Signal Transduction Pathways of Acupuncture for Treating Some Nervous System Diseases

In this article, we review signal transduction pathways through which acupuncture treats nervous system diseases. We electronically searched the databases, including PubMed, MEDLINE, clinical Key, the Cochrane Library, and the China National Knowledge Infrastructure from their inception to December 2018 using the following MeSH headings and keywords alone or in varied combination: acupuncture, molecular, signal transduction, genetic, cerebral ischemic injury, cerebral hemorrhagic injury, stroke, epilepsy, seizure, depression, Alzheimer's disease, dementia, vascular dementia, and Parkinson's disease. Acupuncture treats nervous system diseases by increasing the brain-derived neurotrophic factor level and involves multiple signal pathways, including p38 MAPKs, Raf/MAPK/ERK 1/2, TLR4/ERK, PI3K/AKT, AC/cAMP/PKA, ASK1-JNK/p38, and downstream CREB, JNK, m-TOR, NF-κB, and Bcl-2/Bax balance. Acupuncture affects synaptic plasticity, causes an increase in neurotrophic factors, and results in neuroprotection, cell proliferation, antiapoptosis, antioxidant activity, anti-inflammation, and maintenance of the blood-brain barrier.


Introduction
Acupuncture is a form of therapy practiced for more than 3000 years in Asia. Medical doctors practice acupuncture under the guidance of meridian theory to achieve "de qi" status [1]. To perform acupuncture, doctors use thin and sterile metal needles to penetrate specific stimulation points termed acupoints. Both manual and electroacupuncture (EA) are used in medical practice. Many studies have reported the benefits of acupuncture for treating diseases such as stroke, musculoskeletal disorders, chronic urticaria, irritable bowel syndrome, overactive bladder, cancer-related fatigue, and pain in humans [2][3][4][5][6]. Furthermore, few adverse effects have been observed when acupuncture is performed correctly, even in children and pregnant women [7,8]. The widely known mechanism of acupuncture is that it results in the secretion of endorphins that exert an analgesic effect. With advances in understanding, more mechanisms of acupuncture have been determined, including the local segmental effect, somatoautonomic reflex, immune system regulation, neurotransmitter modulation, the neuroendocrine effect, and the functional connectivity neural network [9][10][11].
Nowadays, signal transduction has been applied for explaining acupuncture mechanisms. The signal transduction pathway of acupuncture has been mentioned with respect to many diseases, including neurological [12], cardiovascular [13], metabolic [14], and gynecological [15] diseases. Among the aforementioned diseases, nervous system diseases are the most common complaints in daily practice. When used to treat nervous system diseases, acupuncture enhances cell proliferation and neuroblast differentiation by increasing the levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response elementbinding (CREB) protein [16]. Acupuncture was reported to exert a neuroprotective effect on dopaminergic neurons through anti-inflammatory and neurotrophic effects [17].   Tables 1-7. Other mechanisms, including antioxidation, antiapoptosis, and improved energy metabolism in the brain, have been reported [18][19][20]. Although many studies on the signal transduction pathway of acupuncture have been conducted, few reviews have been published on this topic. In the present review, we discuss the involvement of the signal transduction pathway as a mechanism underlying the effects of acupuncture when used for treating nervous system diseases.

Method
We electronically searched the databases, including PubMed, MEDLINE, clinical Key, the Cochrane Library, and the China National Knowledge Infrastructure from their inception to December 2018 using the following MeSH headings and keywords alone or in varied combination: acupuncture, molecular, signal transduction, genetic, cerebral ischemic injury, cerebral hemorrhagic injury, stroke, epilepsy, seizure, depression, Alzheimer's disease (AD), dementia, vascular dementia (VD), and Parkinson's disease (PD). In addition, we used Boolean operators ("not," "and," "or") to narrow or widen search results. All articles written in English or Chinese were manually screened, and relevant studies were identified. We included additional articles after performing a manual review of the reference lists of identified studies or review articles. Excluded articles included those with unavailable full text, those written in other languages, those not mainly related to the mechanism of the signal transduction pathway, or those with limited details of experimental methods or results. Flowchart of the search processes was as shown in Figure 1.

