reviewarticle - hindawi publishing...

Review ArticleEffects of Acupuncture on Alzheimerrsquos Disease inAnimal-Based Research

Sunjung Park1 Jun-Hwan Lee12 and Eun Jin Yang12

1Department of Clinical Research Korea Institute of Oriental Medicine 1672 Yuseong-daero Yuseong-guDaejeon 305-811 Republic of Korea2Korean Medicine Life Science University of Science and Technology (UST) Daejeon 34054 Republic of Korea

Correspondence should be addressed to Eun Jin Yang yej4823hanmailnet

Received 11 April 2017 Accepted 20 August 2017 Published 27 September 2017

Academic Editor Gorazd Drevensek

Copyright copy 2017 Sunjung Park et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Alzheimerrsquos disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid beta (A120573) plaquesneurofibrillary tangles and severe functional deficits in the brain The pathogenesis and treatment of AD remain topics ofinvestigation and significant global socioeconomic issuesThe effect of complementarymedicine has been investigated inmanagingAD Acupuncture a form of therapy practiced for more than 3000 years has shown positive effects on several neurologicaldisorders including AD Animal studies have evaluated the specific utility and neuropathological mechanisms addressed byacupointmanipulation however no study has summarized the relationships among different acupoints and their therapeutic effectsin the context of AD Therefore we reviewed the effects of acupuncture at different acupoints in animal models of AD In generalacupuncture produced therapeutic benefits in rodent models of AD Studies demonstrate the utility of GV20 as a valuable acupointfor electroacupuncture and manual acupuncture GV20 stimulation suppresses A120573 generation improves glucose metabolism andattenuates neuropathological features in various disease models However a lack of sufficient evidence in preclinical and clinicalstudies makes these results controversial Additional studies are required to confirm the exact utility of specific acupoints inclinically managing AD

1 Introduction

AD is a neurodegenerative disorder that is clinically charac-terized by progressive memory loss and cognitive deficits [1]AD is the fourth leading cause of death in individuals over 65years of age worldwide and is the underlying cause of 60ndash70of cases of dementia The global prevalence of dementia wasestimated to be 53 million in 2015 with potential for thisnumber to approach 80 million by 2040 Neuropathologicalhallmarks of AD include the abnormal production andaccumulation of amyloid beta (A120573) plaques and neuro-fibrillary tangles of hyperphosphorylated tau protein in thebrain [2] Accordingly the uncontrolled generation of patho-logical A120573 and tau hyperphosphorylation is thought to driveneuronal loss and cognitive impairment inADDespite globalawareness about the severity and socioeconomic effects ofAD effective treatments remain an important unmet need

Treatments based on Western medical science are proposedto delay functional memory impairment but produce unre-liable effects and only delay disease progression in best-casescenarios [3]

Acupuncture is a traditional therapy that has beenpracticed in Korea China and Japan for centuries and isconsidered a useful form of complementary medicine [45] The efficacy of acupuncture has been demonstrated fortreating numerous of severe disease states including gas-trointestinal disorders [6] breast cancer [7] colorectal cancer[8] chronic pain [9] and cognitive impairment Commonacupuncture techniques include electroacupuncture (EA)and manual acupuncture (MA) MA involves the insertionof fine stainless steel needles into specific acupoints followedby manual manipulation such as twisting or thrusting [10]EA is a technique in which two needles are inserted togenerate electric current [10] and is generally amore common

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017 Article ID 6512520 5 pageshttpsdoiorg10115520176512520

2 Evidence-Based Complementary and Alternative Medicine

technique than MA An important advantage of EA is thatit combines the beneficial effects of transcutaneous electricnerve stimulation and MA [3]

EA andMA have demonstrated therapeutic utility for thetreatment of AD in numerous animal studies [13ndash24] Forexample EA stimulation at GV14 and BL23 downregulatesbeta-secretase 1 (BACE1) an enzyme responsible for A120573generation in AD and increases ATP levels in the hippocam-pus of AD mice [14] MA stimulation at ST36 alleviatesglycerol metabolism in a rat model of AD generated by D-galactose injection [22] Studies suggest that acupuncturehas positive effects on cognition in AD and dementia bymodulating neuronal signaling pathways These pathways[13 17 19 20 22 24] include those related to apoptosiscell survival and glucose metabolism and are suggested tomediate the beneficial effects of acupuncture on cognitive andphysiological functions in animal models Moreover studiessuggest that specific acupoints may exert specific therapeuticeffects

