IMR Press / JIN / Volume 23 / Issue 2 / DOI: 10.31083/j.jin2302031
Cite this article
Nanoparticles: Properties, applications and toxicities
36
Downloads
131
Views
Submit to JIN
Review for JIN
Apply for Special Issue
  • Academic Editor
    Gernot Riedel
Chapters
Figure
References
Abstract
Keywords
1. Introduction
2. Ischemic Stroke and Electroacupuncture
3. Method
4. Mechanism of Action Underlying the Effect of EA on Neurogenesis and Cell Proliferation
5. Mechanism Underlying the Effect of EA in Cerebral Ischemia/Reperfusion Injury
6. Mechanism Underlying the Effect of EA on Pathological Changes Related to the Blood‒Brain Barrier, Cerebrovascular Function, and Cerebral Blood Flow after Ischemic Stroke
7. The Mechanism by Which EA Inhibits Apoptosis and Autophagy
8. EA Pretreatment for Cerebral Ischemic Tolerance
9. Rehabilitation Phase
10. Issues Related to Acupuncture
11. Conclusions
Author Contributions
Ethics Approval and Consent to Participate
Acknowledgment
Funding
Conflict of Interest
References
Open Access Review
Mechanisms by Which Electroacupuncture Alleviates Neurovascular Unit Injury after Ischemic Stroke: A Potential Therapeutic Strategy for Ischemic Brain Injury after Stroke
Qing Xu1,†, Mengchen Guo2,†, Changzhuo Feng3, Sheng Tu4, Anwen Shao5,*, Anke Zhang5,*, Yongzhi Deng1,6,*
Show Less
1 College of Acupuncture and Massage, Changchun University of Chinese Medicine, 130117 Changchun, Jilin, China
2 Department of Dermatology, Tongji Hospital, School of Medicine, Tongji University, 200092 Shanghai, China
3 Department of Chinese Medicine Internal Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, 130021 Changchun, Jilin, China
4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310027 Hangzhou, Zhejiang, China
5 Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009 Hangzhou, Zhejiang, China
6 Department of Acupuncture, The Third Affiliated Hospital to Changchun University of Chinese Medicine, 130117 Changchun, Jilin, China
*Correspondence: shaoanwen@zju.edu.cn (Anwen Shao); theanke@163.com (Anke Zhang); dyz1028@126.com (Yongzhi Deng)
†These authors contributed equally.
J. Integr. Neurosci. 2024, 23(2), 31; https://doi.org/10.31083/j.jin2302031
Submitted: 15 July 2023 | Revised: 24 August 2023 | Accepted: 31 August 2023 | Published: 18 February 2024
Copyright: © 2024 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Download PDF
Brower Figures
Cite
Abstract

Stroke is the most common cerebrovascular disease and one of the leading causes of death and disability worldwide. The current conventional treatment for stroke involves increasing cerebral blood flow and reducing neuronal damage; however, there are no particularly effective therapeutic strategies for rehabilitation after neuronal damage. Therefore, there is an urgent need to identify a novel alternative therapy for stroke. Acupuncture has been applied in China for 3000 years and has been widely utilized in the treatment of cerebrovascular diseases. Accumulating evidence has revealed that acupuncture holds promise as a potential therapeutic strategy for stroke. In our present review, we focused on elucidating the possible mechanisms of acupuncture in the treatment of ischemic stroke, including nerve regeneration after brain injury, inhibition of inflammation, increased cerebral blood flow, and subsequent rehabilitation.

Keywords
ischemic stroke
electroacupuncture
inflammation
nervous system
rehabilitation
1. Introduction

According to previous studies, approximately 13.7 million people are affected and afflicted by stroke each year [1, 2]. Stroke is currently the second leading cause of death worldwide [3], accounting for 10% of all deaths [4, 5]. Its high mortality, disability, and recurrence rates impose a heavy economic burden on global health care systems. Stroke is broadly categorized as ischemic or hemorrhagic; this review focuses on the mechanisms associated with ischemic stroke. This is the most common type of stroke and is caused by occlusion of cerebral blood vessels or cerebral thrombosis, which results in blockage of cerebral blood flow (CBF) and thereby causes ischemia, hypoxia, and softening or even necrosis of brain tissue.

After ischemic stroke onset, restoring cerebrovascular function to reinitiate the blood supply to the brain is the first priority. Current conventional treatment strategies include angioplasty, stenting, intravenous thrombolytic therapy, and thrombectomy. However, there are obvious limitations to these therapies, including stringent treatment time windows, strict indications for administration, and many contraindications [6, 7]. The safety and efficacy of these treatment strategies are also controversial according to previous clinical research [8]. Therefore, there is an urgent need to identify novel effective therapeutic strategies for clinical use.

Acupuncture originated in China, has a history of more than 3000 years, and is an important component of Chinese medicine [9]. It involves the stimulation of specific acupuncture points on the body surface with specially designed metal needles within the theoretical framework of traditional Chinese medicine and utilizes twisting and lifting techniques or electrical impulses to treat diseases [10, 11, 12]. Acupuncture is rapidly developing; its use has spread to many countries and its efficacy is widely recognized. Scientists have studied the efficacy and underlying mechanisms of acupuncture, and the effectiveness of acupuncture as an alternative therapy for stroke has been described in the literature [13]. However, the potential mechanisms through which acupuncture may aid the treatment of stroke are not yet fully understood. Therefore, the purpose of this study is to investigate the possible mechanisms of acupuncture in the treatment of stroke. Various studies have demonstrated that acupuncture pretreatment can treat ischemic stroke by inducing cerebral ischemic tolerance, regulating oxidative stress, increasing CBF, inhibiting apoptosis, and promoting neural regeneration; thus, it is a promising prevention strategy and alternative therapy for stroke [14].

2. Ischemic Stroke and Electroacupuncture

Ischemic stroke is caused by a reduction in or interruption of blood flow in the cerebral arteries due to various causes, including atherosclerosis, cardiogenic embolism, vasculitis, hereditary diseases, and hematologic disorders [15, 16]. Ischemic stroke directly impairs neurological function in three main ways. First, ischemia and infarction during ischemic stroke cause direct damage to brain tissue. Second, ischemia induces the production of excess reactive oxygen species (ROS), causing oxidative stress, which exacerbates neuronal dysfunction. Finally, the inflammatory cascade caused by ischemic stroke is thought to result in further neuronal damage.

Acupuncture, which originated in China, has been developed as a unique treatment modality during its long history and is an important part of Chinese medicine [17, 18]. Several clinical studies have shown that acupuncture improves postural balance, reduces muscle spasms, and increases muscle strength [19, 20, 21]. In electroacupuncture (EA) therapy, a fine needle is inserted into the selected acupoint. After tactile confirmation that the needle is correctly placed, an EA machine is connected to the acupuncture needle, and a low-frequency pulse current similar to that of human bioelectric currents is delivered with different stimulation parameters to treat different diseases [22]. A systematic review and meta-analysis published in 2015 evaluated the clinical efficacy and safety of EA in the treatment of ischemic stroke [23]. The mechanism of EA in the treatment of ischemic stroke has also received much attention recently; scientists conducted a systematic review and analysis of recent clinical studies and found that EA can play a role in the treatment of ischemic stroke through the following five mechanisms: (1) EA can promote neuronal proliferation and differentiation and induce poststroke neurogenesis and neuroprotection, (2) EA can effectively ameliorate the damage caused by cerebral ischemia‒reperfusion, (3) EA can increase CBF and alleviate blood–brain barrier dysfunction after stroke, (4) EA can inhibit apoptosis, and (5) EA pretreatment can induce cerebral ischemic tolerance [24, 25, 26, 27, 28]. Herein, we review the main potential mechanisms of acupuncture in the treatment of stroke.

3. Method

Studies on the mechanism of acupuncture in treating ischemic stroke models were obtained by a PubMed literature search, which was limited to full-text studies published in English between January 1, 2000, and December 31, 2022. The following search string was used for the literature search: (“electroacupuncture” OR “acupoint”) AND (“ischemic stroke” OR “neurogenesis” OR “cerebral ischemia” OR “cerebral reperfusion” OR “cerebral blood flow” OR “apoptosis autophagy” OR “preconditioning” OR “rehabilitation”). We identified a total of 120 published articles. Papers that did not describe the specific mechanisms by which EA treated ischemic stroke injury, papers that had information on stroke and EA but were unrelated, and papers that used EA as a secondary treatment were excluded. Of these, a total of 40 published articles met the inclusion criteria. All searches were limited to animal studies, most of which used a similar animal model of ischemic stroke, the unilateral transient middle cerebral artery occlusion (MCAO) model.