Cerebral Ischemic Injury
Ischemic injury of the brain, also known as cerebral infarction, is a crucial health issue in the modern world because of its associated disability and socioeconomic burden. Acupuncture has shown beneficial effects on ischemic stroke rehabilitation by exerting the antiapoptosis effect on the ischemic area, promoting neurogenesis and cell proliferation, and regulating cerebral blood flow [21,22]. A retrospective cohort study reported that acupuncture was effective at reducing the stroke recurrence rate [23]. Ischemic stroke causes neural cell damage related to excitotoxicity, oxygen free radical injury, inflammatory status, and bloodbrain barrier (BBB) damage [24]. Experimental pathways that can reverse apoptosis and improve cell proliferation and differentiation have been proposed.
Acupuncture causes an increase in the expression of neurotrophic factors, such as BDNF and glial-derived neurotrophic factor (GDNF), in the central nervous system (CNS), exerts a neuroprotective effect on hypoxic-ischemic insults, and results in neurogenesis after the reconstruction phase [25,26]. In addition, acupuncture increased the vascular endothelial growth factor (VEGF) level in the hippocampus, promoting the proliferation and differentiation of neuronal stem cells [27]. Thus, acupuncture can be used to treat ischemic injury in the brain. Zhang et al. performed manual acupuncture on GV20 and Ex-HN 1 to increase GDNF and BDNF levels in a rat model [19]. The elevation of the BDNF level was related to the increased expression of BDNF/tyrosine receptor kinase B (TrkB) and the induction of neurogenesis [28]. systems were noted during ischemia and reperfusion phases. During ischemia, Akt reduces Raf/MAPK/ ERK1/2 activity through phosphorylation of Raf-1. During reperfusion, abrupt reactive oxygen species (ROS) increases the phosphatase and tensin homolog and reactivates Raf/MAPK/ERK1/2 signaling [54]. For the modulation of the PI3K pathway, some studies have reported that EA on GV12, GV20, GV24, GV26, KI1, LI11, and ST36 activates the PI3K/AKT pathway and exerts antiapoptosis and neuroprotective effects [12,[55][56][57][58][59][60]. The effect of EA on the PI3K pathway can activate the downstream mTOR complex 1-UNC-51-like kinase 1 complex-Beclin-1 pathway, reduce caspase-3, caspase-8, and caspase-9 levels, and inhibit the autophagy process [61,62]. EA also reduces nitric oxide (NO), neuronal NO synthase (nNOS), and inducible NO synthase (iNOS) levels by activating the PI3K pathway [58]. Xie et al. demonstrated that EA improved neurological deficit scores and increased the expression of p-AKT protein and bone marrow CD34+ endothelial progenitor cells in rats [63].
Because of the balance between Raf/MAPK/ERK1/2 and PI3K/AKT systems, some studies have included the pretreatment protocol [64,65]. EA pretreatment in a rat model reduced the expression of p-Akt protein and prevented the downregulation of tight junction proteins, namely, claudin-5 and occludin, attenuating BBB disruption and brain edema [65].
NF-B is another protein complex related to cell survival. Some studies have demonstrated that EA regulates the NF-B-mediated apoptosis pathway and provides neuroprotection [66,67].
Acupuncture improved neurogenic defects and cognitive impairment in a cerebral ischemic/reperfusion animal model. In summary, acupuncture not only increases the levels of neurotrophic factors but also modulates signaling pathways, such as Raf/MAPK/ERK1/2 and PI3K/AKT and downstream CREB and NF-B. Therefore, acupuncture results in cell proliferation, antiapoptosis, neuroprotection, and BBB maintenance. The most frequently chosen acupoints include GV20, GV14, and ST36. The mechanisms and main results of identified articles are summarized in Table 1.

