Electroacupuncture Exerts Analgesic Effects by Restoring Hyperactivity via Cannabinoid Type 1 Receptors in the Anterior Cingulate Cortex in Chronic Inflammatory Pain.

As one of the commonly used therapies for pain-related diseases in clinical practice, electroacupuncture (EA) has been proven to be effective. In chronic pain, neurons in the anterior cingulate cortex (ACC) have been reported to be hyperactive, while the mechanism by which cannabinoid type 1 receptors (CB1Rs) in the ACC are involved in EA-mediated analgesic mechanisms remains to be elucidated. In this study, we investigated the potential central mechanism of EA analgesia. A combination of techniques was used to detect the expression and function of CB1R, including quantitative real-time PCR (q-PCR), western blot (WB), immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and in vivo multichannel optical fibre recording, and neuronal activity was examined by in vivo two-photon imaging and in vivo electrophysiological recording. We found that the hyperactivity of pyramidal neurons in the ACC during chronic inflammatory pain is associated with impairment of the endocannabinoid system. EA at the Zusanli acupoint (ST36) can reduce the hyperactivity of pyramidal neurons and exert analgesic effects by increasing the endocannabinoid ligands anandamide (AEA), 2-arachidonoylglycerol (2-AG) and CB1R. More importantly, CB1R in the ACC is one of the necessary conditions for the EA-mediated analgesia effect, which may be related to the negative regulation of the N-methyl-D-aspartate receptor (NMDAR) by the activation of CB1R downregulating NR1 subunits of NMDAR (NR1) via histidine triad nucleotide-binding protein 1 (HINT1). Our study suggested that the endocannabinoid system in the ACC plays an important role in acupuncture analgesia and provides evidence for a central mechanism of EA-mediated analgesia.

Electroacupuncture Ameliorates Cognitive Impairment by Regulating γ-Amino Butyric Acidergic Interneurons in the Hippocampus of 5 Familial Alzheimer's Disease Mice.

OBJECTIVES: γ-amino butyric acid (GABA)-ergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD). Inhibitory interneurons play an important role in the regulation of E/I balance, synaptic transmission, and network oscillation through manipulation of GABAergic functions, showing positive outcomes in AD animal models. Mice expressing 5 familial AD mutation (5xFAD) exhibited a series of AD-like pathology and learning and memory deficits with age. Because electroacupuncture (EA) treatment has been used for a complementary alternative medicine therapy in patients with AD, we aimed to examine any usefulness of EA therapy in GABA interneuron function and its associated synaptic proteins, to determine whether EA could effectively improve inhibitory transmission and network oscillation and eventually alleviate cognitive impairments in 5xFAD mice, and to further elucidate the GABAergic system function underlying the antidementia response of EA. MATERIALS AND METHODS: 5xFAD mice were used to evaluate the potential neuroprotective effect of electroacupuncture at Baihui (DU 20) and Dazhui (DU 14) through behavioral testing, immunofluorescence staining, electrophysiology recording, and molecular biology analysis. RESULTS: First, we observed that EA improved memory deficits and inhibitory synaptic protein expression. Second, EA treatment alleviated the decrease of somatostatin-positive interneurons in the dorsal hippocampus. Third, EA attenuated E/I imbalance in 5xFAD mice. Last, EA treatment enhanced theta and gamma oscillation in the hippocampus of 5xFAD mice. CONCLUSIONS: EA stimulation at DU20 and DU14 acupoints may be a potential alternative therapy to ameliorate cognitive deficits in AD through the regulation of the function of the GABAergic interneuron.

Comparative efficacy of acupuncture-related techniques for mild cognitive impairment: A Bayesian network analysis.

Background: A comparison and ranking of the clinical effects of various acupuncture and acupuncture-related therapies on patients with mild cognitive impairment. Methods: Using network meta-analysis, we assessed the direct and indirect evidence from relevant research. Seven databases [PubMed, Web of Science, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), VIP Database, and Wanfang database] were examined to find randomized controlled trials of acupuncture-related therapies for individuals with mild cognitive impairment. Two researchers independently reviewed the literature, retrieved the data, and evaluated the risk of bias in the included studies. The data were analyzed using Stata15.0 and R3.6.1 software. Results: A total of 27 randomized controlled trials involving 2,210 patients were included. Bayesian NMA showed that manual acupuncture combined with conventional therapy, moxibustion combined with conventional therapy, manual acupuncture, and electroacupuncture were most effective in improving the MMSE score. The most effective interventions related to the MoCA score were moxibustion combined with conventional therapy, followed by manual acupuncture combined with conventional therapy, acupressure combined with conventional therapy, and manual acupuncture combined with moxibustion. Manual acupuncture combined with moxibustion was dominant in the cluster ranking. The results of the node splitting method revealed that direct and indirect evidence were consistent (P > 0.05). In addition, publication bias was detected. Conclusion: This research will add to the body of knowledge about the safety and efficacy of acupuncture-related therapies in the treatment of mild cognitive impairment. The results of this study will also assist in the choice of clinical guidelines that optimize acupuncture treatment for patients with mild cognitive impairment.

Loss of SST and PV positive interneurons in the ventral hippocampus results in anxiety-like behavior in 5xFAD mice.

Neuropsychiatric symptoms, such as anxiety and depression often appear early in patients with Alzheimer's disease (AD), and a comorbid, anxiety-like phenotype is also found in rodents with AD. However, the underlying mechanisms behind these conditions and potential therapeutic targets to treat them remain unclear. In this study, we used 5 familial AD mutations (5xFAD) mice that developed early amyloid ß-amyloid deposition and related synaptic loss and memory deficits to identify a potential mechanism behind abnormally high anxiety levels observed in these subjects. We observed anxiety-like behavior in mice that had an excitatory/inhibitory (E/I) imbalance in the ventral hippocampus (vHPC) of 5xFAD mice. Both the number of parvalbumin-positive (PV+) and somatostatin-positive (SST+) cells decreased in the ventral hippocampus of the subject 5xFAD mice, however, no reductions were observed in calretinin-positive cells. We found that selectively inhibiting vHPC pyramidal cells via hM4Di expression normalized anxiety-like behaviors and E/I balance in 5xFAD mice. Finally, we found that the ventral hippocampus SST+ or PV+ neurons were activated through selectively expressed hM3Dq, which ameliorated anxiety-like behaviors and the synaptic E/I imbalance of vCA1 in 5xFAD mice. These results determined that anxiety-like behaviors accompanied by hippocampal synaptic E/I imbalance in 5xFAD mice are due to the loss of SST+ and PV+ interneurons in the vHPC. This provides a better understanding of high anxiety levels observed in patients with early-stage AD.

Low-frequency electroacupuncture improves disordered hepatic energy metabolism in insulin-resistant Zucker diabetic fatty rats via the AMPK/mTORC1/p70S6K signaling pathway.

BACKGROUND AND AIM: Disordered hepatic energy metabolism is found in obese rats with insulin resistance (IR). There are insufficient experimental studies of electroacupuncture (EA) for IR and type 2 diabetes mellitus (T2DM). The aim of this study was to probe the effect of EA on disordered hepatic energy metabolism and the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase, 70-kDa (p70S6K) signaling pathway. METHODS: Zucker Diabetic Fatty (ZDF) rats were randomly divided into three groups: EA group receiving EA treatment; Pi group receiving pioglitazone gavage; and ZF group remaining untreated (n = 8 per group). Inbred non-insulin-resistant Zucker lean rats formed an (untreated) healthy control group (ZL, n = 8). Fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, C-reactive protein (CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) indices were measured. Hematoxylin-eosin (H&E) staining was used to investigate the liver morphologically. The mitochondrial structure of hepatocytes was observed by transmission electron microscopy (TEM). Western blotting was adopted to determine protein expression of insulin receptor substrate 1 (IRS-1), mTOR, mTORC1, AMPK, tuberous sclerosis 2 (TSC2) and p70S6K, and their phosphorylation. RT-PCR was used to quantify IRS-1, mTOR, mTORC1, AMPK and p70S6K mRNA levels. RESULTS: Compared with the ZF group, FPG, FINS, C-peptide, CRP and HOMA-IR levels were significantly reduced in the EA group (p < 0.05, p < 0.01). Evaluation of histopathology showed improvement in liver appearances following EA. Phosphorylation levels of AMPK, mTOR and TSC2 decreased, and IRS-1 and p70S6K increased, in hepatocytes of the ZF group, while these negative effects appeared to be alleviated by EA. CONCLUSIONS: EA can effectively ameliorate IR and regulate energy metabolism in the ZDF rat model. AMPK/mTORC1/p70S6K and related molecules may represent a potential mechanism of action underlying these effects.