4. Mechanism of Action Underlying the Effect of EA on Neurogenesis and Cell Proliferation

The beneficial effect of EA on neurogenesis after brain injury may be related to neurotrophic factors. Neurogenesis in adult mammals is accomplished primarily through the division of stem and progenitor cells [29]. Adult neurogenesis, i.e., neuronal growth and development, mainly occurs in two brain regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus [30, 31]. Reports indicate the presence of neural stem cells (NSCs) in the neocortex, amygdala, striatum, and substantial nigra [32]. These NSCs have the ability to differentiate into different types of neurons, astrocytes, and oligodendrocytes at the time of brain injury [33, 34]. Neural progenitor cells (NPCs) are present in the SVZ and migrate to the site of the injury, where they form new functional synapses with the remaining neurons and connect new neural circuits [35, 36]. Brain injury activates endogenous neural repair systems, and the proliferation and survival of these neural cells are thought to play a role in neural repair in the brain, which is a potential therapeutic target [37, 38, 39]. Neurotrophic factors can prevent ischemic injury and exert neuroprotective effects. Glial cell-derived neurotrophic factor (GDNF) belongs to the transforming growth factor beta (TGF-β) family and was originally found to enhance the function of midbrain dopaminergic neurons by promoting survival and differentiation during the development of the central and peripheral nervous systems [40, 41]. Moreover, it was shown that GDNF ligands can promote the neurogenic differentiation of NPCs [42]. Brain-derived neurotrophic factor (BDNF) is a protein that regulates neuronal survival and synaptic plasticity by binding to tyrosine kinase beta (Trkβ) and p75 neurotrophin receptor (p75 NTR) and activates intracellular signaling pathways [43, 44]. Lu et al. [45] reported in a meta-analysis of 34 studies (1617 animals) that acupuncture can promote the proliferation, differentiation, and migration of nerve cells after stroke. Brain injury can activate the neural repair system, but spontaneous regeneration cannot meet the requirements of brain function recovery [46]. Nerve growth factor (NGF) can promote the growth and differentiation of central and peripheral neurons and accelerate the repair of the nervous system after injury, and EA can induce the expression of NGF; the number of BrdU-positive cells was found to be significantly increased by the combination of NGF and EA, indicating increased proliferation and survival of neuronal cells [47, 48]. In addition, EA pretreatment elevates stroke-induced striatal neurogenesis and improves neurological recovery through modulation of the resinous acid (RA) pathway [49, 50]. Acupuncture alters the expression level of growth-associated protein-43 (GAP-43), a protein specific to the nervous system, and promotes nerve regeneration in the marginal zone of the ischemic lesion [51]. In some MCAO animal models, the expression of BDNF, GDNF, and vascular endothelial growth factor (VEGF) was found to be increased significantly after EA stimulation of Baihui GV20, Dazhui GV14, and Quchi LI11; this resulted in increased proliferation and differentiation of NSCs in the DG and SVZ and promoted the differentiation of proliferating NSCs into neurons and glial cells [24, 52, 53, 54, 55].

Notch receptors are highly conserved, single-channel transmembrane proteins that are involved in various cytogenesis-related processes, including cell differentiation, apoptosis, and proliferation, and play an important role in the regulation of self-renewal and differentiation of NSCs after ischemic injury. In the MCAO animal model, EA at LI11 and Zusanli ST36 was found to activate the Notch signaling pathway, significantly decreasing cerebral infarct size, improving cerebral nerve function, and promoting the proliferation of NSCs in rats [56, 57, 58, 59]. Basic fibroblast growth factor (bFGF) promotes the regeneration and repair of mesodermal ectodermal cells, which is essential for the development and differentiation of the central nervous system (CNS). In both cerebral ischemia/reperfusion (CI/R) and MCAO models, EA treatment was found to significantly increase the expression level of bFGF in the striatum and cortex and thus exert neurogenic and protective effects [60, 61, 62]. One of the most abundant neuropeptides in the nervous system, neuropeptide Y (NPY), is a key regulator of homeostasis inside and outside the CNS, while NPY can also promote neurogenesis in the SVZ and DG regions. Furthermore, acupuncture can upregulate the expression of NPY in the CNS [63, 64, 65, 66]. In addition to affecting neurogenesis and proliferation, ischemic stroke also severely impairs brain function due to cerebral ischemia/reperfusion.

5. Mechanism Underlying the Effect of EA in Cerebral Ischemia/Reperfusion Injury
5.1 Oxidative Stress and EA

CI/R leads to the generation of large amounts of ROS, resulting in an imbalance between oxidative and antioxidative status in the body and thus oxidative stress, which in turn causes cellular damage and necrosis, which is a key factor in ischemic brain injury [67, 68]. Mitochondria are the main site of aerobic cellular respiration, supplying energy to cells and participating in cell differentiation, apoptosis, and information transfer [69]. Under normal physiological conditions, the respiratory chain of mitochondria is the main source of ROS, but CI/R increases the leakage of electrons generated in the respiratory chain, resulting in the production of large amounts of ROS [70]. Furthermore, CI/R causes a large decrease in the level of superoxide dismutase (SOD), a key factor in maintaining oxidative and antioxidative balance, impairing its function as a free radical scavenger and the redox balance of mitochondria, and causing the excessive production of ROS and free radicals with impaired antioxidant capacity, ultimately leading to mitochondrial dysfunction [71, 72]. Experiments have shown that EA of Fengchi GB 20 can activate the antioxidant enzyme system and increase the ability of SOD and glutathione peroxidase (GSH-Px) to scavenge excessive ROS; this increase in SOD activity involves the nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase (HO-1) signaling pathway, and the increase in GSH-Px activity may be associated with increased antioxidant activity by glutathione (GSH) [73, 74]. CI/R causes lipid peroxidation to produce malondialdehyde (MDA) and 4-hydroxynonenoic acid (4-HNE), and EA at GB20 and ST36 can reduce the degree of lipid peroxidation and MDA production during MCAO [75]. A systematic review and meta-analysis published in 2014 showed that EA reduced the infarct size and improved neural function in animal models of cerebral ischemia [76]. The respiratory chain function of mitochondria was found to be significantly improved after EA at Shuigou GV26 and GV20, and the activities of succinate dehydrogenase (SDH), cytochrome C oxidoreductase, and NADH dehydrogenase (NADH-Q) reductase were found to be increased, resulting in an elevated antioxidant capacity and inhibition of ROS production [77]. It was also found that CI/R impaired the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-mediated autophagy–lysosome pathway (ALP) to increase the percentage of dysfunctional mitochondria while impairing mitochondrial autophagy, an important change associated with CI/R, and EA restored mitochondrial autophagy through the Pink1/Parkin signaling pathway to ameliorate the impairment of the ALP [78, 79].

5.2 Anti-Inflammatory Effect of EA

The inflammatory cascade after ischemic stroke results in the activation of a series of inflammatory cells and the release of inflammatory signals. Acupuncture exerts anti-inflammatory effects by regulating multiple immune cell populations and inflammatory transmission, which involves glial cells, vagal cholinergic anti-inflammatory pathways, and leukocytes (Fig. 1).

Fig. 1.

Anti-inflammatory effects of EA. EA, Electroacupuncture; GFAP, glial fibrillary acidic protein; M1, M1 microglia; M2, M2 microglia; CI/R, cerebral infarction/reperfusion; DAMPs, damage-related molecular patterns; MAPK, mitogen-activated protein kinase; ERK, extracellular regulatory protein kinase; TLR4, Toll-like receptor 4; NF-κB, enhanced κ-light chain in B cells activated by nuclear factor; a7nAChR, a7 nicotinic acetylcholine receptor; HMGB1, high mobility group protein B1; AchE, acetylcholinesterase; IS, ischemic stroke; ANS, autonomic nervous system; BM, bowel movement; BBB, blood brain barrier; γδT, T cell subpopulation; IL17, interleukin 17; Treg, regulatory T cell; IL10, interleukin 10; ICAM-1, intercellular cell adhesion molecule-1; P-selection, platelet p-selectin; BDNF-TrkG, brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB); DOR, delta-opioid receptor; CB1, type I cannabinoid receptor; CB2, type II cannabinoid receptor; NMDAR, N-methyl-D-aspartate type glutamate receptor; ATP, adenosine triphosphate; ROS, reactive oxygen species.

5.2.1 Glial Cells

Microglia are the most numerous immune cells in the brain, accounting for 5–10% of all cells in the brain [80]. Damaged neurons release damage-related molecular patterns (DAMPs) after CI/R, and DAMPs rapidly activate microglia [56]. On the one hand, the anti-inflammatory factors (interleukin, IL-4, IL-10, IL-13, TGF-β) and neuroprotective factors secreted by activated microglia can remove harmful substances from damaged neurons in the CNS and promote the repair of neurological functions [81, 82]. On the other hand, excessively activated microglia secrete high levels of proinflammatory factors (e.g., tumor necrosis factor alpha (TNF-α), IL-1β, IL-6, and matrix metalloproteinases), causing neurotoxicity, inhibiting the repair of the nervous system, and aggravating damage [83, 84, 85]. EA effectively reduces microglial activation, which is associated with inhibition of the P38 mitogen-activated protein kinase (MAPK) and extracellular regulatory protein kinase (ERK) pathways, reduces the levels of proinflammatory factors, and controls inflammatory responses [86]. In an animal model of MCAO, acupuncture at Neiguan PC6 and LI11 inhibited Toll-like receptor 4/enhanced κ-light chain in B cells activated by nuclear factor (TLR4/NF-κB) pathway activation; decreased the expression of IL-1β, TLR4, TNF-α, inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ), NF-κB, RelA (P65), and tumor necrosis factor-associated factor 6 (TRAF6); and alleviated neuronal injury [87]. Microglia can be polarized toward two phenotypes, the proinflammatory M1 phenotype and the anti-inflammatory M2 phenotype, which contribute to neurological damage and neuroprotection, respectively [87]. Acupuncture at ST36 was shown to induce a shift from M1 polarization to M2 polarization, achieving a balance between the two polarization states by suppressing proinflammatory factor expression and increasing anti-inflammatory and repair factor expression [74]. At the site of CI/R injury, many reactive astrocytes and microglia proliferate and differentiate, forming a glial scar [88]. Increased secretion of chondroitin sulfate proteoglycans (CSPGs) by cells forming the glial scar is an important hindrance to regeneration and functional recovery of axons [89, 90]. Astrocytes have a nutritional and protective role in neuronal development and are involved in the formation of the blood‒brain barrier and synaptic signaling [91]. In an animal model of stroke, the expression of the astrocyte activation marker GFAP was found to increase substantially after EA at GV20 and GV14 but decrease after a period of time, suggesting that EA has the potential to activate astrocytes in the area of injury and prevent excessive glial scar production [92]. In addition, EA increases the synaptic density and thickness and plays an active role in synaptic reorganization [93].

5.2.2 Vagus Nerve

Stimulation of the vagus nerve may be a potential therapeutic strategy to effectively reduce the inflammatory response and promote neurological recovery [94]. The vagal cholinergic anti-inflammatory pathway can inhibit the release of TNF-α and proinflammatory factors such as IL-1β, IL-6, and IL-18 by macrophages through electrical stimulation [95, 96]. The a7 nicotinic acetylcholine receptor (a7nACHR) is the key to the function of the cholinergic anti-inflammatory pathway [97]. EA can exert anti-inflammatory effects by suppressing the function of the reflex center of the innate immune system [96]. In an experimental model of stroke, EA activates a7nACHR to inhibit high mobility group protein B1 (HMGB1), a nuclear protein with proinflammatory effects [98]. Acetylcholine secreted by the vagal nerve inhibits peripheral inflammation in the brain, and EA of the rat forepaw increases acetylcholine release, which may be related to the targeting of miR-132, an inflammatory regulator, by acetylcholinesterase (AchE) [99, 100]. In addition, EA at GV20 and GV14 exerts neuroprotective effects by reducing the expression of five subtypes of another muscarinic cholinergic receptor to ameliorate damage to the central cholinergic system [101].

