Applications of Acupuncture Therapy in Modulating Plasticity of Central Nervous System.

OBJECTIVE: Acupuncture is widely applied for treatment of various neurological disorders. This manuscript will review the preclinical evidence of acupuncture in mediating neural plasticity, the mechanisms involved. MATERIALS AND METHODS: We searched acupuncture, plasticity, and other potential related words at the following sites: PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and VIP information data base. The following keywords were used: acupuncture, electroacupuncture, plasticity, neural plasticity, neuroplasticity, neurogenesis, neuroblast, stem cell, progenitor cell, BrdU, synapse, synapse structure, synaptogenesis, axon, axon regeneration, synaptic plasticity, LTP, LTD, neurotrophin, neurotrophic factor, BDNF, GDNF, VEGF, bFGF, EGF, NT-3, NT-4, NT-5, p75NTR, neurotransmitter, acetylcholine, norepinephrine, noradrenaline, dopamine, monamine. We assessed the effects of acupuncture on plasticity under pathological conditions in this review. RESULTS: Relevant references were reviewed and presented to reflect the effects of acupuncture on neural plasticity. The acquired literatures mainly focused on neurogenesis, alterations of synapses, neurotrophins (NTs), and neurotranimitters. Acupuncture methods mentioned in this article include manual acupuncture and electroacupuncture. CONCLUSIONS: The cumulative evidences demonstrated that acupuncture could induce neural plasticity in rodents exposed to cerebral ischemia. Neural plasticity mediated by acupuncture in other neural disorders, such as Alzheimer's disease, Parkinson's disease, and depression, were also investigated and there is evidence of positive role of acupuncture induced plasticity in these disorders as well. Mediation of neural plasticity by acupuncture is likely associated with its modulation on NTs and neurotransmitters. The exact mechanisms underlying acupuncture's effects on neural plasticity remain to be elucidated. Neural plasticity may be the potential bridge between acupuncture and the treatment of various neurological diseases.

Acupuncture Attenuated Vascular Dementia-Induced Hippocampal Long-Term Potentiation Impairments via Activation of D1/D5 Receptors.

BACKGROUND AND PURPOSE: Emerging evidence suggests that acupuncture could improve cognitive impairment in vascular dementia by enhancing synaptic plasticity in the hippocampus. The purpose of this study is to investigate whether dopamine, a key mediator of synaptic plasticity, is involved in this cognitive improvement. METHODS: Vascular dementia model was established by bilateral common carotid arteries occlusion in male Wistar rats. Three days after the operation, animals received acupuncture treatment for 2 weeks, once daily. The D1/D5 receptors antagonist SCH23390 was administered intraperitoneally 15 minutes before each acupuncture treatment. Morris water maze was examined after acupuncture. Long-term potentiation was studied by an electrophysiological technique. Dopamine and metabolites levels were detected by microdialysis and high-performance liquid chromatography from brain tissue. The expression of D1R and D5R was analyzed by immunofluorescence. RESULTS: Acupuncture remarkably reversed cognitive deficits in 2-vessel occlusion model (2VO) rats, and the acupuncture points Zusanli (ST36) and Baihui (GV20) were confirmed to be the most effective combination. Electrophysiological recording data showed that 2VO-induced impairments of long-term potentiation were prevented by acupuncture. In addition, acupuncture promoted the release of dopamine and its major metabolites in the hippocampus of 2VO rats. The immunofluorescence experiment showed that the decrease of D1R and D5R in hippocampal dentate gyrus region of 2VO rats was reversed by acupuncture. Furthermore, we found that the effects of acupuncture against 2VO-induced impairments in cognition and synaptic plasticity were abolished by SCH23390. CONCLUSIONS: Improvement in cognition and hippocampal synaptic plasticity induced by acupuncture was achieved via activation of D1/D5 receptors in 2VO rats.

Potential Mechanisms and Clinical Effectiveness of Acupuncture in Depression.