While several reviews have summarized data gleanedfrom studies in animal models of AD no previous reviewhas summarized the relationships between acupuncture stim-ulation at specific acupoints and their therapeutic effects inAD Here we review recent animal studies supporting theuse of acupuncture as an effective therapeutic tool in AD andhighlight specific acupoints that have demonstrated utility fortargeting the neuropathological mechanisms of AD

2 Effects of Acupuncture on AD

21 Electroacupuncture EA has been widely used in moderninvestigations of acupuncture because it can be standardizedin terms of frequency voltage and duration [3] Severalstudies have suggested that EA stimulation produces cog-nitive improvements and positive changes in AD-relatedpathology in rodent disease models [14ndash18 20 21 23 24]For EA acupoints GV14 (Daechu) and BL23 (Sinsu) arethe most well studied in animal models of AD (Figure 1)Multipoint EA stimulation at GV14 and BL23 significantlydecreases hippocampal A120573 accumulation in senescenceaccelerated mouse-prone8 (SAMP8) transgenic mice [14]which is an AD-like model characterized by cortical andhippocampal A120573 accumulation [13 14] Another importantprotein implicated in AD is 51015840 adenosine monophosphate-activated protein kinase (AMPK) which serves as a masterregulator of cellular energy homeostasis and thus glucoseand lipid metabolism [14] Activation of AMPK represses tauphosphorylation and A120573 production The phosphorylation-dependent activation of AMPK is increased in SAMP8 miceafter EA at GV14 and BL23 [14] suggesting that EA at theseacupoints may affect glucose metabolism and ATP synthesisin the AD brain Consistent with this suggestion EA stimu-lation at GV14 and BL23 increases cortical and hippocampalATP levels in SAMP8 mice Cortical and hippocampal Sir-tuin1 (SIRT1) and peroxisome proliferator-activated receptor120574 coactivator 1-120572 (PGC1-120572) were also upregulated and PGC1-120572 acetylation was decreased in SAMP8 mice after GV14 andBL23EA stimulation [15] In another study by the same group

BL23

ST36

SP6HT7

GV14GV20

GV26

EX-HN3

Figure 1 Standard acupuncture acupoint locations in mouse and ratGV26 is located at the junction of the upper and middle third of thephiltrumGV20 is located on themidline between the top of the earsGV14 is located below the spinous process of the seventh vertebraeat the approximate level of the shoulders BL23 is located on theposterior midline at the level of the lower border of the spinousprocess of the second lumbar vertebra HT7 is located on the wrist atthe ulnar end of the transverse crease of the wrist in the depressionon the radial side of the tendonmusculus flexor carpi ulnaris ST36 islocated below the lower border of the patella one finger width lateralfrom the anterior border of the tibia SP6 is located on the insideof the leg just above the ankle EX-HN3 is located on the anteriormidline between the eyes Anatomical locations of the stimulatedacupuncture points inmice and ratswere equivalent to the acupointsin humans [11 12] The location of EX-HN3 was determined inaccordancewith theNationalAcupuncture Society for ExperimentalResearch ldquoLaboratory Animal Acupuncture Atlasrdquo

EA at GV14 and BL23 reduced A120573 generation and downreg-ulated BACE1 in the hippocampus of SAMP8 mice whichwas associated with improvements in spatial learning andmemory (Table 1) [16] In summary concurrent stimulationof GV14 and BL23 may regulate glucose metabolism ATPsynthesis and A120573 generation to improve AD-like symptomsin SAMP8 mice