5.2.3 Leukocytes

After ischemic injury, the production of adhesion molecules and chemotactic mediators of leukocytes increases, resulting in the recruitment of large numbers of leukocytes to the injured area and their adhesion to endothelial cells, as well as an increase in neutrophil infiltration, which exacerbates the release of proinflammatory factors and the inflammatory response [102, 103]. Intercellular cell adhesion molecule-1 (ICAM-1) is an important receptor that mediates the leukocyte adhesion response, and its expression level is increased in response to inflammatory stimuli in ischemic injury, thereby exacerbating leukocyte adhesion and infiltration [104, 105]. The expression of platelet p-selectin (P-selectin), an adhesion molecule, is upregulated after ischemic injury, causing leukocytes to roll on stimulated endothelial cells, resulting in leukocyte extravasation and aggravating the inflammatory response while causing platelets to adhere and aggregate and lose their stability, thus forming a thrombus [106]. EA was found to inhibit the expression of ICAM-1 and P-selectin, reduce the adhesion and infiltration of leukocytes, and exert an anti-inflammatory effect [107].

5.2.4 Other Transmitters and Receptors Involved in Inflammation

In addition to its analgesic and sedative effects, activation of the delta-opioid receptor (DOR) has been shown to effectively protect against ischemic-hypoxic injury during CI/R by reducing excitatory neurotransmitter expression through ion homeostasis and reducing impaired neurotransmission, which may be related to the BDNF-tyrosine kinase receptor B (TrkB) signaling pathway. EA at GV26 and PC6 was shown to upregulate DOR expression by mediating the BDNF-TrkB signaling pathway and significantly reduce ischemic infarction and functional impairment [108, 109]. Glutamate is an important excitatory neurotransmitter in the CNS. Ischemic transporter dysfunction in the brain after stroke leads to excessive release of glutamate and overactivation of N-methyl-D-aspartate (NMDA) glutamate receptor (NMDAR), which induces excitotoxicity leading to neuronal cell injury and death [110]. In an animal model of ischemia induced by vascular occlusion, glutamate levels were found to be significantly higher in the control group (135.19 ± 23.76 µm) than in the needle stimulation group (72.20 ± 27.15 µm) after acupuncture at Yanglingquan GB34 versus Xuanzhong GB39, which may be related to the reversal of high expression of the NMDAR1 subunit by EA [111, 112]. Calcium overload due to abnormal release of glutamate causes an imbalance in calcium ion homeostasis [113]. Calcium overload blocks ATP synthesis and contributes to excessive ROS production, leading to mitochondrial dysfunction while inducing NLRP3 inflammasome activation and exacerbating the inflammatory cascade [114, 115]. Calmodulin-dependent protein kinase (CaMKII), an important receptor for calcium signaling, inhibits CaMKII-AMPA receptor 1 (GluA1) phosphorylation to exert anti-inflammatory effects in a complete Freund’s adjuvant (CFA)-induced mouse model of inflammation [116]. The analgesic and anti-inflammatory effects of EA in a CFA-induced inflammation model are closely related to the cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors [117]. Studies have shown that endogenous cannabinoids can regulate various ion channels, including T-type calcium channels, and that CB1 and CB2 receptors are key regulators that can help maintain calcium homeostasis and reduce subsequent inflammatory damage [118, 119]. NLRP3 is involved in the inflammatory response by inducing the secretion and maturation of IL-18 and IL-1β. As a conserved anti-inflammatory miRNA, miR-223 can negatively regulate NLRP3 expression to inhibit the inflammatory response [120, 121]. In an MCAO rat model, EA at Waiguan TE5 and ST36 was shown to upregulate the expression of miR-223 in the peri-infarct cortex, by inhibiting the miR-223/NLRP3 pathway, and to reduce the expression of NLRP3, caspase-1, IL-1β, and IL-18 to alleviate neuroinflammation [122].

5.2.5 Microbiota–Gut–Brain Axis

The gut is the most important immune organ of the human body, accounting for approximately 70% of the immune function of the whole body. The microbiota–gut–brain axis (MGBA) is a bidirectional regulatory network between the brain and the gut [123]. After stroke, homeostasis of the intestinal microbiota is disrupted, dysregulation of the autonomic nervous system (ANS) leads to the weakening of intestinal movement and barrier function, and proinflammatory factors in the intestine enter the brain through the damaged blood‒brain barrier to aggravate injury [124]. Studies have shown that T cells play a key role in tissue damage secondary to ischemic stroke [125]. The initial inflammatory cascade causes T cells to migrate to, and T cell subpopulation (γδT) cells to be transported to, the pia mater of the brain where they secrete the proinflammatory factor IL-17 to aggravate the inflammatory response [123, 126]. CD4+CD25+ regulatory T (Treg) cells play an important role in peripheral immunity. After stroke, Treg cells migrate to the intestine with the help of mesenteric lymph node dendritic cells, and the expression of the anti-inflammatory factor IL-10 is upregulated to inhibit IL-17-mediated inflammation and the proliferation and differentiation of γδT cells [123, 127]. Studies have shown that EA at GV20, GV14, Shenshu BL23, and ST36 can alleviate the disruption of the intestinal microbiota, inhibit the inflammatory response, and promote the recovery of neurological function [128]. In an MCAO model, the proportion of CD3+TCRγδ+carboxyfluorescein diacetate succinimidyl ester (CFSE)+ cells was found to decrease from 12.06% to 6.52% after EA at GV20, and this change was related to an increase in the number of Treg cells in the brain and small intestine and the inhibition of γδT cell function [129].

6. Mechanism Underlying the Effect of EA on Pathological Changes Related to the Blood‒Brain Barrier, Cerebrovascular Function, and Cerebral Blood Flow after Ischemic Stroke
6.1 Blood‒Brain Barrier

The blood‒brain barrier (BBB) consists of the brain capillary wall and glial cells and is a barrier between the blood circulation and brain tissue. Due to its poor permeability, the BBB can limit the exchange of free substances between blood and brain tissue, and it has a role in maintaining the homeostasis of the brain’s internal environment and protecting neural tissue from damage by toxins and pathogens [130, 131, 132]. After ischemic injury, the integrity of the BBB is disrupted and its permeability increases, resulting in vasogenic edema and hemorrhagic transformation [133]. In a CI/R rat model, EA at GV20 and GV14 can reduce ischemic damage to brain cortical neurons and the BBB [134]. In addition, EA downregulates the expression of Nogo-A, an inhibitory neuroregenerative factor, to alleviate BBB damage [135]. EA at GV20, GV26, and ST36 improved the vascular ultrastructure of brain tissue in CI/R rats, promoting capillary generation and restoration of vascular function, which was closely related to the upregulation of VEGF mRNA expression [136]. The expression of metalloproteinase inhibitor-1 (TIMP-1) mRNA and protein tissue inhibitor was found to be dysregulated after EA at GV20, Hegu LI4, and Taichong LR3 in an MCAO animal model [137]. The protein and mRNA expression levels of matrix metalloproteinase 9 (MMP-9) were shown to significantly reduced in the BBB of CI/R rats after EA at GV20 and GV26 [138]. Reduced inflammatory cell infiltration and upregulation of matrix metalloproteinase 2/water channel protein (MMP2/AQP) expression occurred after EA at GV20 and ST36 [139]. The above experimental results all indicate that acupuncture can ameliorate BBB injury and exert neuroprotective effects on ischemic brain tissue.

6.2 Angiogenesis

VEGF promotes the proliferation and division of endothelial cells, increases vascular permeability, and promotes neoangiogenesis [132, 140]. EA was shown to activate the HIF-1α/VEGF/Notch1 signaling pathway and promote angiogenesis after ischemic injury via exosomal miR-210 [141]. Furthermore, in an MCAO animal model, EA can effectively promote angiogenesis and neurological recovery through the EphB4/EphB2-mediated Src/PI3K signaling pathway [142]. The PI3K-AKT pathway increases the secretion of VEGF through hypoxia-inducible factor 1 (HIF-1) and regulates the expression of angiogenesis factors such as nitric oxide and angioplasty, which play a major role in the process of angiogenesis, while the activation of the PI3K-AKT pathway promotes the neuroprotective effect of the opiate receptor agonist (D-Ala2, D-Leu5)-Enkephalin (DADLE) [143, 144]. In a CI/R animal model, the relative protein expression of PI3K p85, PI3K p110 and p-AKT was found to be upregulated in the acupuncture group, and the expression of VEGF, GAP-43, and synaptophysin (SYN) was shown to be significantly increased, which indicates that acupuncture exerts its angiogenic and protective effects through the PI3K-AKT signaling pathway [145].

6.3 Cerebral Blood Flow

A >100% increase in blood flow at the ischemic foci and significant alleviation of ischemic infarction and nerve injury were observed in MCAO model animals treated with EA at GV26 (1.0–1.2 mA and 5–20 Hz) compared with those treated with EA at GV20 [146]. Data from another experiment showed that CBF was elevated in all brain regions in CI rats after two applications of EA at bilateral ST36 or 15 Hz EA [147]. After EA at ST36 and LI11, cerebrovascular resistance (CVR) was reduced, cerebral blood flow was increased, and meningeal microcirculation was improved [148].

