Acupuncture for Parkinson’s Disease: Efficacy Evaluation and Mechanisms in the Dopaminergic Neural Circuit

Table 2

The neuroprotective mechanisms of acupuncture in the treatment of Parkinson’s disease.

Study	PD model	Intervention	Acupoints	Acupuncture parameters	Behavioral measurements	Biochemical measurements
Hong et al. (2010) [49]	MPTP mice	MA	GB34	Turned at a rate of two spins per second for 15 s	—	Grm5↓, Itpr1↓, Itpr2↓, Pde1c↓, Prkcb1↓, Plcb4↓, Atp2b3↓, Slc8a3↑, Htr5a↑, Adcy1↑, Drd5↓, Npy1r↓, Gpr156↓, Cxcl10↓, Rxfp2↑, Agtrl1↑, Inhbb↓, Cxcl5↓, IL21↓, Cox6a1↓, Uqcrq↓, Ndufc1↓, Atp5e↓, Mapt↓, Ngfr↓, Nefh↓
Choi et al. (2011) [50]	MPTP mice	MA	GB34, LR3	Turned at a rate of two spins per second for 15 s	—	TH levels in the ST and the SNpc↑, DAT↑, Ctla2a↓, EG383229↓, Ppbp↓, Ube2l6↓, EG665033↑, ENSMUSG00000055323↑, Obox6↑, Pbp2↑, Tmem150↑
Yeo et al. (2013) [51]	MPTP mice	MA	GB34, LR3	Turned at a rate of two spins per second for 15 s	—	TH in the ST, SNpc, and thalamus↑, Dusp4↑, Mafg↑, Pgm5↑, Ndph↑, Dnase1l2↑, Ucp2↓, Sp2↓, Serinc2↓
Yeo et al. (2015) [39]	MPTP mice	MA	GB34, LR3	Turned at a rate of two spins per second for 15 s	—	TH in the ST and SNpc↑, Cdh1↓, Slc6a13↓, Tph2↓, Mpzl2↓, Serping1↓, Itih2↓, Slc6a20a↓, Slc6a4↓, Ucma↓, Rdh9↓, 4921530L21Rik↑, Gm13931↑
Jeon et al. (2008) [52]	MPTP mice	EA	GB34	2/100 Hz, 1 mA for 20 minutes	Pole test: time on the pole↓	TH-positive cells in the SN↑, CyPA in the SN↑, MBP↑, Ube2N↑, LMP6↑, LMP2↑, lipocalin/cytosolic fatty acid-binding protein↑, eIF5A↑, CLP↑, ATPase, H1-transporting V1 subunit F↑, NSF↑
Wang et al. (2013) [53]	MPTP mice	EA	ST36, SP6	0/100 Hz, 1-1.25-1.5 mA for 30 minutes	Open-field test: total movement time↓, movement velocity↓, total movement distance↓	—
Kim et al. (2005) [54]	6-OHDA rats	MA	ST36	Left in acupoint for 20 minutes	Rotational behavior test: the average net number of turns/min↓	The survival rate of TH-positive neurons↑, the density of TH-positive fibers↑
Yang et al. (2011) [55]	MPTP mice	RA/EA	PC7	Left in acupoint for 15 minutes/2 and 15 Hz, alternatively, 1 mA for 15 minutes	Pole test: descending time↓	TH-positive neurons (RA)↑, DA in the SN↓, the intensity of radionuclide or radiopharmaceutical uptake (RA)↑, the peak time of [^123I]IBZM uptake (RA)↓, HVA concentration in the SN (EA)↓
Yeo and Lim (2019) [56]	MPTP mice	MA	GB34, LR3	Turned at a rate of two spins per second for 15 s	—	TH in the ST and SNpc↑, α-syn in the SN↓, SGK1↑
Yeo et al. (2020) [57]	MPTP mice	MA	GB34, LR3	Turned at a rate of two spins per second for 15 s	—	TH in the ST and SNpc↑, α-syn in the ST and SN↓, p-α-syn 32↓, p-α-syn 16↓, p-α-syn 32/total α-syn values↑
Tian et al. (2016) [58]	MPTP mice	MA	GB34	Turned at a rate of two spins per second for 15 s, retained for 10 minutes	Rotarod test: the ORP scores↑	α-syn in the SNpc↓, autophagosome accumulation↓, LC3-II↓, LAMP1↓, the number and function of DA neurons↑, density of TH-positive neurons in the SNpc and ST↑, DA concentration↑, synaptophysin protein↑