GV20 (Baekhoe) has been used for single acupointtherapy in animal models of AD (Figure 1) EA stimu-lation at GV20 in APPPS1 transgenic mice expressing achimeric mousehuman amyloid precursor protein (APP)and a mutant human presenilin 1 (PS1) significantly amelio-rated learning and memory deficits [20 21] Studies suggeststhat brain-derived neurotrophic factor (BDNF) is a criticalfactor in adult neurogenesis and memory [26 27] which isdeficient in patients with AD [28] GV20 stimulation wasfound to upregulate BDNF in the hippocampus and cortex ofAPPPS1 transgenic mice [20 21] Moreover mature BDNFand pro-BDNF expression the BDNFpro-BDNF ratio andtropomyosin receptor kinase (Trk) phosphorylation wereenhanced by EA at GV20 inAPPPS1mice [21] Furthermoreit was found that GV20 stimulation increased neurogenesis[20] and decreased neuronal apoptosis [21] in the APPPS1mouse brain Taken together it can be hypothesized thatGV20 promotes BDNF signaling to enhance neurogenesisand decrease cell death in the APPPS1 brain EA stimulationat GV20 has also been reported to affect glial fibrillary acidicprotein (GFAP) and N-myc downstream-regulated gene 2(NDRG2) signaling in the APPPS1 mouse brain GFAP and

Evidence-Based Complementary and Alternative Medicine 3

Table 1 Acupoint targets of EA and MA for the treatment of Alzheimerrsquos disease (AD) GV14 and GV20 single-point EA stimulation andmultipoint EA stimulation of BL23 GV26 and EX-HN3 have been preclinically studied for the treatment of AD Single-pointMA stimulationof GV20 ST36 and HT7 has also been evaluated in rodent models of AD

AD model Acupoint Frequency Action mechanism

EA

SAMP8 [14ndash16] GV14 BL23 minus2Hz 1mA AMPK uarr SIRT1 PGC1a darrBACE1 darr

A1205731-40 injection[17 24] GV20 BL23 minus20Hz 2mA

minus2Hz 1mA

Bcl2 uarr BAX darr Notch darrPPAR-gamma uarrp-p38MAPK darr

SAMP8 [18] GV20 GV26EX-HN3 minus2Hz 06mA Glucose metabolism uarr

APPPS1 [20 21 23] GV20 minus215Hz 1mA NDRG2 darrBDNF uarr P75 uarr pTRK-B darr

MA

Scopolamineinjection [19] GV20 ndash BDNF uarr CREB uarr

cholinergic system uarrD-Galactose injection

[22] ST36 60ndash90 twistmin Glycerol metabolism uarr

D-Galactose injection[25] HT7 120ndash150

twistmin Glucose metabolism uarr

NDRG2 upregulation and associated memory deficits weresignificantly improved after EA at GV20 (Table 1) [23]

GV20 has also been studied in the context of multipointEA stimulation EA at GV20 and BL23 ameliorated memoryimpairment in a ratmodel of AD induced byA120573

1-40 injectionEA at GV20 and BL23 was found to reverse A120573-induceddownregulation of B-cell lymphoma 2 (Bcl-2) to upregulateBcl-2 associated X protein (BAX) expression and to upreg-ulate Notch in a rat model of AD [17] In another studyEA stimulation at GV20 and BL23 significantly improvedcognitive impairment and reduced the brain expression ofA120573and p-tau proteins [24]

In the A1205731-40 injection model of AD EA at GV20

and BL23 restored peroxisome proliferator-activated receptorgamma (PPAR-120574) expression and mitigated increases inphosphorylated-p38 mitogen-activated protein kinase (p-p38MAPK) [24] Taken together these findings suggest thatEA stimulation at GV20 and BL23 improves cognitive deficitsvia inhibition of the Notch pathway [17] andor upregulationof PPAR-120574 [24] in rat models of AD (Table 1)

Finally Jiang and colleagues examined the utility ofmultipoint EA stimulation of GV20 GV26 (Sugu) and EX-HN3 (Yintang) in SAMP8 mice (Figure 1) and determinedthat stimulation improved hippocampal glucose metabolism[18] consistent with the results of studies examining single-point EA of GV20 Multipoint EA at GV20 GV26 and EX-HN3 also improved spatial learning and memory in SAMPmice These findings ultimately highlight the importance ofmetabolic changes in AD and the potential for GV20 EA topromote healthy glucose and energy metabolism in the agingor pathological AD brain (Table 1)