7. The Mechanism by Which EA Inhibits Apoptosis and Autophagy

Apoptosis is a genetically controlled, programmed process of autonomous cell death, and can be induced by excess free radicals generated in acute cerebral ischemia, by a Ca2+ concentration surge, or by excitotoxicity; however, apoptosis in the ischemic penumbra seems to be reversible [149, 150]. NGF, a nerve growth factor involved in neuroprotection and functional repair, acts through the ERK pathway and the PI3K pathway mediated by TrkA, a high-affinity receptor for NGF. EA was found to decrease NR1 subunit expression while upregulating TrkA expression and to mediate the TrkA-PI3K pathway to inhibit the increase in transient receptor potential melastatin-subfamily member 7 (TRPM7) expression induced by ischemia [110, 112, 151]. In a rat model of I/R injury, EA at LI11 and ST36 was found to activate the PI3K-AKT signaling pathway, increase the expression of the PI3K activators BDNF and GDNF, upregulate the expression of the antiapoptotic protein Bcl-2, and decrease the expression of the proapoptotic protein Bax, inducing the formation of a stable heterogeneous structure and thus exerting an inhibitory and neuroprotective effect against cell apoptosis [152]. Pretreatment by EA at GV20, BL23, and Sanyinjiao SP6 was found to reduce the Bax/Bcl 2 ratio and inhibit the expression of cleaved cystatin-3, which attenuated neuronal apoptosis and was associated with EA-mediated inhibition of transient receptor vanilloid (TRPV1) [153, 154].

Autophagy is a process by which cells degrade their own components using lysosomes; autophagy and apoptosis jointly maintain cellular homeostasis under normal physiological conditions [155, 156]. Cellular autophagy is regulated by Unc-51-like autophagy-activated kinase 1 (UIK1) and FUN14-containing structural domain protein 1 (FUNDC1) [157]. Pretreatment by EA at GV20 and GV26 was shown to suppress p-ULK1 and FUNDC1 expression and upregulate p-mTORC1 and microtubule-associated protein light chain 3 (LC3-I) expression, thereby improving neurological function and reducing the infarct volume [158]. The silent information regulator 1 (SIRT1)-forkhead box proteins O1 (FOXO1) signaling pathway is an important factor in autophagy regulation. After EA pretreatment, the ratio of IC3-II/LC3-I is decreased; the complex effect of acetylated (AC)-FOXO1 and Atg7 is reduced; the levels of p62, SIRT1, and FOXO1 are elevated; and the number of autophagosomes in CI/R rats is significantly reduced. The neuroprotective effect of EA pretreatment may be related to the activation of the SIRT1-FOXO1 signaling pathway [159].

8. EA Pretreatment for Cerebral Ischemic Tolerance

As early as the pre-Qin period in ancient China, the concept of prevention before disease has been followed in Chinese medicine [28]. Preventive acupuncture can open the meridians, regulate the organs, balance yin and yang, support the positive, and eliminate the evil [160]. Acupuncture is widely used in the prevention and treatment of ischemic stroke because of its few side effects and high safety and efficacy [28]. EA pretreatment was found to confer tolerance to cerebral ischemic injury in rats; Furthermore, neurological impairment was shown to be significantly increased and the infarct volume (38.3 ± 25.4 mm3) was found to be significantly reduced in MCAO model animals subjected to repeated pretreatments with EA at GV20 compared with control MCAO model animals (220.5 ± 66.0 mm3) and animals in the isoflurane anesthesia group (168.6 ± 57.6 mm3) [161]. In addition, cerebral ischemia tolerance induced by EA preconditioning is closely related to the endocannabinoid system, and the CB1 receptor-mediated PI3K/Akt/GSK-3β signaling pathway plays an important role in cerebral ischemic injury [162]. In MCAO rat models, EA preconditioning enhances the activation of signal transducer and activator of transcription 3 (STAT3) and protein kinase Cϵ (PKCϵ) by upregulating the expression of the CB1 receptor and increases the levels of the endocannabinoids 2-arachidonic glycerol and n-arachidonic ethanolamine, which significantly reduces the infarct volume after reperfusion, improves nerve function, and inhibits neuronal apoptosis [163, 164, 165]. In addition, monocyte chemotactic protein-inducible protein 1 (MCPIP1) is also involved in EA preconditioning-induced cerebral ischemic tolerance, and the neuroprotective effects of EA preconditioning were found to be significantly decreased in MCPIP1-deficient MCAO model animals [166].

9. Rehabilitation Phase

The main sequelae of ischemic stroke sequelae are numbness, hemiparesis, motor dysfunction, cognitive dysfunction, and memory loss, which are often responsible for the high disability rate and poor outcomes. Zhan et al. [167] reported in a meta-analysis of 14 randomized controlled trials {896 patients with poststroke cognitive impairment (PSCI)} that EA improved cognitive function and motor function in patients with PSCI. In a stroke rehabilitation experiment, the control group was given standard physiotherapy, and the intervention group received acupuncture. Analysis of the experimental data showed that the immediate and long-term outcomes of the intervention group were better than those of the control group, with EA significantly ameliorating spasticity and motor dysfunction of the limbs caused by stroke and restoring the ability of the patients to perform daily life activities [168]. Another study on stroke hemiplegia found that acupuncture significantly improved muscle spasms and mobility in hemiplegic limbs [169]. Ischemic stroke induces vascular cognitive impairment (VCI), and the learning and memory abilities of VCI model rats are improved after EA at GV20 and Shenting GV24, which may be related to the fact that EA increases the postsynaptic current frequency in neurons in the hippocampal CA3-CA1 regions, promoting connectivity and plasticity [170]. Furthermore, acupuncture at ST36 was shown to alleviate cognitive dysfunction and normalize cAMP concentrations, Protein kinase A (PKA) activity, and phosphorylation of cAMP response element binding protein (pCREB) and pERK expression in patients with vascular dementia, while blocking the PKA signaling pathway was found to reverse the beneficial effect of acupuncture, indicating that acupuncture improves hippocampal function through the regulation of the cAMP/PKA/CREB signaling pathway [171]. Long-term potentiation (LTP) in the hippocampus is responsible for memory formation and learning, and induction of LTP is dependent on NMDAR activation [172]. EA is able to reverse LTP impairment in a rat depression model, possibly by upregulating the expression of the NMDAR subunit NMDARs with NR2B subunits (GluN2B) in the hippocampus [173]. EA at ST36 and SP6 was shown to reduce local circuit inhibition and enhance LTP, possibly by promoting synaptic transmission via inhibition of gamma-aminobutyric acid (GABA) release from interneurons to increase the excitability of granule cells [174]. Acupuncture can activate language-related brain areas and rebuild the neural network responsible for language to relieve language impairment [175] (Table 1, Ref. [52, 75, 77, 87, 101, 111, 137, 152, 153, 170, 174, 176]).

Table 1.Summary of the acupuncture frequency and effects for the selected acupoints mentioned in this review.
Acupoint Acupuncture Parameters Outcome Model Year Reference
Fengchi GB20 2 Hz, 30 min Affected the degree of lipid peroxidation and MDA production after MCAO MCAO 2004 Siu et al. [75]
Shuigou GV26 5/20 Hz, 2–4 mA, 30 min, 1 mm Significantly increased respiratory enzyme activity and reduced ROS production MCAO 2009 Zhong et al. [77]
Yanglingquan GB34 Xuanzhong GB39 2 Hz, 10 min, 5 mm Decreased glutamate levels MCAO 2010 Lee et al. [111]
Quchi LI11 1/20 Hz, 30 min, 2–3 mm Promoted the activation of the PI3K/Akt pathway and inhibited apoptosis in the brain MCAO 2012 Chen et al. [152]
Sanyinjiao SP6 2 Hz, 20 min Increased LTP AD 2012 He et al. [174]
Baihui GV20 2 Hz, 20 min, 10 days, 2 mm Significantly increased the mRNA expression of BDNF and VEGF MCAO 2014 Kim et al. [52]
Neiguan PC6 2/15 Hz, 1 mA, 30 min, 5 days Decreased IL-1β, TLR4, TNF-α, IKKβ, NF-κB, P65, and TRAF6 levels MCAO 2015 Han et al. [87]
Zusanli ST36 1–20 Hz, 0.2 mA, 30 min, 3 days Decreased NF-κB p65, p38MAPK, MyD88, TNF-α, IL-1β, and IL-6 levels MCAO 2016 Liu et al. [176]
Hegu LI4 Taichong LR3 2 Hz, 1 mA, 7 days Increased Bcl-2 protein and TIMP-1 levels and decreased Bax protein and MMP-9 levels MCAO 2016 Ma et al. [137]
Dazhui GV14 2/15 Hz, 1 mA, 30 min, 5 mm Significantly reduced the mRNA levels of choline acetyltransferase, five subtypes of muscarinic receptors, and a7NACHR MCAO/R 2018 Chi et al. [101]
Shenshu BL23 2/100 Hz, 1 mA, 40 min Decreased the Bax/Bcl 2 ratio and cleaved cystatin-3 levels MCAO 2022 Long et al. [153]
Shenting GV24 2/20 Hz, 1–3 mA, 30 min, 3 mm, 20 days Increased synaptic transmission efficiency and plasticity in the CA3-CA1 region of the hippocampus VCI 2022 Dai et al. [170]

MDA, malondialdehyde; MCAO, middle cerebral artery occlusion; VCI, vascular cognitive impairment; LTP, long-term potentiation; AD, Alzheimer’s disease; VEGF, vascular endothelial growth factor; MMP-9, matrix metalloproteinase 9; MCAO/R, Middle cerebral artery occlusion/reperfusion; TNF-α, tumor necrosis factor alpha; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; P65, RelA; TRAF6, tumor necrosis factor-associated factor 6; p38MAPK, p38 mitogen-activated protein kinase; MyD88, Myeloid differentiation factor-88; TIMP-1, tissue inhibitor of metalloproteinases-1.

