neurologic deficit (MD -2.86, 95% CI -3.87 to -1.86), for improving quality of life (MD 9.48, 95% CI 8.34-10.63), and for improving response rates (RR 1.20, 95% CI 1.15-1.25). No serious adverse drug events (ADE) were reported. CONCLUSIONS: DZXX injection may have a potential therapeutic effect for cerebral infarction in reducing neurologic deficit, improving life quality and response rates. However, we could not draw any definitive conclusions due to the insufficient evidences. More high-quality trials are needed to provide more strong evidence and to assess the safety of DZXX injection.