22 Manual Acupuncture MA is widely used as a traditionaltherapy and involves twisting thrusting or other manipula-tions of the acupuncture needle as a key feature Several stud-ies have demonstrated the utility of MA for improving cog-nitive impairments in animal models of AD GV20 has been

identified as a valuable acupoint for MA as well as EA MAat GV20 improves memory impairment in a scopolamine-induced rat model of AD [19] This benefit was associatedwith increases in choline acetyltransferase (ChAT) BDNFand cAMP response element binding (CREB) expression inthe hippocampus [19] Decreased cholinergic function inthe brain was also observed in patients with AD produc-ing defects in memory and cognitive function Cholinergicfunction is associated with attention and working memory[29] MA at GV20 was also found to upregulate hippocampalcholine transporter 1 (CHT1) vesicular acetylcholine trans-porter (VAChT) BDNF andCREB inADmodel rats (Table 1)[19] suggesting that manual GV20 stimulation may promotecholinergic neurotransmission as a component of its effectson memory and cognition

In a previous study MA at ST36 and SP6 was foundto modulate the function of hippocampal interneurons toimprovememory inmice (Figure 1) [30] A positron emissiontomographic study of MA stimulation at ST36 revealedelevated glucose metabolism in the left olfactory cortex andbilateral amygdaloid bodies in the MA group compared tothat in a sham group in a rat model of AD generated byD-galactose injection (Table 1) [22] Accordingly MA atST36 may have specific effects on regional brain activationThe regions activated by MA at ST36 were centered in thelimbic system which is involved in emotion sensation andmemory therefore MA at ST36 may improve emotionalprocessing and help patients get over fear or pain

Acupuncture stimulation at HT7 (Sinmun) has beenclinically used to treat cognitive impairment and sleepdisturbances (Figure 1) [25 31] and is considered a usefultherapy for memory impairment HT7 stimulation in a ratmodel of AD generated by D-galactose injection producedimprovements in cognitive function and increased corticaland hippocampal glucose metabolism compared to that incontrol AD rats (Table 1) [32] A shorter total reaction timein the Y maze test was observed in HT7-treated AD rats than


in nontreated AD rats [32] Similar to ST36 stimulation MAstimulation atHT7 appears to have specific effects on cerebralglucose metabolism and thus regional brain activation inrodent models of AD

3 Conclusion

In summary data from studies on acupuncture in rodentmodels of AD show that MA or EA at specific acupointsimproves cognitive impairment andhas therapeutic effects ondisease pathology Additionally unique acupoints appear tohave targeted effects on specific neuropathological pathwaysAlthough EA andMA are distinct techniques associated withdifferent therapeutic benefits they appear to induce similareffects when targeting the same acupoints in rodent modelsof AD EA or MA single- or multipoint stimulation at GV20is widely studied and is associated with effects on BDNFsignaling and cognitive impairment GV20 is located on themidline between the apices of the ears andhas been a previoustarget for the treatment of headache in a clinical trial [33]GV14 is another promising acupoint formanagingADwhichhas been studied in conjunction with EA at BL23 GV14is located on the midline of the neck and is indicated forthe treatment of memory impairment EA stimulation atGV14 and BL23 exerts beneficial effects on pathological A120573and tau protein generation as well as energy metabolismFinally single-point MA at ST36 or HT7 appears to havespecific effects on regional cerebral blood flow and glucosemetabolism ST36 is located on the anterior aspect of thelower leg and it is a target for normalizing blood circulationHT7 is located on the wrist and it is indicated for thetreatment of insomnia and amnesia Future studies shouldexamine the exact regional brain effects of targeting theseacupoints in clinical AD

Acupuncture is a useful form of complementaryalter-native medicine for the managing neurodegenerative disor-ders because it can reduce the side effects of therapy aswell as the financial burden of treatment on patients andtheir families In addition to AD studies have reportedthe utility of acupuncture treatment in Parkinsonrsquos diseaseshowing that it improves symptoms andhas a neuroprotectiverole [34] Furthermore acupuncture has been reported as aprospective therapy for stroke [35 36] where it could regulateglucose metabolism and be involved in poststroke neuro-genesis Acupuncture may have a potential neuroprotectiverole worth studying regarding the treatment of neurologicaldiseases