10. Issues Related to Acupuncture

Acupuncture is a promising alternative treatment option for ischemic stroke with high efficacy, safety, and convenience. However, the efficacy of acupuncture has been challenged and questioned, the fundamental reason being that some of the mechanisms of action are still unclear. At present, there have been few international reports or studies on acupuncture treatment; high-quality acupuncture research studies are lacking and the theoretical basis for the benefits of acupuncture has not yet been adequately described. Furthermore, most of the research on acupuncture has been performed in China; clinical research results from China are not accepted by international mainstream medicine, and the acupuncture methods used in this research are not in line with international standards. Research methods for studying acupuncture are not consistent with modern scientific methods, and no method has yet been established to evaluate the clinical efficacy of acupuncture. It is difficult to perform a randomized controlled trial (RCT) study on acupuncture; furthermore, the use of blinding and placebos in acupuncture research is also controversial and it can be difficult to determine the criteria for a meta-analysis of acupuncture studies. The qualifications of the physician are also an important consideration related to acupuncture, as the teaching modes of major universities and training institutions vary greatly; thus, the theoretical knowledge and operational skills of acupuncturists worldwide are not necessarily consistent, meaning that treatment effects vary from person to person. In addition, due to interindividual variability, the location of acupuncture points differs among individuals, which in turn leads to biased clinical conclusions, and the optimal frequency, timing, and methods of acupuncture have also yet to be determined.

11. Conclusions

This study reviewed the evidence for the beneficial effects of EA on ischemic stroke in animal studies. EA can promote nerve cell regeneration after ischemic stroke and alleviate CI/R injury by reducing oxidative stress and inhibiting the inflammatory response. EA can also improve cerebrovascular function, affect angiogenesis, and reduce apoptosis and autophagy. Furthermore, EA preconditioning can increase ischemic tolerance and contribute substantially to subsequent rehabilitation.

Author Contributions

QX and MG designed the review and wrote the manuscript. AS, CF and ST designed and drew pictures and tables. YD and AZ collected and organized reference materials. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