Major depressive disorder is the most common mental disorder with significant economic burden and limited treatments. Acupuncture has emerged as a promising non-pharmacological treatment for reducing depressive symptoms. However, the potential mechanisms and clinical effectiveness of acupuncture are not fully understood. This review aimed to: (1) summarize the available evidence on the mechanisms and clinical effectiveness of acupuncture for depression, and then (2) compare with pharmacological interventions, guiding future studies. Studies with animal models of depression and patients have shown that acupuncture could increase hippocampal and network neuroplasticity and decrease brain inflammation, potentially to alleviating depressive disorders. Overall clinical studies indicated that acupuncture could relieve primary depression, particularly milder cases, and was helpful in the management of post-stroke depression, pain-related depression, and postpartum depression both as an isolated and adjunct treatment. It was emphasized that acupuncture combined with antidepressant pharmacological treatment not only enhanced the improvement of primary and secondary depressive symptoms but also reduced the side effects of the medical treatment, which is the main cause for high dropout rates with drug treatment. In summary, substantial evidence from animal and human researches supported the beneficial effect of acupuncture in depression. However, most clinical trials of acupuncture were small, and it is unclear whether their findings can be generalized, so more studies are needed.

Moxibustion attenuates neurogenic detrusor overactivity in spinal cord injury rats by inhibiting M2/ATP/P2X3 pathway.

PURPOSE: Activation of muscarinic receptors located in bladder sensory pathways is generally considered to be the primary contributor for driving the pathogenesis of neurogenic detrusor overactivity following spinal cord injury. The present study is undertaken to examine whether moxibustion improves neurogenic detrusor overactivity via modulating the abnormal muscarinic receptor pathway. MATERIALS AND METHODS: Female Sprague-Dawley rats were subjected to spinal cord injury with T9-10 spinal cord transection. Fourteen days later, animals were received moxibustion treatment for one week. Urodynamic parameters and pelvic afferents discharge were measured. Adenosine triphosphate (ATP) content in the voided cystometry fluid was determined. Expressions of M2, M3, and P2X3 receptors in the bladder mucosa were evaluated. RESULTS: Moxibustion treatment prevented the development of detrusor overactivity in spinal cord injury rats, with an increase in the intercontraction interval and micturition pressure threshold and a decrease in afferent activity during filling. The expression of M2 was markedly suppressed by moxibustion, accompanied by a reduction in the levels of ATP and P2X3. M2 receptor antagonist methoctramine hemihydrate had similar effects to moxibustion on bladder function and afferent activity, while the M2-preferential agonist oxotremorine methiodide abolished the beneficial effects of moxibustion. CONCLUSION: Moxibustion is a potential candidate for treating neurogenic bladder overactivity in a rat model of spinal cord injury, possibly through inhibiting the M2/ATP/P2X3 pathway.

Effects of Electroacupuncture at Different Acupoints on Functional Dyspepsia Rats.

Although, acupoint specificity is regarded as the core of scientific issues in electroacupuncture (EA), the difference of EA on treating functional dyspepsia (FD) at different acupoints is unclear. Therefore, this study aims to investigate the different therapeutic effects of EA at lower extremity or abdominal acupoints on the mucosal integrity and lower-inflammatory response in FD. The intragastric administration of iodoacetamide (IA) was performed in 48 rats to establish the FD model. These rats were randomly divided into the control group, the model group and the six EA groups receiving stimulation at the lower extremity (ST36, ST37, and ST39) or abdominal acupoints (ST25, CV4, and CV12) separately. The open-field test (OFT) was measured after 8 weeks of IA, and gastric emptying was evaluated after 10 days of the EA treatment. The local inflammation markers of CD45, eosinophil major basic protein (EMBP), and the tight junction proteins ZO1 and Claudin3 were assessed by immunofluorescence in all groups. Western blot analysis showed that the EMBP and Occludin1 levels in the duodenal. EA at lower extremity acupoint ST36 could improve the gastric emptying. EA at lower extremity acupoints reduced the immunoreactivity of EMBP, but the CD45 was reregulated by the ST37 and ST39 acupoints. The lower extremity acupoints also ameliorated FD-tight junction protein in the expression of Claudin3 and ZO1. However, only the ST36 suppressed the expression of EMBP and recovered the expression of Occludin1. Similarly, the effect of EA at abdominal acupoints was not obvious either in facilitating gastric motility or in improving inflammatory and mucosal injury. EA at lower extremity and abdominal acupoints with the same stimulation parameters had different therapeutic effects in gastric emptying, intestinal mucosal integrity, and inflammation response, thus proving the specificity of acupoints.