Cerebral Hemorrhagic Injury
Hemorrhagic stroke is less common than ischemic stroke. The causes of hemorrhagic stroke include high blood pressure, brain trauma, aneurysms, arteriovenous malformations, and brain tumors. In cerebral hemorrhagic injury, blood vessel spasms and oxidative stress caused by ischemia and reperfusion cause an injury to neural cells. Acupuncture could improve the hypoperfusion status and hematoma absorption, reduce brain edema, and promote neurogenesis in the brain [68]. Thus, some studies have reported that acupuncture is beneficial for treating cerebral hemorrhage because it results in functional improvements [69,70]. Acupuncture also regulates inflammatory factors, such as IL-6, IL-1 , and NF-B, prevents apoptosis by reducing the expression of p53 protein, and promotes neurogenesis by increasing the levels of BDNF and nerve growth factors [71].   [35] Evidence-Based Complementary and Alternative Medicine 5 2018 [52] Evidence-Based Complementary and Alternative Medicine 7  Male, SD rats, MCAO Acupuncture increased the expression of endogenous GDNF and inhibited the early expression of VEGF, thus regulating nerve remodeling after cerebral hemorrhagic injury [72]. At the level of molecular signal transduction, acupuncture exerts a neuroprotective effect by increasing the angiopoietin level and reducing TNF-and NF-B levels [73,74]. Li et al. reported that EA on GV20 and GB7 could reduce BBB permeability and improve brain edema by activating the caveolin-1/matrix metalloproteinase pathway [75]. Antiapoptosis is also an important pathway for neural preservation. Zhu et al. and Li et al. have demonstrated that EA activated the Bcl-2 pathway to increase hematoma absorption and antiapoptosis. This effect is combined with the suppression of caspase-3 and Bcl-2-associated X (Bax) proteins [76,77]. However, the chosen acupoints were heterogeneous, including ST36, GV14, GV20, GV26, GB7, and PC6.
Taken together, acupuncture could improve neurogenic disability and reduce brain edema by increasing caveolin-1/matrix metalloproteinase levels and inducing antiapoptosis through the activation of the Bcl-2 pathway in a cerebral hemorrhagic model. The mechanisms and main results of identified articles are summarized in Table 2.

Seizure
Seizure is an abrupt, spontaneous, excessive, or synchronous neuronal activity in the brain that leads to various uncontrolled shaking movements or loss of consciousness. Seizure attack affects 8%-10% of the general population in their lifetimes. The recurrence of seizure results in epileptic syndrome, which affects 2%-3% of the general population [78]. Epileptic seizures can be induced by metabolic imbalance, electrolyte imbalance, encephalitis, traumatic brain injury, brain tumor, stroke, and medication [78]. During the process of an epileptic seizure, changes occur in molecular, anatomical, or circuit development, including cell death, inflammatory cytokine production, and neurotransmitter dysregulation. This process is called epileptogenesis [79]. Involvement of BDNF-TrkB signaling, the mTOR pathway, and the repressor element 1-silencing transcription factor pathway was considered to be the underlying molecular mechanism [79].
In addition to the use of medication, some studies have reported that acupuncture reduced the frequency of seizures and improved the quality of life [80][81][82]. Some studies reported that acupuncture has effect on change of anatomical, neurotransmitter, inflammatory cytokines and molecular level. The augmentation of -aminobutyric acid neurotransmission, including the upregulation of glutamic acid decarboxylase 67 (GAD67), is a self-protective and anticonvulsive mechanism [83,84]. Acupuncture reduced seizure attacks by enhancing GAD67 mRNA production in the dentate gyrus of epileptic rats [85]. Acupuncture changed the brain structure and reduced the mossy fiber sprouting in the dentate gyrus and exerted an antiepileptic effect [86]. Inflammation can increase neuronal excitability and result in the frequent onset of epilepsy, which is related to epileptogenesis [87]. Acupuncture also contributes to the antiepileptic effect accompanied by the anti-inflammatory effect of reducing IL-1 , TNF-, and cyclooxygenase-2 (COX-2) levels in the hippocampus of an epileptic rat model [88,89]. Wang et al. and Wang et al. have demonstrated that EA attenuated the seizure-induced increase in c-fos protein and preproenkephalin messenger ribonucleic acid (mRNA) levels in the hippocampus of a penicillin-induced seizure rat model [90,91]. Yang et al. reported that EA on GV16 and GV8 exerted an anticonvulsant effect combined with a reduction in nNOS and iNOS levels [92].