References
[1]
Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ (Clinical Research Ed.). 2020; 368: l6983.
[2]
Zhang T, Zhao J, Li X, Bai Y, Wang B, Qu Y, et al. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of stroke rehabilitation. Stroke and Vascular Neurology. 2020; 5: 250–259.
[3]
Katan M, Luft A. Global Burden of Stroke. Seminars in Neurology. 2018; 38: 208–211.
[4]
GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet (London, England). 2017; 390: 1151–1210.
[5]
Wang YJ, Li ZX, Gu HQ, Zhai Y, Jiang Y, Zhao XQ, et al. China Stroke Statistics 2019: A Report From the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations. Stroke and Vascular Neurology. 2020; 5: 211–239.
[6]
Menon BK, Al-Ajlan FS, Najm M, Puig J, Castellanos M, Dowlatshahi D, et al. Association of Clinical, Imaging, and Thrombus Characteristics With Recanalization of Visible Intracranial Occlusion in Patients With Acute Ischemic Stroke. JAMA. 2018; 320: 1017–1026.
[7]
Baron JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nature Reviews. Neurology. 2018; 14: 325–337.
[8]
Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009; 40: 2438–2441.
[9]
Zhong LL, Zheng Y, Lau AY, Wong N, Yao L, Wu X, et al. Would integrated Western and traditional Chinese medicine have more benefits for stroke rehabilitation? A systematic review and meta-analysis. Stroke and Vascular Neurology. 2022; 7: 77–85.
[10]
Liu Y, Wang XJ, Wang N, Cui CL, Wu LZ. Electroacupuncture Ameliorates Propofol-Induced Cognitive Impairment via an Opioid Receptor-Independent Mechanism. The American Journal of Chinese Medicine. 2016; 44: 705–719.
[11]
Chen N, Wang J, Mucelli A, Zhang X, Wang C. Electro-Acupuncture is Beneficial for Knee Osteoarthritis: The Evidence from Meta-Analysis of Randomized Controlled Trials. The American Journal of Chinese Medicine. 2017; 45: 965–985.
[12]
Seo SY, Lee KB, Shin JS, Lee J, Kim MR, Ha IH, et al. Effectiveness of Acupuncture and Electroacupuncture for Chronic Neck Pain: A Systematic Review and Meta-Analysis. The American Journal of Chinese Medicine. 2017; 45: 1573–1595.
[13]
Qin H, Chen Y, Liu G, Turnbull I, Zhang R, Li Z, et al. Management characteristics and prognosis after stroke in China: findings from a large nationwide stroke registry. Stroke and Vascular Neurology. 2021; 6: 1–9.
[14]
Chang QY, Lin YW, Hsieh CL. Acupuncture and neuroregeneration in ischemic stroke. Neural Regeneration Research. 2018; 13: 573–583.
[15]
Li Y, Tang Y, Yang GY. Therapeutic application of exosomes in ischaemic stroke. Stroke and Vascular Neurology. 2021; 6: 483–495.
[16]
Hollist M, Morgan L, Cabatbat R, Au K, Kirmani MF, Kirmani BF. Acute Stroke Management: Overview and Recent Updates. Aging and Disease. 2021; 12: 1000–1009.
[17]
Jin ZR, Fang D, Liu BH, Cai J, Tang WH, Jiang H, et al. Roles of CatSper channels in the pathogenesis of asthenozoospermia and the therapeutic effects of acupuncture-like treatment on asthenozoospermia. Theranostics. 2021; 11: 2822–2844.
[18]
Shao G, Xie W, Jia X, Bade R, Xie Y, Qi R, et al. Overview of Traditional Mongolian Medical Warm Acupuncture. Aging and Disease. 2022; 13: 1030–1041.
[19]
Liu SY, Hsieh CL, Wei TS, Liu PT, Chang YJ, Li TC. Acupuncture stimulation improves balance function in stroke patients: a single-blinded controlled, randomized study. The American Journal of Chinese Medicine. 2009; 37: 483–494.
[20]
Zhao JG, Cao CH, Liu CZ, Han BJ, Zhang J, Li ZG, et al. Effect of acupuncture treatment on spastic states of stroke patients. Journal of the Neurological Sciences. 2009; 276: 143–147.
[21]
Yan T, Hui-Chan CWY. Transcutaneous electrical stimulation on acupuncture points improves muscle function in subjects after acute stroke: a randomized controlled trial. Journal of Rehabilitation Medicine. 2009; 41: 312–316.
[22]
Napadow V, Makris N, Liu J, Kettner NW, Kwong KK, Hui KKS. Effects of electroacupuncture versus manual acupuncture on the human brain as measured by fMRI. Human Brain Mapping. 2005; 24: 193–205.
[23]
Liu AJ, Li JH, Li HQ, Fu DL, Lu L, Bian ZX, et al. Electroacupuncture for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. The American Journal of Chinese Medicine. 2015; 43: 1541–1566.
[24]
Tao J, Xue XH, Chen LD, Yang SL, Jiang M, Gao YL, et al. Electroacupuncture improves neurological deficits and enhances proliferation and differentiation of endogenous nerve stem cells in rats with focal cerebral ischemia. Neurological Research. 2010; 32: 198–204.
[25]
Zou R, Wu Z, Cui S. Electroacupuncture pretreatment attenuates blood brain barrier disruption following cerebral ischemia/reperfusion. Molecular Medicine Reports. 2015; 12: 2027–2034.
[26]
Dong H, Fan YH, Zhang W, Wang Q, Yang QZ, Xiong LZ. Repeated electroacupuncture preconditioning attenuates matrix metalloproteinase-9 expression and activity after focal cerebral ischemia in rats. Neurological Research. 2009; 31: 853–858.
[27]
Kim YR, Kim HN, Jang JY, Park C, Lee JH, Shin HK, et al. Effects of electroacupuncture on apoptotic pathways in a rat model of focal cerebral ischemia. International Journal of Molecular Medicine. 2013; 32: 1303–1310.
[28]
Li X, Luo P, Wang Q, Xiong L. Electroacupuncture Pretreatment as a Novel Avenue to Protect Brain against Ischemia and Reperfusion Injury. Evidence-based Complementary and Alternative Medicine: ECAM. 2012; 2012: 195397.
[29]
Cope EC, Gould E. Adult Neurogenesis, Glia, and the Extracellular Matrix. Cell Stem Cell. 2019; 24: 690–705.
[30]
Kenmuir CL, Wechsler LR. Update on cell therapy for stroke. Stroke and Vascular Neurology. 2017; 2: 59–64.
[31]
Shu H, Guo Z, Chen X, Qi S, Xiong X, Xia S, et al. Intracerebral Transplantation of Neural Stem Cells Restores Manganese-Induced Cognitive Deficits in Mice. Aging and Disease. 2021; 12: 371–385.
[32]
Gould E. How widespread is adult neurogenesis in mammals? Nature Reviews. Neuroscience. 2007; 8: 481–488.
[33]
Yuan Y, Tang X, Bai YF, Wang S, An J, Wu Y, et al. Dopaminergic precursors differentiated from human blood-derived induced neural stem cells improve symptoms of a mouse Parkinson’s disease model. Theranostics. 2018; 8: 4679–4694.
[34]
Liu Z, Wang X, Jiang K, Ji X, Zhang YA, Chen Z. TNFα-induced Up-regulation of Ascl2 Affects the Differentiation and Proliferation of Neural Stem Cells. Aging and Disease. 2019; 10: 1207–1220.
[35]
Tian T, Cao L, He C, Ye Q, Liang R, You W, et al. Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia. Theranostics. 2021; 11: 6507–6521.
[36]
Qin W, Chen S, Yang S, Xu Q, Xu C, Cai J. The Effect of Traditional Chinese Medicine on Neural Stem Cell Proliferation and Differentiation. Aging and Disease. 2017; 8: 792–811.
[37]
Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008; 132: 645–660.
[38]
Gage FH. Mammalian neural stem cells. Science (New York, N.Y.). 2000; 287: 1433–1438.
[39]
Geraerts M, Krylyshkina O, Debyser Z, Baekelandt V. Concise review: therapeutic strategies for Parkinson disease based on the modulation of adult neurogenesis. Stem Cells (Dayton, Ohio). 2007; 25: 263–270.
[40]
Budni J, Bellettini-Santos T, Mina F, Garcez ML, Zugno AI. The involvement of BDNF, NGF and GDNF in aging and Alzheimer’s disease. Aging and Disease. 2015; 6: 331–341.
[41]
Chen L, Wang Y, Li S, Zuo B, Zhang X, Wang F, et al. Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway. Theranostics. 2020; 10: 9425–9442.
[42]
Yuzwa SA, Yang G, Borrett MJ, Clarke G, Cancino GI, Zahr SK, et al. Proneurogenic Ligands Defined by Modeling Developing Cortex Growth Factor Communication Networks. Neuron. 2016; 91: 988–1004.
[43]
Rothman SM, Mattson MP. Activity-dependent, stress-responsive BDNF signaling and the quest for optimal brain health and resilience throughout the lifespan. Neuroscience. 2013; 239: 228–240.
[44]
Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Current Opinion in Neurobiology. 2000; 10: 381–391.
[45]
Lu L, Zhang XG, Zhong LLD, Chen ZX, Li Y, Zheng GQ, et al. Acupuncture for neurogenesis in experimental ischemic stroke: a systematic review and meta-analysis. Scientific Reports. 2016; 6: 19521.
[46]
Zhu W, Cheng S, Xu G, Ma M, Zhou Z, Liu D, et al. Intranasal nerve growth factor enhances striatal neurogenesis in adult rats with focal cerebral ischemia. Drug Delivery. 2011; 18: 338–343.
[47]
Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annual Review of Neuroscience. 2001; 24: 1217–1281.
[48]
Cheng S, Ma M, Ma Y, Wang Z, Xu G, Liu X. Combination therapy with intranasal NGF and electroacupuncture enhanced cell proliferation and survival in rats after stroke. Neurological Research. 2009; 31: 753–758.
[49]
Yang ZJ, Shen DH, Guo X, Sun FY. Electroacupuncture enhances striatal neurogenesis in adult rat brains after a transient cerebral middle artery occlusion. Acupuncture & Electro-therapeutics Research. 2005; 30: 185–199.
[50]
Hong J, Wu G, Zou Y, Tao J, Chen L. Electroacupuncture promotes neurological functional recovery via the retinoic acid signaling pathway in rats following cerebral ischemia-reperfusion injury. International Journal of Molecular Medicine. 2013; 31: 225–231.
[51]
Wu Z, Hu J, Du F, Zhou X, Xiang Q, Miao F. Long-term changes of diffusion tensor imaging and behavioural status after acupuncture treatment in rats with transient focal cerebral ischaemia. Acupuncture in Medicine: Journal of the British Medical Acupuncture Society. 2012; 30: 331–338.
[52]
Kim YR, Kim HN, Ahn SM, Choi YH, Shin HK, Choi BT. Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS ONE. 2014; 9: e90000.
[53]
Tao J, Zheng Y, Liu W, Yang S, Huang J, Xue X, et al. Electro-acupuncture at LI11 and ST36 acupoints exerts neuroprotective effects via reactive astrocyte proliferation after ischemia and reperfusion injury in rats. Brain Research Bulletin. 2016; 120: 14–24.
[54]
Ahn SM, Kim YR, Kim HN, Shin YI, Shin HK, Choi BT. Electroacupuncture ameliorates memory impairments by enhancing oligodendrocyte regeneration in a mouse model of prolonged cerebral hypoperfusion. Scientific Reports. 2016; 6: 28646.
[55]
Yang Z, Yu H, Rao X, Liu Y, Pi M. Effects of electroacupuncture at the conception vessel on proliferation and differentiation of nerve stem cells in the inferior zone of the lateral ventricle in cerebral ischemia rats. Journal of Traditional Chinese Medicine. 2008; 28: 58–63.
[56]
Cao BQ, Tan F, Zhan J, Lai PH. Mechanism underlying treatment of ischemic stroke using acupuncture: transmission and regulation. Neural Regeneration Research. 2021; 16: 944–954.
[57]
Wang X, Mao X, Xie L, Greenberg DA, Jin K. Involvement of Notch1 signaling in neurogenesis in the subventricular zone of normal and ischemic rat brain in vivo. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2009; 29: 1644–1654.
[58]
Wang L, Chopp M, Zhang RL, Zhang L, Letourneau Y, Feng YF, et al. The Notch pathway mediates expansion of a progenitor pool and neuronal differentiation in adult neural progenitor cells after stroke. Neuroscience. 2009; 158: 1356–1363.
[59]
Tao J, Chen B, Gao Y, Yang S, Huang J, Jiang X, et al. Electroacupuncture enhances hippocampal NSCs proliferation in cerebral ischemia-reperfusion injured rats via activation of notch signaling pathway. The International Journal of Neuroscience. 2014; 124: 204–212.
[60]