Acupuncture attenuates cognitive deficits through α7nAChR mediated anti-inflammatory pathway in chronic cerebral hypoperfusion rats.

AIMS: Chronic cerebral hypoperfusion (CCH) elicits inflammatory response, which contributes to the pathology of cognitive impairment. Several studies demonstrate that the alpha-7 nicotinic acetylcholine receptor (α7nAChR) can be a key component to modulate the inflammatory responses. We have reported previously that acupuncture attenuated cognitive deficits induced by CCH. In present study, whether effect of acupuncture was related to α7nAChR mediated anti-inflammatory pathway in CCH rats was further explored. MAIN METHODS: Acupuncture was performed in CCH rats induced by bilateral common carotid arteries occlusion. Neuronal injury, the activation of microglia, the release of inflammatory cytokines, the expression of α7nAChR, and the activation of JAK2/STAT3 signaling pathways were detected. Cognitive function and central inflammation were evaluated after the intraperitoneal injection of an α7nAChR agonist PNU282987, or intracerebroventricular injection of an α7nAChR antagonist α-bungarotoxin (α-BGT). KEY FINDINGS: We found that there were neuronal damage and inflammation, accompanied with the decreased expressions of α7nAChR in the hippocampus under CCH condition. Acupuncture inhibited neuronal damage, activation of microglia, and inflammatory cytokines. The expressions of α7nAChR, together with its downstream JAK2/STAT3 pathways were up regulated by acupuncture. PNU282987 mimicked the anti-inflammatory and neuroprotective effects as well as the cognitive improvements of acupuncture. Meanwhile, the benefit effects of acupuncture above were blocked by α-BGT. SIGNIFICANCE: It was demonstrated that acupuncture promoted cognitive function and afforded neuroprotective effects against inflammation via activation of α7nAChR and its downstream JAK2-STAT3 pathway in CCH rats. It provides a new insight for acupuncture as an anti-inflammatory intervention for cognitive impairment.

Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus.

Inflammatory cytokines produced by muscularis macrophages largely contribute to the pathological signs of postoperative ileus (POI). Electroacupuncture (EA) can suppress inflammation, mainly or partly via activation of vagal efferent. The goal of this study was to investigate the mechanisms by which EA stimulation at an hindlimb region ameliorates inflammation in POI. Methods: Intestinal motility and inflammation were examined after 24 h after intestinal manipulation (IM)-induced POI in mice. Local immune response in the intestinal muscularis, expression of macrophages, α7 nicotinic acetylcholine receptor (α7nAChR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined by flow cytometry, Western Blot, qPCR and immunofluorescence. The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. In the parasympathetic pathways, intestinal motility and inflammation were determined after cervical vagotomy and sub-diaphragmatic vagotomy. The expression of gamma absorptiometry aminobutyric acid (GABAA) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABAA receptor) or muscimol (agonist of GABAA receptor) were assessed. Results: EA suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABAA receptor in DMV to ameliorate inflammation. Conclusions: The present study revealed that EA of hindlimb regions inhibited the expression of GABAA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.

Standardizing therapeutic parameters of acupuncture in vascular dementia rats.