With regard to molecular pathways, acupuncture on the auricular acupoint suppressed transient receptor potential ankyrin 1 (TRPA1) pathways by increasing the phosphorylated protein kinase C (pPKC)-level and reducing pPKC and pERk1/2 levels in a kainic acid-induced rat model [93]. Liao et al. used a similar rat model and reported that acupuncture exerted an antiepileptic effect by inactivating the Toll-like receptor 4 (TLR4) pathway, which was accompanied by a decrease in pCaMKII , pERK, pp38, pJNK, and pNF B levels [94]. Yang et al. demonstrated that acupuncture on GV20 and GV14 reduced epileptic seizures by exerting a protective effect on the pyramidal cells of hippocampal CA 1 and CA 3. This effect was related to the activation of the PI3 K/Akt pathway [95]. The upregulation of glucoseregulated protein 78 (GRP78) and the downregulation of C/EBP homologous protein (CHOP) prevent neuronal cell death induced by endoreticulum stress. Acupuncture on GV20 and GV14 elevated the GRP78 level, reduced CHOP and caspase-12 levels, and exerted an antiapoptosis effect on the hippocampus, thus reducing epileptic seizure attacks [96,97].
Taken together, acupuncture exerts the antiepileptic effect by changing anatomical, neurotransmitter, inflammatory cytokines and molecular level. With respect to signal transduction, acupuncture reduces seizure frequency by suppressing TRPA1/pERK and TLR4/ERK pathways and activating the PI3K/Akt pathway. Furthermore, acupuncture augments the antiapoptosis process and provides neuroprotection by increasing the GRP78 level and reducing the CHOP level. The mechanisms and main results of identified articles are summarized in Table 3.

Depression
Depressive disorders are common psychiatric disorders that affect approximately 17% of people in their lifetimes. A study reported that 12%-20% of depressed patients experience treatment-resistant depression, resulting in a considerable social burden [98]. In addition to medication and psychosocial support, acupuncture serves as an alternative option for patients with depression that exhibits promising effects and fewer side effects [99]. The mechanism of depression includes dysregulation of neuroinflammatory cytokines, neurotransmitters, neuroplasticity, and the neuroendocrine system [100,101]. At the molecular level, dysregulation of striatal-enriched tyrosine protein phosphatase inactivates the neuronal signaling pathway, including ERK1/2, p38, Src family tyrosine kinases, and glutamate receptors. This process attenuates the neurogenesis effect of BDNF and causes depression [102].

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Evidence-Based Complementary and Alternative Medicine Acupuncture treats depression by regulating neurotransmitters, neuroinflammatory cytokines, the hypothalamus-pituitary-adrenal axis, and the hypothalamus-pituitary-sex gland axis [103]. Furthermore, acupuncture plays a role in molecular signaling pathways. Acupuncture elevated BDNF production and excitatory amino acid transporter levels and maintained neural regeneration of the hippocampus in a depressive rat model [104,105]. The chosen acupoints include GV20, EX-HN3, and PC6 [104,105]. Fan et al. demonstrated that acupuncture on LI4 and LR3 regulated the expression of soluble Nethylmaleimide-sensitive factor attachment receptor protein, a fusion mediator, and promoted depression remission [106]. NO is a small molecule that freely diffuses across cell membranes and serves as a neurotransmitter in the CNS. NO initiates the NO-cyclic guanosine monophosphate (NO-cGMP) pathway and activates protein kinases. Acupuncture regulates the NO-cGMP pathway by increasing nNOS and cGMP levels, which contribute to its effect on depression relief [107]. Shao et al. demonstrated that acupuncture on GV20 and PC6 inhibited the proinflammatory pathway of depression by reducing NF-B protein and COX-2 levels [108].
Molecular studies have reported that acupuncture plays a role in the neuroendocrine model of depression. Lu et al. demonstrated that acupuncture could relieve the symptoms of depression and increase cortisol, PKA, and PKC levels [117]. Oh et al. reported that acupuncture on HT8 elevated the serum corticosterone level and hippocampal mTOR phosphorylation, Akt, ERK, p70S6K, p4E-BP1, and CREB enhanced the effect of BDNF on neuroprotection and synaptic plasticity. Furthermore, acupuncture elevated the levels of synaptic proteins (e.g., PSD95, Syn1, and GluR1), which are crucial for neuronal synaptic plasticity [121].
The results of the Gene Ontology functional term and Kyoto Encyclopedia of Genes and Genomes database analysis indicated that the regulation of the Toll-like receptor signaling pathway, nucleotide-binding oligomerization domain-like receptor signaling pathway, MAPK/ERK pathway, PI3K/Akt pathway, neurotrophin signaling pathway, TNF pathway, and NF-B pathway is the mechanism through which acupuncture treats depression. The aforementioned pathways cause cell survival, differentiation, antiapoptosis, and synaptic plasticity of neurons, thus alleviating depression symptoms and improving learning/memory dysfunction [122][123][124].