Woodbury ME, Ikezu T. Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology. 2014; 9: 92–101.
[61]
Ou YW, Han L, Da CD, Huang YL, Cheng JS. Influence of acupuncture upon expressing levels of basic fibroblast growth factor in rat brain following focal cerebral ischemia–evaluated by time-resolved fluorescence immunoassay. Neurological Research. 2001; 23: 47–50.
[62]
Wei OY, Huang YL, Da CD, Cheng JS. Alteration of basic fibroblast growth factor expression in rat during cerebral ischemia. Acta Pharmacologica Sinica. 2000; 21: 296–300.
[63]
Geloso MC, Corvino V, Di Maria V, Marchese E, Michetti F. Cellular targets for neuropeptide Y-mediated control of adult neurogenesis. Frontiers in Cellular Neuroscience. 2015; 9: 85.
[64]
Agasse F, Bernardino L, Kristiansen H, Christiansen SH, Ferreira R, Silva B, et al. Neuropeptide Y promotes neurogenesis in murine subventricular zone. Stem Cells (Dayton, Ohio). 2008; 26: 1636–1645.
[65]
Decressac M, Wright B, David B, Tyers P, Jaber M, Barker RA, et al. Exogenous neuropeptide Y promotes in vivo hippocampal neurogenesis. Hippocampus. 2011; 21: 233–238.
[66]
Kim EH, Jang MH, Shin MC, Lim BV, Kim HB, Kim YJ, et al. Acupuncture increases cell proliferation and neuropeptide Y expression in dentate gyrus of streptozotocin-induced diabetic rats. Neuroscience Letters. 2002; 327: 33–36.
[67]
Yan F, Cheng X, Zhao M, Gong S, Han Y, Ding L, et al. Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia. Stroke and Vascular Neurology. 2021; 6: 344–351.
[68]
Pérez-García C, Maegerlein C, Rosati S, Rüther C, Gómez-Escalonilla C, Zimmer C, et al. Impact of aspiration catheter size on first-pass effect in the combined use of contact aspiration and stent retriever technique. Stroke and Vascular Neurology. 2021; 6: 553–560.
[69]
Horbay R, Bilyy R. Mitochondrial dynamics during cell cycling. Apoptosis: an International Journal on Programmed Cell Death. 2016; 21: 1327–1335.
[70]
Young TA, Cunningham CC, Bailey SM. Reactive oxygen species production by the mitochondrial respiratory chain in isolated rat hepatocytes and liver mitochondria: studies using myxothiazol. Archives of Biochemistry and Biophysics. 2002; 405: 65–72.
[71]
Miao L, St Clair DK. Regulation of superoxide dismutase genes: implications in disease. Free Radical Biology & Medicine. 2009; 47: 344–356.
[72]
Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Letters. 2018; 592: 692–702.
[73]
Siu FKW, Lo SCL, Leung MCP. Electroacupuncture reduces the extent of lipid peroxidation by increasing superoxide dismutase and glutathione peroxidase activities in ischemic-reperfused rat brains. Neuroscience Letters. 2004; 354: 158–162.
[74]
Li N, Guo Y, Gong Y, Zhang Y, Fan W, Yao K, et al. The Anti-Inflammatory Actions and Mechanisms of Acupuncture from Acupoint to Target Organs via Neuro-Immune Regulation. Journal of Inflammation Research. 2021; 14: 7191–7224.
[75]
Siu FKW, Lo SCL, Leung MCP. Effectiveness of multiple pre-ischemia electro-acupuncture on attenuating lipid peroxidation induced by cerebral ischemia in adult rats. Life Sciences. 2004; 75: 1323–1332.
[76]
Wang WW, Xie CL, Lu L, Zheng GQ. A systematic review and meta-analysis of Baihui (GV20)-based scalp acupuncture in experimental ischemic stroke. Scientific Reports. 2014; 4: 3981.
[77]
Zhong S, Li Z, Huan L, Chen BY. Neurochemical Mechanism of Electroacupuncture: Anti-injury Effect on Cerebral Function after Focal Cerebral Ischemia in Rats. Evidence-based Complementary and Alternative Medicine: ECAM. 2009; 6: 51–56.
[78]
Wang H, Chen S, Zhang Y, Xu H, Sun H. Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion. Nitric Oxide: Biology and Chemistry. 2019; 91: 23–34.
[79]
Wang MM, Zhang M, Feng YS, Xing Y, Tan ZX, Li WB, et al. Electroacupuncture Inhibits Neuronal Autophagy and Apoptosis via the PI3K/AKT Pathway Following Ischemic Stroke. Frontiers in Cellular Neuroscience. 2020; 14: 134.
[80]
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends in Neurosciences. 1996; 19: 312–318.
[81]
Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. Journal of Neuroinflammation. 2014; 11: 98.
[82]
Xu S, Lu J, Shao A, Zhang JH, Zhang J. Glial Cells: Role of the Immune Response in Ischemic Stroke. Frontiers in Immunology. 2020; 11: 294.
[83]
Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Research Bulletin. 2012; 87: 10–20.
[84]
Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Progress in Neurobiology. 2017; 157: 247–272.
[85]
Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al. Microglial and macrophage polarization—new prospects for brain repair. Nature Reviews. Neurology. 2015; 11: 56–64.
[86]
Choi DC, Lee JY, Lim EJ, Baik HH, Oh TH, Yune TY. Inhibition of ROS-induced p38MAPK and ERK activation in microglia by acupuncture relieves neuropathic pain after spinal cord injury in rats. Experimental Neurology. 2012; 236: 268–282.
[87]
Han B, Lu Y, Zhao H, Wang Y, Li L, Wang T. Electroacupuncture modulated the inflammatory reaction in MCAO rats via inhibiting the TLR4/NF-κB signaling pathway in microglia. International Journal of Clinical and Experimental Pathology. 2015; 8: 11199–11205.
[88]
Koyama Y. Signaling molecules regulating phenotypic conversions of astrocytes and glial scar formation in damaged nerve tissues. Neurochemistry International. 2014; 78: 35–42.
[89]
Huang L, Wu ZB, Zhuge Q, Zheng W, Shao B, Wang B, et al. Glial scar formation occurs in the human brain after ischemic stroke. International Journal of Medical Sciences. 2014; 11: 344–348.
[90]
Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2004; 24: 2143–2155.
[91]
Guillamón-Vivancos T, Gómez-Pinedo U, Matías-Guiu J. Astrocytes in neurodegenerative diseases (I): function and molecular description. Neurologia (Barcelona, Spain). 2015; 30: 119–129.
[92]
Han X, Huang X, Wang Y, Chen H. A study of astrocyte activation in the periinfarct region after cerebral ischemia with electroacupuncture. Brain Injury. 2010; 24: 773–779.
[93]
Luo Y, Xu NG, Yi W, Yu T, Yang ZH. Study on the correlation between synaptic reconstruction and astrocyte after ischemia and the influence of electroacupuncture on rats. Chinese Journal of Integrative Medicine. 2011; 17: 750–757.
[94]
Neumann S, Shields NJ, Balle T, Chebib M, Clarkson AN. Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective. International Journal of Molecular Sciences. 2015; 16: 29029–29046.
[95]
Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. The Journal of Physiology. 2016; 594: 5781–5790.
[96]
Kavoussi B, Ross BE. The neuroimmune basis of anti-inflammatory acupuncture. Integrative Cancer Therapies. 2007; 6: 251–257.
[97]
Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003; 421: 384–388.
[98]
Wang Q, Wang F, Li X, Yang Q, Li X, Xu N, et al. Electroacupuncture pretreatment attenuates cerebral ischemic injury through α7 nicotinic acetylcholine receptor-mediated inhibition of high-mobility group box 1 release in rats. Journal of Neuroinflammation. 2012; 9: 24.
[99]
Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, et al. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity. 2009; 31: 965–973.
[100]
Uchida S, Kagitani F, Suzuki A, Aikawa Y. Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats. The Japanese Journal of Physiology. 2000; 50: 495–507.
[101]
Chi L, Du K, Liu D, Bo Y, Li W. Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2018; 38: 479–491.
[102]
Yilmaz G, Granger DN. Leukocyte recruitment and ischemic brain injury. Neuromolecular Medicine. 2010; 12: 193–204.
[103]
Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. Journal of Leukocyte Biology. 2010; 87: 779–789.
[104]
Long EO. ICAM-1: getting a grip on leukocyte adhesion. Journal of Immunology (Baltimore, Md.: 1950). 2011; 186: 5021–5023.
[105]
Bui TM, Wiesolek HL, Sumagin R. ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis. Journal of Leukocyte Biology. 2020; 108: 787–799.
[106]
Chen M, Geng JG. P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Archivum Immunologiae et Therapiae Experimentalis. 2006; 54: 75–84.
[107]
Mao QJ, Li HX, Kong L, Chen BG. Effects of electroacupuncture on the expression of microvascular endothelial ICAM-1 and P-selectin in rats with cerebral ischemia-reperfusion 2007; 29: 734–737.
[108]
Sheng S, Huang J, Ren Y, Zhi F, Tian X, Wen G, et al. Neuroprotection Against Hypoxic/Ischemic Injury: δ-Opioid Receptors and BDNF-TrkB Pathway. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2018; 47: 302–315.
[109]
Tian X, Hua F, Sandhu HK, Chao D, Balboni G, Salvadori S, et al. Effect of δ-opioid receptor activation on BDNF-TrkB vs. TNF-α in the mouse cortex exposed to prolonged hypoxia. International Journal of Molecular Sciences. 2013; 14: 15959–15976.
[110]
Waxman EA, Lynch DR. N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. The Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2005; 11: 37–49.
[111]
Lee GJ, Yin CS, Choi SK, Choi S, Yang JS, Lee H, et al. Acupuncture attenuates extracellular glutamate level in global ischemia model of rat. Neurological Research. 2010; 32: 79–83.
[112]
Sun N, Zou X, Shi J, Liu X, Li L, Zhao L. Electroacupuncture regulates NMDA receptor NR1 subunit expression via PI3-K pathway in a rat model of cerebral ischemia-reperfusion. Brain Research. 2005; 1064: 98–107.
[113]
Coultrap SJ, Vest RS, Ashpole NM, Hudmon A, Bayer KU. CaMKII in cerebral ischemia. Acta Pharmacologica Sinica. 2011; 32: 861–872.
[114]
Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. American Journal of Physiology. Cell Physiology. 2004; 287: C817–C833.
[115]
Mohsin M, Tabassum G, Ahmad S, Ali S, Ali Syed M. The role of mitophagy in pulmonary sepsis. Mitochondrion. 2021; 59: 63–75.
[116]
Gu Y, Chen S, Mo Y, Tu Y, Chen N, Zhao X, et al. Electroacupuncture Attenuates CFA-Induced Inflammatory Pain by Regulating CaMKII. Neural Plasticity. 2020; 2020: 8861994.
[117]
MacDonald IJ, Chen YH. The Endocannabinoid System Contributes to Electroacupuncture Analgesia. Frontiers in Neuroscience. 2021; 14: 594219.
[118]
van der Stelt M, Di Marzo V. Anandamide as an intracellular messenger regulating ion channel activity. Prostaglandins & other Lipid Mediators. 2005; 77: 111–122.
[119]
Mato S, Alberdi E, Ledent C, Watanabe M, Matute C. CB1 cannabinoid receptor-dependent and -independent inhibition of depolarization-induced calcium influx in oligodendrocytes. Glia. 2009; 57: 295–306.
[120]
Jeffries J, Zhou W, Hsu AY, Deng Q. miRNA-223 at the crossroads of inflammation and cancer. Cancer Letters. 2019; 451: 136–141.
[121]
Huang T, Xiao Y, Zhang Y, Wang C, Chen X, Li Y, et al. miR-223 ameliorates thalamus hemorrhage-induced central poststroke pain via targeting NLRP3 in a mouse model. Experimental and Therapeutic Medicine. 2022; 23: 353.
[122]
Sha R, Zhang B, Han X, Peng J, Zheng C, Zhang F, et al. Electroacupuncture Alleviates Ischemic Brain Injury by Inhibiting the miR-223/NLRP3 Pathway. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2019; 25: 4723–4733.
[123]
Arya AK, Hu B. Brain-gut axis after stroke. Brain Circulation. 2018; 4: 165–173.
[124]
Hu W, Kong X, Wang H, Li Y, Luo Y. Ischemic stroke and intestinal flora: an insight into brain-gut axis. European Journal of Medical Research. 2022; 27: 73.
[125]