The studies summarized in this review supports the utilityof acupuncture as a form of complementary medicine forAD and the ability of specific acupoint targets to addresspathological disease features Acupuncture improves cog-nitive impairment decreases pathological A120573 generationdecreases neuronal apoptosis and ameliorates neuroinflam-mation however the concept of acupoint specificity is notcompletely validated [4] Moreover the results of preclinicalstudies in animal models of AD require validation in clinicalsettings with human patients Future preclinical and clinicalstudies should be expedited to inform the exact use and

efficacy of different acupuncture methods and targets for thetreatment of AD

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

This work was supported by grant from the Korea Instituteof Oriental Medicine (KIOM) (no K17051) and the BasicScience Research Program through the National ResearchFoundation of Korea funded by the Ministry of Science ICTamp Future Planning (no NRF-2015R1C1A2A01053248) SouthKorea

References

[1] P Meena A Manral V Saini and M Tiwari ldquoProtectiveeffects of a piperazine derivative [N-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-phenyl Carbamic Acid Ethyl Ester] againstaluminium-induced neurotoxicity insights from in silico andin vivo studiesrdquo Neurotoxicity Research vol 27 no 3 pp 314ndash327 2015

[2] M C P Leung K K Yip Y S Ho F K W Siu W C Li and BGarner ldquoMechanisms underlying the effect of acupuncture oncognitive improvement a systematic review of animal studiesrdquoJournal of Neuroimmune Pharmacology vol 9 no 4 pp 492ndash507 2014

[3] J-G Lin and W-L Chen ldquoAcupuncture analgesia a review ofits mechanisms of actionsrdquo The American Journal of ChineseMedicine vol 36 no 4 pp 635ndash645 2008

[4] Y Cao L-W Zhang JWang et al ldquoMechanisms of acupunctureeffect on Alzheimerrsquos disease in animal-based researchesrdquo Cur-rent Topics in Medicinal Chemistry vol 16 no 5 pp 574ndash5782016

[5] B-Y Zeng S Salvage and P Jenner ldquoEffect and mechanismof acupuncture on alzheimerrsquos diseaserdquo International Review ofNeurobiology vol 111 pp 181ndash195 2013

[6] H Li T He Q Xu et al ldquoAcupuncture and regulation ofgastrointestinal functionrdquo World Journal of Gastroenterologyvol 21 no 27 pp 8304ndash8313 2015

[7] M S Lee K-H Kim S-M Choi and E Ernst ldquoAcupuncturefor treating hot flashes in breast cancer patients A systematicreviewrdquo Breast Cancer Research and Treatment vol 115 no 3pp 497ndash503 2009

[8] K H Kim D H Kim H Y Kim and G M Son ldquoAcupuncturefor recovery after surgery in patients undergoing colorec-tal cancer resection a systematic review and meta-analysisrdquoAcupuncture in Medicine vol 34 no 4 pp 248ndash256 2016

[9] L Eshkevari ldquoAcupuncture and chronic pain managementrdquoAnnual Review of Nursing Research vol 35 no 1 pp 117ndash1342017

[10] B Liu Y Wang H Xu et al ldquoEffect of electroacupunctureversus pelvic floormuscle training plus solifenacin formoderateand severe mixed urinary incontinence in women a studyprotocolrdquo BMC Complementary and Alternative Medicine vol14 no 1 article no 301 2014

[11] I S Jang K H Cho S K Moon et al ldquoA study on the centralneural pathway of the heart Nei-Kuan (EH-6) and Shen-Men


(HE-7) with neural tracer in ratsrdquo The American Journal ofChinese Medicine vol 31 no 4 pp 591ndash609 2003

[12] C S Yin H-S Jeong H-J Park et al ldquoA proposed transposi-tional acupoint system in a mouse and rat modelrdquo Research inVeterinary Science vol 84 no 2 pp 159ndash165 2008

[13] H Cheng J Yu Z Jiang et al ldquoAcupuncture improves cognitivedeficits and regulates the brain cell proliferation of SAMP8micerdquo Neuroscience Letters vol 432 no 2 pp 111ndash116 2008

[14] W G DongW Q Guo X H Zheng et al ldquoElectroacupunctureimproves cognitive deficits associated with AMPK activation inSAMP8 micerdquo Metabolic Brain Disease vol 30 no 3 pp 777ndash784 2015

[15] W Dong W Guo F Wang et al ldquoElectroacupuncture upreg-ulates SIRT1-dependent PGC-1120572 expression in SAMP8 MicerdquoMedical Science Monitor vol 21 pp 3356ndash3362 2015

[16] W-G Dong F Wang Y Chen et al ldquoElectroacupuncturereduces A120573 production and bace1 expression in SAMP8 micerdquoFrontiers in Aging Neuroscience vol 7 article no 148 2015

[17] H-D Guo J-X Tian J Zhu et al ldquoElectroacupuncturesuppressed neuronal apoptosis and improved cognitive impair-ment in the ad model rats possibly via downregulation ofnotch signaling pathwayrdquo Evidence-based Complementary andAlternative Medicine vol 2015 Article ID 393569 2015

[18] J Jiang K Gao Y Zhou et al ldquoElectroacupuncture treat-ment improves learning-memory ability and brain glucosemetabolism in a mouse model of Alzheimerrsquos disease usingMorris water maze and micro-PETrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2015 Article ID 1421297 pages 2015

[19] B Lee B Sur J Shim D Hahm and H Lee ldquoAcupuncturestimulation improves scopolamine-induced cognitive impair-ment via activation of cholinergic system and regulation ofBDNF andCREB expressions in ratsrdquoBMCComplementary andAlternative Medicine vol 14 no 1 article 338 2014

[20] X Li F Guo Q Zhang et al ldquoElectroacupuncture decreasescognitive impairment and promotes neurogenesis in theAPPPS1 transgenic micerdquo BMC Complementary and Alterna-tive Medicine vol 14 article 37 2014

[21] R Lin J Chen X Li et al ldquoElectroacupuncture at the Baihuiacupoint alleviates cognitive impairment and exerts neuropro-tective effects by modulating the expression and processing ofbrain-derived neurotrophic factor in APPPS1 transgenicmicerdquoMolecular Medicine Reports vol 13 no 2 pp 1611ndash1617 2016

[22] Y Lu Y Huang C Tang et al ldquoBrain areas involved in theacupuncture treatment of AD model rats A PET studyrdquo BMCComplementary and Alternative Medicine vol 14 no 1 article178 2014

[23] F Wang H Zhong X Li et al ldquoElectroacupuncture attenu-ates reference memory impairment associated with astrocyticNDRG2 suppression in APPPS1 transgenic micerdquo MolecularNeurobiology vol 50 no 2 pp 305ndash313 2014

[24] M Zhang G-H Xv W-X Wang D-J Meng and Y JildquoElectroacupuncture improves cognitive deficits and activatesPPAR-120574 in a rat model of Alzheimerrsquos diseaserdquo Acupuncture inmedicine journal of the British Medical Acupuncture Societyvol 35 no 1 pp 44ndash51 2017

[25] J L Shergis X Ni M L Jackson et al ldquoA systematic reviewof acupuncture for sleep quality in people with insomniardquoComplementary Therapies in Medicine vol 26 pp 11ndash20 2016

[26] R A Henry S M Hughes and B Connor ldquoAAV-mediateddelivery of BDNF augments neurogenesis in the normal and

quinolinic acid-lesioned adult rat brainrdquo European Journal ofNeuroscience vol 25 no 12 pp 3513ndash3525 2007

[27] M H Larsen H Rosenbrock F Sams-Dodd and J DMikkelsen ldquoExpression of brain derived neurotrophic factoractivity-regulated cytoskeleton protein mRNA and enhance-ment of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensinerdquo European Journal of Pharmacol-ogy vol 555 no 2-3 pp 115ndash121 2007

[28] G J Siegel and N B Chauhan ldquoNeurotrophic factors inAlzheimerrsquos and Parkinsonrsquos disease brainrdquo Brain ResearchReviews vol 33 no 2-3 pp 199ndash227 2000

[29] E J Mufson S E Counts S E Perez and S D GinsbergldquoCholinergic system during the progression of Alzheimerrsquosdisease Therapeutic implicationsrdquo Expert Review of Neurother-apeutics vol 8 no 11 pp 1703ndash1718 2008

[30] X He T Yan R Chen and D Ran ldquoAcute effects of electro-acupuncture (EA) on hippocampal long term potentiation(LTP) of perforant path-dentate gyrus granule cells synapserelated to memoryrdquo Acupuncture amp Electro-TherapeuticsResearch vol 37 no 2-3 pp 89ndash101 2012

[31] J Wattanathorn and C Sutalangka ldquoLaser acupuncture at HT7acupoint improves cognitive deficit neuronal loss oxidativestress and functions of cholinergic and dopaminergic sys-tems in animal model of parkinsonrsquos diseaserdquo Evidence-basedComplementary and Alternative Medicine vol 2014 Article ID937601 8 pages 2014

[32] X Lai J Ren Y Lu et al ldquoEffects of acupuncture at HT7 onglucose metabolism in a rat model of Alzheimerrsquos disease An18F-FDG-PET studyrdquo Acupuncture in Medicine vol 34 no 3pp 215ndash222 2016

[33] Y Cayir G Ozdemir M Celik et al ldquoAcupuncture decreasesmatrix metalloproteinase-2 activity in patients with migrainerdquoAcupuncture in Medicine vol 32 no 5 pp 376ndash380 2014

[34] D Xiao ldquoAcupuncture for Parkinsonrsquos Disease a review ofclinical animal and functional Magnetic Resonance Imagingstudiesrdquo Journal of Traditional Chinese Medicine vol 35 no 6pp 709ndash717 2015

[35] Y Huang C Tang S Wang et al ldquoAcupuncture regulates theglucose metabolism in cerebral functional regions in chronicstage ischemic stroke patientsmdasha PET-CT cerebral functionalimaging studyrdquo BMCNeuroscience vol 13 no 1 article 75 2012

[36] L Lu X G Zhang L L Zhong et al ldquoAcupuncture forneurogenesis in experimental ischemic stroke a systematicreview andmeta-analysisrdquo Scientific Reports vol 6 no 1 ArticleID 19521 2016

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


technique than MA An important advantage of EA is thatit combines the beneficial effects of transcutaneous electricnerve stimulation and MA [3]

EA andMA have demonstrated therapeutic utility for thetreatment of AD in numerous animal studies [13ndash24] Forexample EA stimulation at GV14 and BL23 downregulatesbeta-secretase 1 (BACE1) an enzyme responsible for A120573generation in AD and increases ATP levels in the hippocam-pus of AD mice [14] MA stimulation at ST36 alleviatesglycerol metabolism in a rat model of AD generated by D-galactose injection [22] Studies suggest that acupuncturehas positive effects on cognition in AD and dementia bymodulating neuronal signaling pathways These pathways[13 17 19 20 22 24] include those related to apoptosiscell survival and glucose metabolism and are suggested tomediate the beneficial effects of acupuncture on cognitive andphysiological functions in animal models Moreover studiessuggest that specific acupoints may exert specific therapeuticeffects

While several reviews have summarized data gleanedfrom studies in animal models of AD no previous reviewhas summarized the relationships between acupuncture stim-ulation at specific acupoints and their therapeutic effects inAD Here we review recent animal studies supporting theuse of acupuncture as an effective therapeutic tool in AD andhighlight specific acupoints that have demonstrated utility fortargeting the neuropathological mechanisms of AD

2 Effects of Acupuncture on AD

21 Electroacupuncture EA has been widely used in moderninvestigations of acupuncture because it can be standardizedin terms of frequency voltage and duration [3] Severalstudies have suggested that EA stimulation produces cog-nitive improvements and positive changes in AD-relatedpathology in rodent disease models [14ndash18 20 21 23 24]For EA acupoints GV14 (Daechu) and BL23 (Sinsu) arethe most well studied in animal models of AD (Figure 1)Multipoint EA stimulation at GV14 and BL23 significantlydecreases hippocampal A120573 accumulation in senescenceaccelerated mouse-prone8 (SAMP8) transgenic mice [14]which is an AD-like model characterized by cortical andhippocampal A120573 accumulation [13 14] Another importantprotein implicated in AD is 51015840 adenosine monophosphate-activated protein kinase (AMPK) which serves as a masterregulator of cellular energy homeostasis and thus glucoseand lipid metabolism [14] Activation of AMPK represses tauphosphorylation and A120573 production The phosphorylation-dependent activation of AMPK is increased in SAMP8 miceafter EA at GV14 and BL23 [14] suggesting that EA at theseacupoints may affect glucose metabolism and ATP synthesisin the AD brain Consistent with this suggestion EA stimu-lation at GV14 and BL23 increases cortical and hippocampalATP levels in SAMP8 mice Cortical and hippocampal Sir-tuin1 (SIRT1) and peroxisome proliferator-activated receptor120574 coactivator 1-120572 (PGC1-120572) were also upregulated and PGC1-120572 acetylation was decreased in SAMP8 mice after GV14 andBL23EA stimulation [15] In another study by the same group

BL23

ST36

SP6HT7

GV14GV20

GV26

EX-HN3

Figure 1 Standard acupuncture acupoint locations in mouse and ratGV26 is located at the junction of the upper and middle third of thephiltrumGV20 is located on themidline between the top of the earsGV14 is located below the spinous process of the seventh vertebraeat the approximate level of the shoulders BL23 is located on theposterior midline at the level of the lower border of the spinousprocess of the second lumbar vertebra HT7 is located on the wrist atthe ulnar end of the transverse crease of the wrist in the depressionon the radial side of the tendonmusculus flexor carpi ulnaris ST36 islocated below the lower border of the patella one finger width lateralfrom the anterior border of the tibia SP6 is located on the insideof the leg just above the ankle EX-HN3 is located on the anteriormidline between the eyes Anatomical locations of the stimulatedacupuncture points inmice and ratswere equivalent to the acupointsin humans [11 12] The location of EX-HN3 was determined inaccordancewith theNationalAcupuncture Society for ExperimentalResearch ldquoLaboratory Animal Acupuncture Atlasrdquo

EA at GV14 and BL23 reduced A120573 generation and downreg-ulated BACE1 in the hippocampus of SAMP8 mice whichwas associated with improvements in spatial learning andmemory (Table 1) [16] In summary concurrent stimulationof GV14 and BL23 may regulate glucose metabolism ATPsynthesis and A120573 generation to improve AD-like symptomsin SAMP8 mice

GV20 (Baekhoe) has been used for single acupointtherapy in animal models of AD (Figure 1) EA stimu-lation at GV20 in APPPS1 transgenic mice expressing achimeric mousehuman amyloid precursor protein (APP)and a mutant human presenilin 1 (PS1) significantly amelio-rated learning and memory deficits [20 21] Studies suggeststhat brain-derived neurotrophic factor (BDNF) is a criticalfactor in adult neurogenesis and memory [26 27] which isdeficient in patients with AD [28] GV20 stimulation wasfound to upregulate BDNF in the hippocampus and cortex ofAPPPS1 transgenic mice [20 21] Moreover mature BDNFand pro-BDNF expression the BDNFpro-BDNF ratio andtropomyosin receptor kinase (Trk) phosphorylation wereenhanced by EA at GV20 inAPPPS1mice [21] Furthermoreit was found that GV20 stimulation increased neurogenesis[20] and decreased neuronal apoptosis [21] in the APPPS1mouse brain Taken together it can be hypothesized thatGV20 promotes BDNF signaling to enhance neurogenesisand decrease cell death in the APPPS1 brain EA stimulationat GV20 has also been reported to affect glial fibrillary acidicprotein (GFAP) and N-myc downstream-regulated gene 2(NDRG2) signaling in the APPPS1 mouse brain GFAP and




EA



minus2Hz 1mA




MA


















3 Conclusion







Acknowledgments


References













































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















EA



minus2Hz 1mA




MA


















3 Conclusion







Acknowledgments


References













































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















3 Conclusion







Acknowledgments


References













































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















reviewarticle - hindawi publishing...

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