In summary, acupuncture can treat depression by upregulating MAPK/ERK and AC-cAMP-PKA-CREB pathways and downregulating JNK and NF-B pathways. Because of the aforementioned mechanism, we observed an increase in neuron growth factor levels, neurogenesis, and antiapoptosis accompanied by the alleviation of depression symptoms. The mechanisms and main results of identified articles are summarized in Table 4.

Alzheimer's Disease
AD is a progressive neurodegenerative disease that is presented with dementia, memory loss, disorientation, personality disorder, mood swings, behavior disturbance, and language problems. Because of patients' cognitive decline, they withdraw from their family and society [125]. Risk factors for AD include genetic factors, a history of head trauma, depression, and hypertension [126]. The progression of AD is associated with the formation of amyloid plaques and neurofibrillary tangles in the brain [126]. Treatment of AD should be started immediately after the diagnosis to prevent cognitive decline. Both patients and their families are involved in administration of medication and psychosocial therapy for AD. Medication for AD includes cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), N-methyl-Daspartate receptor antagonists (memantine), atypical antipsychotics, antidepressants, and anticonvulsants [126].
In addition to medication, acupuncture has been reported to improve cognitive function and the global clinical status of patients with AD without causing major adverse effects [127,128]. Mechanisms through which acupuncture improves cognitive impairment in AD include attenuation of A deposits, upregulation of BDNF expression, and regulation of cell proliferation and neural plasticity in the brain [129][130][131]. Acupuncture also regulates cytokine and growth factor levels associated with survival, proliferation, and differentiation of neural stem cells in the brain to promote the repair of damaged cells [130,132].
A deposits in the brain disturb BDNF signaling pathways, such as Ras/ERK, PI3K/Akt, and PKA/cAMP, which regulate BDNF expression and cause AD development [133,134]. Acupuncture on GV20 reduces A deposits in the brain, elevates the BDNF level, and exerts a neuroprotective effect on CNS cells [135,136]. Lin et al. reported that the signaling pathway of BDNF elevation is mediated by the BDNF-TrkB pathway, which exerts an antiapoptosis effect [136]. The central cholinergic pathway is important for learning acquisition and synaptic plasticity in the mammalian limbic system; thus, increasing the acetylcholine level is a type of treatment strategy for AD. Lee et al. reported that acupuncture enhances the cholinergic system-CREB-BDNF pathway and exerts a neuroprotective effect [135].
Evidence-Based Complementary and Alternative Medicine 13 The p38 MAPKs are activated by environmental stresses and inflammatory cytokines and induce apoptosis and inflammation. In an AD animal model, acupuncture could improve cognitive impairment by reducing p38 MAPK levels, thus reducing neuroinflammation in the CNS [18,137,138]. Some studies have reported using Sanjiao acupuncture, which uses CV17, CV12, CV6, ST36, and SP10, as a standard regimen for AD [18,139,140]. A DNA microarray analysis demonstrated that Sanjiao acupuncture could reverse gene expression profiles related to aging in the hippocampus of senescence-accelerated mouse prone 10 (SAMP10) mice and reduce oxidative stress-induced damage [18]. Luo et al. reported that Sanjiao acupuncture attenuated cognitive deficits by regulating the G-protein/inositol triphosphate/Ca 2+ amplitude pathway and signal homeostasis [140]. In an A -induced AD model, acupuncture on GV20 and BL23 reduced the level of peroxisome proliferatoractivated receptor-(PPAR-) level and the deposition of Tau protein, thus reducing neuroinflammation [138].