Zhang D, Ren J, Luo Y, He Q, Zhao R, Chang J, et al. T Cell Response in Ischemic Stroke: From Mechanisms to Translational Insights. Frontiers in Immunology. 2021; 12: 707972.
[126]
Gill D, Veltkamp R. Dynamics of T cell responses after stroke. Current Opinion in Pharmacology. 2016; 26: 26–32.
[127]
Dolati S, Ahmadi M, Khalili M, Taheraghdam AA, Siahmansouri H, Babaloo Z, et al. Peripheral Th17/Treg imbalance in elderly patients with ischemic stroke. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018; 39: 647–654.
[128]
Chen DF, Zhang H, Xie JY, Deng C, Qiu RR, Xu YY, et al. Effect of electroacupuncture on gut microbiota and serum IL-1β and IL-18 in rats with vascular dementia based on principle of “curing brain disorders by treating intestines”. Zhen Ci Yan Jiu. 2022; 47: 216–223. (In Chinese)
[129]
Wang Y, Chen Y, Meng L, Wu B, Ouyang L, Peng R, et al. Electro-acupuncture treatment inhibits the inflammatory response by regulating γδ T and Treg cells in ischemic stroke. Experimental Neurology. 2023; 362: 114324.
[130]
Rajeev V, Fann DY, Dinh QN, Kim HA, De Silva TM, Lai MKP, et al. Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment. Theranostics. 2022; 12: 1639–1658.
[131]
Zhang J, Li H, Xu Z, Lu J, Cao C, Shen H, et al. Oestrogen ameliorates blood-brain barrier damage after experimental subarachnoid haemorrhage via the SHH pathway in male rats. Stroke and Vascular Neurology. 2023; 8: 217–228.
[132]
Mamtilahun M, Jiang L, Song Y, Shi X, Liu C, Jiang Y, et al. Plasma from healthy donors protects blood-brain barrier integrity via FGF21 and improves the recovery in a mouse model of cerebral ischaemia. Stroke and Vascular Neurology. 2021; 6: 561–571.
[133]
Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. American Journal of Physiology. Cell Physiology. 2019; 316: C135–C153.
[134]
Shen MH, Li ZR, Xiang XR, Niu WM. Effect of electroacupuncture on cerebral cortex ultrastructure in rats with cerebral ischemia-reperfusion injury. Zhen Ci Yan Jiu. 2009; 34: 167–170. (In Chinese)
[135]
Liang YQ, Tan F, Chen J. Effects of electroacupuncture on the ultrastructure and the Nogo-A expressions in the cerebral cortex in rats with cerebral ischemia-reperfusion. Zhongguo Zhong Xi Yi Jie he Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi. 2012; 32: 209–213. (In Chinese)
[136]
Mao QJ, Chen BG. Effects of electroacupuncture on microvascular ultrastructure and VEGF expression of the right cerebral cortex in focal cerebral ischemia/reperfusion injury rats. Zhen Ci Yan Jiu. 2012; 37: 476–481. (In Chinese)
[137]
Ma R, Yuan B, Du J, Wang L, Ma L, Liu S, et al. Electroacupuncture alleviates nerve injury after cerebra ischemia in rats through inhibiting cell apoptosis and changing the balance of MMP-9/TIMP-1 expression. Neuroscience Letters. 2016; 633: 158–164.
[138]
Lin XM, Chen LP, Yao X. The impact of different duration of EA-pretreatment on expression of MMP-9 and VEGF in blood-brain barrier in rats with cerebral ischemia-reperfusion injury. Zhen Ci Yan Jiu. 2015; 40: 40–44. (In Chinese)
[139]
Xu H, Zhang Y, Sun H, Chen S, Wang F. Effects of acupuncture at GV20 and ST36 on the expression of matrix metalloproteinase 2, aquaporin 4, and aquaporin 9 in rats subjected to cerebral ischemia/reperfusion injury. PLoS ONE. 2014; 9: e97488.
[140]
Rao F, Wang Y, Zhang D, Lu C, Cao Z, Sui J, et al. Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats. Theranostics. 2020; 10: 1590–1603.
[141]
Xu SY, Zeng CL, Ni SM, Peng YJ. The Angiogenesis Effects of Electro-acupuncture Treatment via Exosomal miR-210 in Cerebral Ischemia-Reperfusion Rats. Current Neurovascular Research. 2022; 19: 61–72.
[142]
Wu Y, Hu R, Zhong X, Zhang A, Pang B, Sun X, et al. Electric Acupuncture Treatment Promotes Angiogenesis in Rats with Middle Cerebral Artery Occlusion Through EphB4/EphrinB2 Mediated Src/PI3K Signal Pathway. Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association. 2021; 30: 105165.
[143]
Karar J, Maity A. PI3K/AKT/mTOR Pathway in Angiogenesis. Frontiers in Molecular Neuroscience. 2011; 4: 51.
[144]
Tian XS, Zhou F, Yang R, Xia Y, Wu GC, Guo JC. Electroacupuncture protects the brain against acute ischemic injury via up-regulation of delta-opioid receptor in rats. Zhong Xi Yi Jie He Xue Bao. 2008; 6: 632–638. (in Chinese)
[145]
Wei L, Zeng K, Gai J, Zhou F, Wei Z, Bao Q. Effect of acupuncture on neurovascular units after cerebral infarction in rats through PI3K/AKT signaling pathway. Clinical Hemorheology and Microcirculation. 2020; 75: 387–397.
[146]
Zhou F, Guo J, Cheng J, Wu G, Xia Y. Electroacupuncture increased cerebral blood flow and reduced ischemic brain injury: dependence on stimulation intensity and frequency. Journal of Applied Physiology (Bethesda, Md.: 1985). 2011; 111: 1877–1887.
[147]
Hsieh CL, Chang QY, Lin IH, Lin JG, Liu CH, Tang NY, et al. The study of electroacupuncture on cerebral blood flow in rats with and without cerebral ischemia. The American Journal of Chinese Medicine. 2006; 34: 351–361.
[148]
Ji G, Zhao L, Shi R, Liu Y, Wang S, Wu F. Effects of electrical acupuncture on the cerebral blood flow and the pial microcirculatory blood flow in dogs. Zhen Ci Yan Jiu. 1996; 21: 43–46. (In Chinese)
[149]
Zhang A, Liu Y, Xu H, Zhang Z, Wang X, Yuan L, et al. CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats. Stroke and Vascular Neurology. 2022; 8: 4–16. (Online ahead of print)
[150]
Liu S, Han S, Dai Q, Li S, Li J. BICAO-induced ischaemia caused depressive-like behaviours and caspase-8/-9-dependent brain regional neural cell apoptosis in mice. Stroke and Vascular Neurology. 2017; 3: 1–8.
[151]
Zhao L, Wang Y, Sun N, Liu X, Li L, Shi J. Electroacupuncture regulates TRPM7 expression through the trkA/PI3K pathway after cerebral ischemia-reperfusion in rats. Life Sciences. 2007; 81: 1211–1222.
[152]
Chen A, Lin Z, Lan L, Xie G, Huang J, Lin J, et al. Electroacupuncture at the Quchi and Zusanli acupoints exerts neuroprotective role in cerebral ischemia-reperfusion injured rats via activation of the PI3K/Akt pathway. International Journal of Molecular Medicine. 2012; 30: 791–796.
[153]
Long M, Wang Z, Shao L, Bi J, Chen Z, Yin N. Electroacupuncture Pretreatment Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through Transient Receptor Potential Vanilloid 1-Mediated Anti-apoptosis via Inhibiting NF-κB Signaling Pathway. Neuroscience. 2022; 482: 100–115.
[154]
Miyanohara J, Shirakawa H, Sanpei K, Nakagawa T, Kaneko S. A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice. Biochemical and Biophysical Research Communications. 2015; 467: 478–483.
[155]
Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of Pathology. 2010; 221: 3–12.
[156]
Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Progress in Neurobiology. 2014; 112: 24–49.
[157]
Wang L, Wang P, Dong H, Wang S, Chu H, Yan W, et al. Ulk1/FUNDC1 Prevents Nerve Cells from Hypoxia-Induced Apoptosis by Promoting Cell Autophagy. Neurochemical Research. 2018; 43: 1539–1548.
[158]
Tian W, Zhu M, Zhou Y, Mao C, Zou R, Cui Y, et al. Electroacupuncture Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury by Regulating Mitophagy via mTOR-ULK1/FUNDC1 Axis in Rats. Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association. 2022; 31: 106202.
[159]
Mei ZG, Huang YG, Feng ZT, Luo YN, Yang SB, Du LP, et al. Electroacupuncture ameliorates cerebral ischemia/reperfusion injury by suppressing autophagy via the SIRT1-FOXO1 signaling pathway. Aging. 2020; 12: 13187–13205.
[160]
Wang H, Liang FX. Analysis on the features of preventive treatment with acupuncture and moxibustion. Journal of Traditional Chinese Medicine. 2008; 28: 281–285.
[161]
Xiong L, Lu Z, Hou L, Zheng H, Zhu Z, Wang Q, et al. Pretreatment with repeated electroacupuncture attenuates transient focal cerebral ischemic injury in rats. Chinese Medical Journal. 2003; 116: 108–111.
[162]
Zhuang Q, Dai C, Yang L, Wen H, Wang H, Jiang X, et al. Stimulated CB1 Cannabinoid Receptor Inducing Ischemic Tolerance and Protecting Neuron from Cerebral Ischemia. Central Nervous System Agents in Medicinal Chemistry. 2017; 17: 141–150.
[163]
Zhou H, Zhang Z, Wei H, Wang F, Guo F, Gao Z, et al. Activation of STAT3 is involved in neuroprotection by electroacupuncture pretreatment via cannabinoid CB1 receptors in rats. Brain Research. 2013; 1529: 154–164.
[164]
Wang Q, Li X, Chen Y, Wang F, Yang Q, Chen S, et al. Activation of epsilon protein kinase C-mediated anti-apoptosis is involved in rapid tolerance induced by electroacupuncture pretreatment through cannabinoid receptor type 1. Stroke. 2011; 42: 389–396.
[165]
Wang Q, Peng Y, Chen S, Gou X, Hu B, Du J, et al. Pretreatment with electroacupuncture induces rapid tolerance to focal cerebral ischemia through regulation of endocannabinoid system. Stroke. 2009; 40: 2157–2164.
[166]
Jin Z, Liang J, Wang J, Kolattukudy PE. Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1. Journal of Neuroinflammation. 2013; 10: 63.
[167]
Zhan J, Wang X, Cheng N, Tan F. Electroacupuncture for post stroke cognitive impairment: a systematic review and Meta-analyses. Zhongguo Zhen Jiu. 2017; 37: 1119–1125. (In Chinese)
[168]
Guo X, Cheng B. Clinical Effects of Acupuncture for Stroke Patients Recovery. Journal of Healthcare Engineering. 2022; 2022: 9962421.
[169]
Liu W, Mukherjee M, Sun C, Liu H, McPeak LK. Electroacupuncture may help motor recovery in chronic stroke survivors: a pilot study. Journal of Rehabilitation Research and Development. 2008; 45: 587–595.
[170]
Dai Y, Zhang Y, Yang M, Lin H, Liu Y, Xu W, et al. Electroacupuncture Increases the Hippocampal Synaptic Transmission Efficiency and Long-Term Plasticity to Improve Vascular Cognitive Impairment. Mediators of Inflammation. 2022; 2022: 5985143.
[171]
Li QQ, Shi GX, Yang JW, Li ZX, Zhang ZH, He T, et al. Hippocampal cAMP/PKA/CREB is required for neuroprotective effect of acupuncture. Physiology & Behavior. 2015; 139: 482–490.
[172]
MacDonald JF, Jackson MF, Beazely MA. Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Critical Reviews in Neurobiology. 2006; 18: 71–84.
[173]
She Y, Xu J, Duan Y, Su N, Sun Y, Cao X, et al. Possible antidepressant effects and mechanism of electroacupuncture in behaviors and hippocampal synaptic plasticity in a depression rat model. Brain Research. 2015; 1629: 291–297.
[174]
He X, Yan T, Chen R, Ran D. Acute effects of electro-acupuncture (EA) on hippocampal long term potentiation (LTP) of perforant path-dentate gyrus granule cells synapse related to memory. Acupuncture & Electro-therapeutics Research. 2012; 37: 89–101.
[175]
Chang J, Zhang H, Tan Z, Xiao J, Li S, Gao Y. Effect of electroacupuncture in patients with post-stroke motor aphasia: Neurolinguistic and neuroimaging characteristics. Wiener Klinische Wochenschrift. 2017; 129: 102–109.
[176]
Liu W, Wang X, Zheng Y, Shang G, Huang J, Tao J, et al. Electroacupuncture inhibits inflammatory injury by targeting the miR-9-mediated NF-κB signaling pathway following ischemic stroke. Molecular Medicine Reports. 2016; 13: 1618–1626.

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share
Back to top
J. Integr. Neurosci. Print ISSN 0219-6352 Electronic ISSN 1757-448X
Disclaimer
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept