The influence of electronic acupuncture at a specific frequency in facilitating the passage of NGF through the blood-brain barrier and its effect on learning and memory in MCAO/R rats

Abstract

Background:The blood-brain barrier (BBB) maintains the balance of the internal environment of the brain and strictly controls substance exchange between the brain and blood dynamically but stably. Transient increases in the permeability of the BBB plays an important role in helping macromolecular drugs enter the brain to exert their pharmacological effects. Previous research has revealed that electronic acupuncture (EA) stimulation connecting Baihui (GV20) and Shuigou (GV26) at a specific frequency can enhance the permeability of the BBB at 8 minutes after the intervention and induce the entry of 20 kDa fluorescein isothiocyanate-dextran (FITC-dextran) into the cerebral cortex, but whether it can also allow drugs to pass the BBB remains unknown. We hypothesized that EA at a specific frequency could open the BBB and induce the entry of nerve growth factor (NGF) into the brain to exert its therapeutic effect. Methods: First, the middle cerebral artery occlusion (MCAO) model is adopted and changes in the permeability and structure of the BBB are assessed by measuring both the intensity of Evans blue (EB) staining and the cerebral infarction volume, and by evaluating the ultrastructure of the BBB. Then, a laser spectrometer and immunofluorescence are used to observe entry of NGF into the brain. Finally, the learning and memory ability of rats are assessed and the DeadEnd TM Fluorometric TUNEL System is applied to assess apoptosis in the hippocampus. Results: Our results showed that, in the first, the BBB was essentially repaired three weeks after MCAO operation. Secondly, Electronic Acupuncture (EA) stimulation at a specific frequency can enhance BBB permeability in the prefrontal cortex and induce NGF uptake by prefrontal neurons. Finally, in the presence of EA stimulation, entry of NGF into the brain promoted learning and memory in rats and inhibited the apoptosis of neurons in the hippocampus. Conclusions: In this study, the timing of BBB repair in the MCAO model was determined under pathological conditions and the EA stimulation can induce the entry of NGF into the brain to exert its therapeutic effect. EA could serve as a new strategy for delivering therapeutics to the central nervous system (CNS), given that EA stimulation at a specific frequency was shown to increase the permeability of the BBB. Further study of the mechanism underlying the opening of the BBB and its timing is needed.

Electroacupuncture modulates gut microbiota in mice: A potential target in postoperative cognitive dysfunction

“…In this study, we observed that serum LPS and DAO levels were higher in the APP/AP1‐C and WT‐C groups than in groups that received EA intervention, indicating gut barrier impairment (Du et al, 2019). Interestingly, our study detected the preserved integrity of both the intestinal barrier and BBB in APP/PS1‐E mice, which are consistent with the findings of Wang et al (2020) and Zhao et al (2022). Tight junction protein levels and electron microscopy results revealed that the BBB was destroyed in the absence of EA and the concentration of inflammatory factors was increased in the hippocampal tissue.…”

Acupuncture with specific mode electro-stimulation effectively and transiently opens the BBB through Shh signaling pathway

“…In this study, we first verified the role of EA, and the previous research group also found that opening BBB by EA could induce NGF to enter the brain tissue of rats and improve the learning and memory ability of MCAO/R model rats [6], and started to conduct clinical experimental observation on the sequelae of cerebral apoplexy. Therefore, the experiment was conducted 4 weeks after the animal modeling to ensure the complete repair of BBB, which was also in line with the clinical practice of sequelae of cerebrovascular disease.…”

“…Modern studies have shown that these two acupoints have a regulatory effect on the central nervous system and have the potential to be widely used in the treatment of brain-derived diseases [5]. The results of previous studies have indicated that administration of EA (EA) with certain parameters, specifically 2/100 Hz, 3 mA, and 6 s/6 s, for 40 min, stimulates these two points in rats to effectively open the BBB, allowing Evans Blue (EB) and nerve growth factor (NGF) to enter the brain tissue [6]. It has been found that after EA stimulation, neurons in the brain were activated, and the expression of tight junction (TJ) proteins such as Occludin and zona occludens-1 (ZO-1) was significantly lower [7].…”

Acupuncture Interventions for Alzheimer’s Disease and Vascular Cognitive Disorders: A Review of Mechanisms

“…A fixed frequency of 2 or 100 Hz may show easy adaptability and a relatively continuous and stable stimulation, which may reduce the effect of EA [ 143 ]. Therefore, 2/100 Hz EA was applied to the GV20 and GV26 acupoints for 40 min, effectively increasing BBB permeability in rats [ 144 ]. However, for hippocampal synaptic transmission, high-frequency EA could demonstrate a better effect in rats with Alzheimer's disease [ 145 ].…”

“…Acupuncture can upregulate vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), basic fibroblast growth factor (bFGF), and CD34 + , thereby promoting the proliferation of vascular endothelial cells, increasing local cerebral blood flow, activating multiple signaling pathways, and mediating vascular and nerve regeneration [ 158 ]. EA stimulation of “Baihui” (GV20) and “Shuigou” (GV26) at a specific frequency has been reported to increase the permeability of BBB, providing a strategy for the treatment of nervous system diseases [ 143 , 144 ]. Liu et al [ 111 ] found that EA could regulate the expression of VEGF genes and promote angiogenesis in the ischemic cerebral cortex, which may play an important role in the improvement of CI in ischemic stroke.…”