Acupuncture regulated cell cycle and aging in an AD model. N-myc downregulated gene 2 (NDRG2) encodes a cytoplasmic protein that may play a role in neurite outgrowth. Wang et al. demonstrated that EA on GV20 suppressed the astrocyte NDRG2 expression and glial fibrillary acidic protein level, thereby treating memory impairment of amyloid precursor protein/presenilin-1 double transgenic mice [141]. P130, known as retinoblastoma-like protein 2 (RBL2), is a protein encoded by the RBL gene in humans and serves as a tumor suppressor signal. Acupuncture on CV17, CV12, CV6, SP10, and ST36 elevated the p130 level, caused cell proliferation in the brain, and treated dementia and agingrelated diseases in SAMP10 mice [139]. Telomerase is a critical enzyme involved in aging and apoptosis. Lin et al. demonstrated that acupuncture on ST35 of telomerase-deficient mice activated the BDNF-TrkB signaling pathway along with elevating BDNF, TrkB, Akt, and ERK1/2 levels, which resulted in an increase in telomerase activity [142]. Acupuncture also modulates the balance of Bcl-2/Bax to regulate the cell cycle of neurons. However, the chosen acupoints were heterogeneous, including LI20, EX-HN3, GV20, BL23, and KI1 [143][144][145].
Metabolic stress modulates -secretase gene transcription and -site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels in AD through the sirtuin 1 (SIRT1)-PPAR -proliferator-activated receptor coactivator 1 (PGC-1) pathway [146]. A 25-35 suppresses mitochondrial biogenesis by inactivating the AMP-activated protein kinase (AMPK)-SIRT1-PGC-1 pathway in hippocampal neurons [147]. Therefore, brain energy metabolism impairment is considered an underlying pathogenesis of AD progression. Acupuncture on GV20 elevates glucose transporter (GLUT1 and GLUT3), p-AMPK, p-AKT, and mTOR levels in the hippocampus and cortex. Through regulation of brain energy metabolism, acupuncture has effect on decreasing A deposits, suppressing autophagy process and relieving cognition deficits [148]. Acupuncture improved the spatial learning and memory ability of AD mice by increasing blood perfusion and glucose uptake in the bilateral amygdala, hippocampus, and left temporal lobe [149,150]. For the molecular signaling pathway, Dong et al. demonstrated in two series studies that acupuncture in GV14 and BL23 exerted AMPK expression, activated SIRT1-PPAR -PGC-1 pathway, and elevated ATP level. Because of the aforementioned mechanism, acupuncture balances brain metabolism and improves cognition impairment of AD mice [20,151]. Furthermore, the upregulation of SIRT1-PPAR -PGC-1 suppresses BACE1 expression, thus reducing A production in the hippocampus and improving cognitive decline in SAMP8 mice [152].
In summary, acupuncture treats AD by regulating neurotransmitter release, elevating the neurotrophic factor level, and exerting anti-inflammatory effects. Thus, many molecular signaling pathways involved in acupuncture were reported in the AD model, including the BDNF-TrkB pathway, the cholinergic system-CREB-BDNF pathway, G-protein regulation, and the p38 MAPK family. The aforementioned pathways are believed to exert antiapoptosis and antiinflammatory effects and reduce A deposits in the brain, thereby improving learning ability and memory in AD models. The most commonly chosen acupoints were GV20 and the Sanjiao regimen (CV17, CV12, CV6, ST36, and SP10). Acupuncture regulates cell cycle and aging by modulating NDRG2 and P130 expression, telomerase activity, and Bcl-2/Bax balance. Many studies have reported that acupuncture on GV14 and BL23 modulates brain energy metabolism impairment and treats cognitive impairment. The mechanisms and main results of identified articles are summarized in Table 5.

Vascular Dementia
VD, which accounts for 15% of dementia cases, is the second most common cause of dementia after AD. Multiple and recurrent ischemia of the brain caused by ischemia or hemorrhage has been found to be the main causes of VD [169]. Although the pathophysiology of VD remains unclear, approximately 15%-30% of patients develop dementia three months after the occurrence of stroke. Furthermore, approximately 20%-25% of patients develop delayed dementia [170]. Because of intricate coordination in the brain and, sometimes, the presence of other brain damage causes, the cognitive changes and declines in VD can be variable, including impairment of attention, information processing, and executive function [169]. Few medications have been approved specifically for the prevention or treatment of VD. Thus, treatment strategies for VD are similar to those for AD and include the use of cholinesterase inhibitors and memantine and providing psychosocial support.
Acupuncture can improve the scores on the Mini-Mental Status Examination, the revised Hasegawa's dementia scale, and activities of daily living examination for VD patients [171,172]. From the molecular viewpoint, acupuncture on GV20 and KI3 regulates the MAPK/ERK pathway by elevating the pERK level and reducing ionized calcium-binding adaptor molecule 1 (Iba-1), TLR4, and TNF-levels [153]. Acupuncture reduced relevant proinflammatory factors, thus attenuating neuroinflammation and increasing neuronal synaptic plasticity.
Acupuncture exerted antioxidant and antiapoptosis effects in VD models. Zhu et al. reported that acupuncture on 2013 [137] 20 Evidence-Based Complementary and Alternative Medicine  2015 [144] 22 Evidence-Based Complementary and Alternative Medicine  GV20 and ST36 inactivated the apoptosis signal-regulating kinase 1 (ASK1)-JNK/p38 pathway and elevated thioredoxin-1 and thioredoxin reductase-1 levels [154]. The p38 MAPK pathway activates the expression of CREB and reduces the apoptosis of ischemic neural cells. Some studies have reported that acupuncture activates the cAMP/PKA/CREB pathway and elevates the CREB level [47,48,50,51]. The elevated CREB level upregulates Bcl-2 activity and downregulates Bcl-2xl and Bax activities, consequently preventing the apoptosis of neurons injured by vascular events [48,51]. The most discussed acupoint was GV20, followed by GV24. Scalp and Sanjiao acupuncture techniques (CV17, CV12, CV6, ST36, and SP10) have been reported to affect the balance between Bcl-2 and Bax expression and antiapoptosis [155,156]. VD rats had lower expression of mTOR and eukaryotic translation initiation factor 4E (eIF4E) in CA1 accompanied with decreased spatial memory [173]. Zhu et al. demonstrated that EA on GV20, GV14, and BL23 activates the mTOR pathway and increases mTOR and eIF4E levels, thus modulating cell growth, proliferation, and synaptic plasticity [157]. Taken together, acupuncture treats VD by activating MAPK/ERK and ASK1-JNK/p38 pathways; increasing CREB, mTOR, and Bcl-2 levels; and reducing the Bax level. In addition, through the aforementioned mechanism, acupuncture exerts an effect on antioxidant activity, antiapoptosis, and synaptic plasticity. The most commonly chosen acupoints were GV20, GV24, and ST36. The mechanisms and main results of identified articles are summarized in Table 6.

Parkinson's Disease
PD is a chronic neural degenerative disorder that mainly affects the motor system. Patients with PD experience shaking, rigidity, and walking difficulty. In advanced stages of the disease, behavioral disturbance, depression, poor sleep, and cognitive dysfunction are noted [174]. Treatments such as the administration of L-dopa, dopamine agonists, catechol-O-methyl transferase inhibitors, and monoamine oxidase inhibitor and deep brain stimulation are suggested for treating motor problems of patients with PD. However, dyskinesias and motor fluctuations that develop after a longterm use or high dose use of L-dopa and nonmovementrelated symptoms, such as sleep disturbances and psychiatric problems, become problems for patients with PD [174].
Both manual acupuncture and EA help alleviate some motor symptoms in patients with PD and some nonmotor symptoms, such as psychiatric disorders, sleep disorders, and gastrointestinal symptoms. Acupuncture also improved the therapeutic efficacy of levodopa, lowering the necessary dosage [175][176][177]. Reducing dopaminergic neurons in the substantia nigra (SN) results in PD. Acupuncture has been reported to exert neuroprotective effects that increase the levels of endogenous neurotrophins and modulate the apoptosis and neuroinflammation of dopaminergic neurons in the SN [178,179]. Neuroimaging findings of the human brain showed that acupuncture on GB34 and the scalp significantly increased glucose metabolism bilaterally in the frontal and occipital lobes and improved motor dysfunction in patients with PD [179,180].
In light of signal transduction, EA at 2 Hz on GV16 and LR3 inactivate the ERK 1/2 signaling pathway and p38/MAPK signaling pathway, causing an increase in tyrosine hydroxylase-positive neurons and a decrease in COX-2, TNF-, and IL-1 levels. The regulation of cytokines reduces the neuroinflammation of the SN and alleviates PD symptoms [158,159]. Acupuncture also activates the PI3K/Akt pathway, which elevates the Bcl-2 level and reduces dopamine-and cAMP-regulated phosphoprotein of 32 kDa and Fos B. Through the activation of the PI3K/Akt pathway, acupuncture increases the dopamine turnover rate and availability in the synapse of the SN and striatum and regulates the tyrosine hydroxylase-positive cell cycle, thus improving motor function [160][161][162]. Lu et al. demonstrated that EA on KI3 inactivates pPKA/pPKC/CaMKII signaling pathways and reduces neuronal excitotoxicity in the hippocampus [163].
Rapamycin, an inhibitor of mTOR, is a potent inducer of autophagy and has an effect on PD [181]. However, rapamycin-based treatments for PD show adverse effects, including dyslipidemia, proliferative dysregulation, and renal dysfunction [182]. Acupuncture on GB34 affected the downstream autophagy-lysosome pathway through the m-TORindependent pathway; this effect was comparable to that observed in the rapamycin treatment group [164]. Acupuncture induced autophagic clearance of -syn, caused recovery of DA neurons in the SN, and improved motor function of an animal model without any notable adverse effect [164].
Oxidative stress and inflammation both contribute to the neural toxicity and development of PD [183]. Many studies have indicated the use of high-frequency EA for treating PD motor symptoms in animal models [184,185]. Kim et al. reported that high-frequency EA on GB34 and GB39 increased tyrosine hydroxylase-positive neurons and cytochrome c oxidase subunit Vb and reduced cytosolic malate dehydrogenase, munc18-1, and hydroxyacylglutathione hydrolase levels, thus exerting an antioxidative effect on the SN [165]. Lv et al. demonstrated that EA at 100 Hz on ST36 and SP6 exerted a neuroprotective effect on PD mice and reversed the increase in the levels of Iba-1 and proinflammatory cytokines, including TNF-, IL-6, and IL-1 , induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), thus suppressing the neuroinflammatory process [166]. The nuclear factor erythroid 2 -related factor 2 (Nrf2)-antioxidant response element (ARE) pathway regulates oxidative stress and inflammatory responses. EA enhances the Nrf2-ARE pathway and regulates the expression of antioxidants, such as the ARE-driven reporter gene, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase, and heme oxygenase-1 (HO-1), thus relieving PD symptoms [166]. Similarly, Deng et al. reported that EA at 100 Hz on ST36 and SP6 elevated HO-1 and glutamate-cysteine ligase modifier subunits and reduced astrogliosis and neuroinflammation through the Nrf2-ARE pathway [167].
PD symptoms were relieved through the modification of TLR/NF-B and Nrf2/HO-1 pathways [186]. EA on GV16 and 24 Evidence-Based Complementary and Alternative Medicine      LR3 upregulated NF B protein expression and downregulated 26S proteasome protein expression in rotenone-induced PD rats [187]. P53 plays a role in DNA repair or cell death depending on the nature and extent of stress and damage [188]. P53 dysfunction was reported in neurodegenerative diseases and cancers [189]. Park et al. demonstrated that acupuncture on GB34 activated the p53 signaling pathway, protected dopaminergic neurons in the SN and striatum, and treated PD symptoms [168]. At the gene level, Choi et al. demonstrated that EA regulated gene expression in the striatum and exerted a neuroprotective effect on MPTP parkinsonism mice [190,191]. Yeo et al. performed a microarray analysis study of acupuncture on GB34 and LR3 in an MPTP mouse model of parkinsonism and reported that acupuncture reversed the downregulation of five annotated genes and upregulation of three annotated genes through MPTP intoxication [192].
In summary, acupuncture improved motor dysfunction and memory of PD. These effects were accompanied by the regulation of gene expression. Acupuncture modulates neuroinflammation by inactivating ERK 1/2 and p38/MAPK signaling pathway and reduces neuronal excitotoxicity through the pPKA/pPKC/CaMKII signaling pathway. Acupuncture also regulates apoptosis by balancing the Bcl-2 and m-TORindependent pathway. The most chosen acupoints include GB34, LR3, and GV16. Moreover, high-frequency EA (100 30 Evidence-Based Complementary and Alternative Medicine Hz) on ST36 and SP6 reduces neuroinflammation through the Nrf2-ARE pathway. The mechanisms and main results of identified articles are summarized in Table 7.

Data Availability
The data in this study are available to other researchers upon request.

Conflicts of Interest
We declare that there are no conflicts of interest associated with this manuscript, and no significant financial support was received that would influence our findings.