INTRODUCTION: Despite acupuncture having been successfully used for the clinical treatment for vascular dementia in Asian countries for centuries, scientifically rigorous evidence is lacking for standardizing therapeutic parameters. To address this problem, it is necessary to examine the parameters of acupuncture using scientific methodology. The goal of this study is to investigate various therapeutic parameters, including manipulation, retention, and frequency of acupuncture, and their contribution to the efficacy of acupuncture in VD. METHODS: We selected needle retention, treatment frequency, and needle rotation as the parameters. Acupuncture was performed on acupoints ST36 and GV20. Morris Water Maze was selected to assess the effect of acupuncture on cognitive function and Nissl staining indicated the hippocampal neuronal damage in VD rats. RESULTS: Acupuncture stimulation resulted in a significant improvement in the spatial learning and memory deficit and reversed neuronal damage in the hippocampus. The approach of needle retention with 10 min, rotation for 30s every 5 min or daily treatment with acupuncture was more effective than nonretention, nonrotation, or alternative day treatment group. CONCLUSION: This study demonstrated that needle retention, treatment frequency, and needle manipulation are important factors in improving the learning and memory as well as reducing the neuronal damage of the hippocampus in a rat VD model. These findings strongly suggest that the appropriate therapeutic parameters could significant influence the efficiency in animal experiments.

[Challenges and enlightenments of SPARC program on acupuncture and moxibustion researches in China].

The advantages of western medical research were analyzed and the differences between skin nerve stimulation in western medicine and acupuncture-moxibustion in TCM were compared, so as to inspire the scientific researches of acupuncture and moxibustion in China. The related literature was searched and the research basis, content and achievements of the American stimulating peripheral activity to relief condition (SPARC) program were systematically summarized. From the perspectives of theoretical system, stimulation site, stimulation method and mechanism of action, the similarities and differences between skin nerve stimulation in western medicine and acupuncture-moxibustion in TCM were compared. Through comparative analysis, it is found that the systematic construction of SPARC "high-resolution neural circuit map" is essentially the upgraded version of the traditional distribution map of meridians and acupoints in China, which is similar to the research on origin of nervous system and stimulation site of acupuncture-moxibustion of TCM. Under the impact of "localization of traditional Chinese medicine" in other countries, learning from the international advanced research technology, gathering top-level talents, and encouraging openness and innovation will be the necessary pathway to improve the quality of acupuncture-moxibustion research and master the power of knowledge initiative.

Acupuncture Improves White Matter Perfusion and Integrity in Rat Model of Vascular Dementia: An MRI-Based Imaging Study.

White matter lesions induced by chronic cerebral hypoperfusion are associated with cognitive impairment in vascular dementia (VaD). Previous studies have shown that acupuncture can ameliorate the cognitive deficits of individuals with VaD. However, the neuroimaging mechanisms of acupuncture on white matter perfusion and integrity remain elusive. In this study, the VaD model was induced by bilateral common carotid arteries occlusion (BCCAO) in rats. Novel object recognition task and Morris water maze were performed to evaluate short-term memory and spatial learning and memory. Arterial spin labeling and diffusion tensor imaging (DTI) were used to measure the cerebral blood flow (CBF) and the white matter integrity. Pathological examinations detected the myelin loss and concomitant neuroinflammation. The results demonstrate that BCCAO rats with reduced CBF exhibited worse performance and altered DTI parameters, including decreased fractional anisotropy, increased radial diffusivity, and axial diffusivity in white matter regions. Acupuncture ameliorated cognitive impairment, increased CBF, and protected the myelin sheath integrity but not the axons of BCCAO rats. These protective effects of acupuncture on white matter were significantly correlated with improved CBF. Pathological examination confirmed that the loss of myelin basic protein and microglial accumulation associated IL-1ß and IL-6 production were attenuated by acupuncture treatment. Our findings suggest that acupuncture protects cognitive function of BCCAO rats by improving white matter perfusion and integrity.

Mechanisms of Acupuncture in the Regulation of Oxidative Stress in Treating Ischemic Stroke.

Ischemic stroke is the major type of cerebrovascular disease usually resulting in death or disability among the aging population globally. Oxidative stress has been closely linked with ischemic stroke. Disequilibrium between excessive production of reactive oxygen species (ROS) and inherent antioxidant capacity leads to subsequent oxidative damage in the pathological progression of ischemic brain injury. Acupuncture has been applied widely in treating cerebrovascular diseases from time immemorial in China. This review mainly lays stress on the evidence to illuminate the possible mechanisms of acupuncture therapy in treating ischemic stroke through regulating oxidative stress. We found that by regulating a battery of molecular signaling pathways involved in redox modulation, acupuncture not only activates the inherent antioxidant enzyme system but also inhibits the excessive generation of ROS. Acupuncture therapy possesses the potential in alleviating oxidative stress caused by cerebral ischemia, which may be linked with the neuroprotective effect of acupuncture.

Effects of electroacupuncture on the intestinal motility and local inflammation are modulated by acupoint selection and stimulation frequency in postoperative ileus mice.

BACKGROUND: Electroacupuncture (EA) is widely used in various gastrointestinal diseases around the world, including POI. Here, we investigated different therapeutic effects of EA using lower limb and abdomen acupoints. METHODS: Intestinal manipulation was performed in 88 mice, and eight mice underwent a sham operation. Forty mice were randomly divided into model group and four EA groups receiving stimulation at ST36 (2, 10, 30, 100 Hz). The most effective frequency was then used in the following experiments. Forty-eight mice were randomly divided into six groups receiving EA treatment at ST37, ST39, ST25, CV4, CV12, and a non-acupuncture point. Gastrointestinal motility and plasma TNF-α, IL-6 were evaluated in all mice. The local immune response and α-smooth muscle actin (α-SMA) expression were assessed by immunofluorescence, ELISA, and HE staining. RESULTS: ST36 stimulated with 10 or 30 Hz EA significantly increased the gastrointestinal motility and attenuated peripheral inflammation; however, ST36 stimulated with 2 or 100 Hz did not induce any effect. The therapeutic effects on motility and inflammation of 10 Hz EA in the ST36 group were similar in the ST36, ST37, ST39, or CV4 groups, but when applied to ST25, CV12 or non-acupoint had no significant differences. EA at ST36, ST37, ST39, or CV4 significantly inhibited local MPO activity, immune cells infiltration, and increased α-SMA. CONCLUSIONS: EA at lower limb and abdomen acupoints with the same stimulation parameters had different therapeutic effects on postoperative dysmotility and inflammation. Furthermore, EA protected SMC to improve gastrointestinal transit by reducing local inflammation in the intestinal musculature in POI.

Acupuncture attenuates cognitive impairment, oxidative stress and NF-κB activation in cerebral multi-infarct rats.

BACKGROUD: Patients with multiple infarct dementia (MID) have subtle deficits that commonly go unnoticed, and are at risk of developing Alzheimer's disease. Oxidative stress induced by ischaemic injury results in intracellular calcium accumulation and neuronal apoptosis, leading to cognitive impairment by triggering various cellular signal transduction pathways. Several studies have suggested that NF-κB in the presence of p53 has a pro-apoptotic function in various models, but the mechanism is unclear. AIMS: The aim of this study was to investigate whether acupuncture could protect cognitive function against cerebral multi-infarction (CMi) induced oxidative stress by inhibiting the activation of NF-κB and its target gene p53. METHODS: An animal model of CMi was established by injecting homologous blood emboli into the right internal carotid artery of male Wistar rats. After 2 weeks of acupuncture treatment, cognitive function was detected by novel object recognition. Electron spin resonance and Fluo-3 fuorescence imaging were used to test the generation of ROS and intracellular calcium accumulation, respectively. Expression of NF-κB and p53 was examined by Western blot analysis and immunofluorescence. RESULTS: CMi induced spatial learning and memory impairment, overproduction of intracellular hydroxyl radicals, and elevations of Ca2+, which were ameliorated by verum acupuncture treatment. Acupuncture inhibited activation of NF-κB and its downstream target gene p53. CONCLUSION: These findings suggest that acupuncture could protect cognitive function against oxidative stress induced by CMi, which is partially associated with suppression of NF-κB-p53 activation.

Gene-Level Regulation of Acupuncture Therapy in Spontaneously Hypertensive Rats: A Whole Transcriptome Analysis.

Hypertension is a global health problem. It has been reported that acupuncture at Taichong acupoints (LR3) decreases high blood pressure in spontaneously hypertensive rats. A transcriptome analysis can profile gene expression and its relationship with acupuncture. In this study, rats were treated with 2 weeks of acupuncture followed by regular recording of blood pressure (BP). The mRNA changes in the rostral ventrolateral medulla (RVLM) were evaluated to uncover the genetic mechanisms of acupuncture by using a whole transcript array (Affymetrix Rat Gene 1.0 ST array). BP measurements showed that acupuncture significantly decreased systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR). In the bioinformatics results, 2371 differentially expressed genes (DEGs) were identified, where 83 DEGs were overlapped among Wistar-Kyoto rats (WKYs), spontaneously hypertensive rats (SHRs), and SHRs + acupuncture rats (SHRs+Acu). Gene ontology (GO) and pathway analysis revealed that 279 GO terms and 20 pathways with significant differences were related to oxidative stress, inflammation, and vascular endothelial function. In addition, coexpressed DEGs networks indicated that Cd4 and Il-33 might mediate the cascade of inflammation and oxidative stress responses, which could serve as a potential target of acupuncture treatment. In conclusion, our study demonstrated that acupuncture is a promising therapy for treating hypertension and could regulate multiple biological processes mainly involving oxidative stress, inflammation, and vascular endothelial function.

Acupuncture Prevents the Impairment of Hippocampal LTP Through ß1-AR in Vascular Dementia Rats.

It is widely accepted that the synaptic dysfunction and synapse loss contribute to the cognitive deficits of vascular dementia (VD) patients. We have previously reported that acupuncture improved cognitive function in rats with VD. However, the mechanisms involved in acupuncture improving cognitive ability remain to be elucidated. The present study aims to investigate the pathways and molecules involved in the neuroprotective effect of acupuncture. We assessed the effects of acupuncture on hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation. Acupuncture enhanced LTP and norepinephrine (NE) levels in the hippocampus. Inhibition of the ß-adrenergic receptor (AR), but not the α-AR, was able to block the effects of acupuncture on hippocampal LTP. Furthermore, inhibition of ß1-AR, not ß2-AR, abolished the enhanced LTP induced by acupuncture. The expression analysis revealed a significant upregulation of ß1-AR and unchanged ß2-AR with acupuncture, which supported the above findings. Specifically, increased ß1-ARs in the dentate gyrus were expressed on neurons exclusively. Taken together, the present data supports a beneficial role of acupuncture in synaptic plasticity challenged with VD. A likely mechanism is the increase of NE and activation of ß1-AR in the hippocampus.

Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats.

AIMS: Oxidative stress and inflammation have been implicated in the pathogenesis of vascular dementia (VD). Thioredoxin-interacting protein (TXNIP) plays a vital role in oxidative stress and NOD-like receptor protein 3 (NLRP3) inflammasome activation. There is evidence that acupuncture has an antioxidative and neuroprotective effect in VD. In this study, we investigated whether acupuncture can attenuate cognitive impairment via inhibiting TXNIP-associated oxidative stress and inflammation in VD rats. METHODS: Both common carotid arteries were occluded (2-vessel occlusion [2VO]) in rats to model VD. The neuroprotective effect of acupuncture was assessed by the Morris water maze and Nissl staining. Oxidative stress was assessed by detecting levels of reactive oxygen species, DNA oxidation, and antioxidase. Western blot, real-time PCR, and immunofluorescence were used to detect the expression of TXNIP, NLRP3, caspase-1, and IL-1ß. A TXNIP siRNA intraventricular injection was applied to investigate whether acupuncture mimicked the effect of TXNIP inhibitor. RESULTS: Our findings demonstrated that VD rats treated with acupuncture had reduced hippocampal neuronal loss and oxidative stress. The upregulation of TXNIP, NLRP3, caspase-1, and IL-1ß induced by 2VO was also reversed by acupuncture. Furthermore, TXNIP siRNA had a similar effect as acupuncture on cognition, hippocampal neurons, and ROS production in VD rats. CONCLUSION: In conclusion, our study suggests that the neuroprotective effects of acupuncture in VD are mediated through reducing expression of TXNIP-associated oxidative stress and inflammation.