Wang et al. (2018) [59]	Rotenone rats	Moxibustion	ST36, CV4, GV16	Placed 2-3 cm above each acupoint, retained for 10 minutes	Behavioral scoring [60]↓	TH-immunoreactive neurons↑, α-syn-positive aggregates↓, p-mTOR and p-p70S6K in the SNpc↓, LC3-II in the SNpc↑
Song et al. (2020) [37]	MPTP mice	Acupoint injection	ST36	Choroid plexus cells were injected into ST36, a depth of 3 mm, maintained for 1 week	Pole test: exercise capacity↑	TH in the SNpc↑, Bax↓, cytochrome C↓, BCL-2↑, COX-2↓, iNOS↓
Park et al. (2015) [61]	MPTP mice	MA	GB34	Turned at a rate of two spins, per second for 15 s	Rotarod test: latency time↑; cylinder test: the number of wall touches↑	TH-positive neurons in the SN↑, TH-positive fibers↑, 40 of 76 differentially expressed genes are involved in the p53 signaling network
	MPTP+P53 knockout mice	MA	GB34	Turned at a rate of two spins, per second for 15 s	—	TH-positive cells and fibers slightly↑
Doo et al. (2010) [62]	MPTP mice	BVA	GB34	—	—	TH-positive neurons in the SN↑, DA fibers in the ST↑, p-c-Jun-positive cells in the SN↓
Liang et al. (2002) [63]	MFB rats	EA	GV14, GV20	2/100 Hz, 1-2-3 mA for 30 minutes	—	TH-positive neurons on the lesion side↑, BDNF mRNA expression on the lesioned side of the VTA (100 Hz)↑, BDNF mRNA in the SNpc (100 Hz)↑
Wang et al. (2013) [64]	Rotenone rats	EA	GV16, LR3	100 Hz, 1-1.25-1.5 mA for 30 minutes	—	BDNF mRNA expression in the SN↑, GDNF mRNA expression in the SN↑
Liang et al. (2003) [48]	MFB rats	EA	GV14, GV20	2/100 Hz, 1-2-3 mA for 30 minutes	Rotational behavior test: day 14 the average net number of turns/min↓, day 28 the average net number of turns/min (100 Hz)↓	GDNF mRNA-positive cells in the SNpr (100 Hz)↑, GDNF mRNA expression in the GP of the unlesioned side (2 Hz)↑, GDNF mRNA level in both the lesioned and unlesioned side of GP (100 Hz)↑
Jang et al. (2020) [65]	MPTP mice	MA	GB34, ST36	Turned at a rate of two spins per second for 30 s	Cylinder test: the number of wall touches↑; rotarod test: latency time↑; akinesia test: latency time↓; open-field test: the total distance↑, central distance↑, the ratio of central/total distance↑, the number of crossings in the central zone↑	Dopaminergic fibers and neurons in the ST and SN↑, TH-positive neurons in the ST and SN↑, TH in the ST and SN↑, Bax↓, Bcl-2↑, GFAP↓, Iba-1↓, NF-κB↓, TNF-α↓, the Chao1 index↑, the number of observed OTUs↑, the Shannon index↑, Rikenellaceae↑, Vallitaleaceae↑, Alistipes↑, Vallitalea↑, Lachnoclostridium↑, Pseudoclostridium↑, Bacteroides xylanolyticus↑, Vallitalea pronyensis↑, Clostridium aerotolerans↑, Pseudoclostridium thermosuccinogenes↑, Roseburia faecis↑, holdemania↓, frisingicoccus↓, aestuariispira↓, sporobacter↓, rhodospirillum↓, Bifidobacterium↓, turicibacter↓, marvinbryantia↓, desulfovibrio↓, phascolarctobacterium↓, erysipelatoclostridium↓, butyricimonas↑, gracilibacter↑, phocea↑, desulfitobacterium↑, oscillibacter↑, acutalibacter↑, flintibacter↑, photosynthesis↑, glutathione metabolism↑, tetracycline biosynthesis↑, photosynthetic proteins↑, methane metabolism↓, drug metabolism↓
Park et al. (2003) [66]	6-OHDA rats	MA	Acu1: GB34, LR3; Acu2: LI4, LI11	Turned at a rate of two spins per second for 15 s, retained for 60 s	Rotational behavior test: the average net number of turns/min (Acu1)↓	TH-immunoreactive neurons in the ipsilateral SN (Acu1)↑, TH-immunoreactive terminals in the dorsolateral ST ipsilateral to the lesion (Acu1)↑, TrkB-positive cells in the SN (Acu1)↑
Lin et al. (2017) [67]	MPTP rats	EA	GB34, LR3	0/50 Hz, 1 mA for 20 minutes	Rotarod test: day 9 latency time↑; rotational behavior test: the average net number of turns/min↓	DA content in the ST↑, TH-positive neurons in the SN↑, degeneration in the ST↓, DA depletion in the ipsilateral side↓, mature BDNF, Bcl-2 and TH levels in the ipsilateral side↑, pAkt↑
Zhao et al. (2019) [68]	MFB rats	EA	GV20, GV29	2 Hz, 1.5 mA for 10 minutes	Rotarod test: latency time↑; tail suspension test: the immobility time↓	TH in the midbrain↑, BDNF^+ cells↑, pAkt↑, pERK↑, functional TrkB FL↑, the ratio of TrkB FL/TrkB T1↑
	MFB rats	EA+K252a injection	GV20, GV29	2 Hz, 1.5 mA for 10 minutes	Rotarod test: latency time↓; tail suspension test: the immobility time↑	TH in the midbrain↓, BDNF^+ cells↓, pAkt↓, pERK1/2↓
Kim et al. (2011) [69]	MPTP mice	MA	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↑, the ORP scores↑	pAkt↑
	MPTP mice	MA+LY294002	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↓, the ORP scores↓	pAkt↓, TH-positive dopaminergic neurons in SN↓, TH-positive dopaminergic fibers in ST↓
Hwang et al. (2019) [70]	MPTP mice	MA+Chunggan formula	GB34	Turned at a rate of two spins per second for 30s	Rotarod test: latency time↑; cylinder test: the number of wall touches↑; pole test: descending times↓	TH-positive dopaminergic neurons in the SNpc↑, TH protein in the SNpc and ST↑, pIκBα↓, pAkt↑, pGSK3β↑, pERK↑, pCREB↑, BDNF↑
Jeon et al. (2017) [71]	MPTP mice	MA	Acu1: GB34; Acu2: HT7	Turned at a rate of two spins per second for 30 s	Pole test: day 5 descending times (GB34)↓, day 12 descending times↓	TH-positive cells in the SN (GB34)↑, TH immunoreactivity in the ST (GB34)↑, BrdU-positive cells in the SVZ (GB34)↑, BrdU/DCX-double stained cells in the SVZ↓, BrdU/GFAP-double stained cells in the SVZ (GB34)↑, GFAP-positive cells in the ST↑
Yu et al. (2010) [38]	6-OHDA rats	MA	GB34, LR3, ST36, SP10	Left in acupoints for 20 minutes	Rotational behavior test: the average net number of turns/min↓	SOD↑, GSH-Px↑, GSH↑, MDA↓
Wang et al. (2011) [47]	MPTP mice	EA	ST36, SP6	0/100 Hz, 1-1.25-1.5 mA for 30 minutes	—	TH immunoreactivity↑, day 3 DA, DOPAC, and HVA in the ST↑, H2O2 content in the ST↓, day 3 GSH content↑, days 3 and 7 GSH-Px↓, days 7 and 14 SOD activity↑, day 7 MDA content in the ST↓
Lee et al. (2018) [72]	MPTP mice	MA	Acu1: GB34; Acu2: SI3	Turned at a rate of two spins per second for 30 s	Pole test: descending times (GB34)↓	TH-positive neurons in the SN (GB34)↑, caspase-3 in the ST (GB34)↓, DJ-1 in the ST (GB34)↑, SOD activity (GB34)↑, CAT activity (GB34)↑
Kang et al. (2007) [73]	MPTP mice	MA	GB34, LR3	Turned at a rate of two spins per second for 15 s	—	TH-immunoreactive in the ST↑, TH-positive neurons in the SN↑, MAC-1↓, COX-2↓, iNOS↓, DA, DOPAC, and HVA in the ST↑
Li et al. (2019) [74]	6-OHDA rats	MA	CV12, ST25, CV4	Left in acupoints for 15 minutes	Rotational behavior test: the average net number of turns/min↓	TH-positive neurons in the SN↑, TNF-α↓, IL-1β↓, Fe levels↓, ratio of Fpn1/DMT1 mRNA↓, α-syn in the duodenum↓
Yang et al. (2017) [75]	MPTP mice	MA	GB34	Turned at 2 Hz for 15 s	—	NS
Kim et al. (2019) [76]	Pitx3-deficient ak/ak mice	MA+L-DOPA	GB34	Turned at a rate of two spins per second for 15 s	Three-paw dyskinesia test, abnormal three-paw movements↓; AIM scores↓	Pmch↑, Tac2 mRNA↑, Lcn2 mRNA↑
	Pitx3-deficient ak/ak mice	MA+L-DOPA+TC-MCH7c	GB34	Turned at a rate of two spins per second for 15 s	Three-paw dyskinesia test: abnormal three-paw movements↑	—
	6-OHDA mice	MA+L-DOPA	GB34	Turned at a rate of two spins per second for 15 s	AIM scores↓	Pmch↑
Wattanathorn and Sutalangka (2014) [77]	6-OHDA rats	Laser acupuncture	HT7	Continuous blue laser beam, wavelength of 405 nm, output power 100 mW, a spot diameter of 500 μm for 10 minutes	Morris water maze: escape latency (days 7 and 14)↓, retention time (day 14)↑	Neuron density in CA3 and dentate gyrus↑, AChE in the hippocampus↓, MAO-B activity in the hippocampus↓, GSH-Px activity in the right SN↑, MDA in the right SN↓
Park et al. (2017) [78]	MPTP mice	MA	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↑; cylinder test: the number of wall touches↑	TH-positive neurons in the SN↑, dopaminergic fibers in the ST↑, Pmch in the hypothalamus↑, double-labeled c-Fos^+/MCH^+ cells↑, MCH concentration in the SN↑, the expression levels of TH and synaptophysin in the SN↑, pAkt↑, and pCREB↑
	MPTP mice	MA+TC-MCH7c	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↓; cylinder test: the number of wall touches↓	TH-positive neurons in the SN↓, dopaminergic fibers in the ST↓
	Pitx3^−/+ mice	MA	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↑	—
	Pitx3^−/+ mice	MA+TC-MCH7c	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↓	—
	A53T Tg mice	MA	GB34	Turned at a rate of two spins per second for 15 s	Rotarod test: latency time↑; cylinder test: the number of wall touches↑	pGSK-3β and pAMPK in the SN↑, BDNF expression in the SN↑, synuclein expression in the SN↓

MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MA: manual acupuncture; GB34: Yanglingquan; Grm5: glutamate receptor metabotropic 5; Itpr1: inositol 1,4,5-triphosphate receptor 1; Itpr2: inositol 1,4,5-triphosphate receptor 2; Pde1c: phospho-diesterase 1C; Prkcb1: protein kinase beta 1; Plcb4: phospholipase C beta 4; Atp2b3: ATPase calcium-transporting plasma membrane 3; Slc8a3: solute carrier family 8, sodium/calcium exchange member 3; Htr5a: 5-hydroxytryptamine (serotonin) receptor 5A; Adcy1: adenylate cyclase 1; Drd5: dopamine receptor 5; Npy1r: neuropeptide Y receptor Y1; Gpr156: G protein-coupled receptor 156; Cxcl10: chemokine (C–X–C motif) ligand 10; Rxfp2: relaxin/insulin-like family peptide receptor 2; Agtrl1: angiotensin receptor-like 1; Inhbb: inhibin beta-B; Cxcl5: chemokine (C–X–C motif) ligand 5; IL21: interleukin 21; Cox6a1: cytochrome c oxidase, subunit VI a, polypeptide 1; Uqcrq: ubiquinol-cytochrome c reductase, complex III subunit VII; Ndufc1: NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 1; Atp5e: ATP synthase, epsilon subunit; Mapt: microtubule-associated protein tau; Ngfr: nerve growth factor receptor (TNFR superfamily, member 16); Nefh: neurofilament, heavy polypeptide; LR3: Taichong; TH: tyrosine hydroxylase; ST: striatum; SNpc: substantia nigra pars compacta; DAT: dopamine transporter; Ctla2a: cytotoxic T lymphocyte-associated protein 2 alpha; EG383229: predicted gene EG383229; Ppbp: proplatelet basic protein; Ube2l6: ubiquitin-conjugating enzyme E2L 6; EG665033: predicted gene EG665033; ENSMUSG00000055323: predicted gene ENSMUSG00000055323; Obox6: oocyte-specific homeobox 6; Pbp2: phosphatidylethanolamine-binding protein 2; Tmem150: transmembrane protein 150; Dusp4: dual specificity phosphatase 4; Mafg: v-maf musculoaponeurotic fibrosarcoma oncogene family, protein G; Pgm5: phosphoglucomutase 5; Ndph: Norrie disease homolog; Dnase1l2: deoxyribonuclease 1-like 2; Ucp2: uncoupling protein 2; Sp2: Sp2 transcription factor; Serinc2: serine incorporator 2; Cdh1: cadherin 1; Slc6a13: solute carrier family 6 (neurotransmitter transporter, GABA), member 13; Tph2: tryptophan hydroxylase 2; Mpzl2: myelin protein zero-like 2; Serping1: the serine (or cysteine) peptidase inhibitor, clade G, member 1; Itih2: interalpha trypsin inhibitor, heavy chain 2; Slc6a20a: SLC6 (neurotransmitter transporter), member 20A; Slc6a4: SLC6 (neurotransmitter transporter, serotonin), member 4; Ucma: upper zone of growth plate and cartilage matrix associated; Rdh9: retinol dehydrogenase 9; 4921530L21Rik: RIKEN cDNA 4921530L21 gene; Gm13931: predicted gene 13931; EA: electroacupuncture; CyPA: cyclophilin A; MBP: myelin basic protein; Ube2N: ubiquitin-conjugating enzyme E2N; LMP6: proteasome subunit C7-I; LMP2: 20S proteasome subunit; eIF5A: eukaryotic translation initiation factor 5A; CLP: coactosin-like protein; NSF: N-ethylmaleimidesensitive fusion protein; ST36: Zusanli; SP6: Sanyinjiao; 6-OHDA: 6-hydroxydopamine; LI4: Hegu; RA: retained acupuncture; PC7: Daling; DA: dopamine; [¹²³I] IBZM: [¹²³I] iodobenzamide; HVA: homovanillic acid; α-syn: α-synuclein; SGK1: serum/glucocorticoid-regulated kinase 1; p-α-syn: phosphorylated α-synuclein; ORP: overall rod performance; LC3-II: microtubule-associated protein 1 light chain 3 II; LAMP1: lysosome-associated membrane protein 1; CV4: Guanyuan; GV16: Fengfu; p-mTOR: phosphorylated mammalian target of rapamycin; p-p70S6k: phosphorylated ribosomal protein S6 kinase; BVA: bee venom acupuncture; Bax: Bcl-2-associated X protein; MDA: malondialdehyde; GSH: glutathione; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; Bcl-2: B cell lymphoma-2; GFAP: glial fibrillary acidic protein; Iba-1: ionized calcium-binding adaptor molecule-1; NF-κB: nuclear factor kappa-B; OTUs: operational taxonomic units; COX-2: cyclooxygenase; iNOS: inducible NO synthase; p-c-Jun: phosphorylated c-Jun kinase; MFB: medial forebrain bundle; GV14: Dazhui; GV20: Baihui; BDNF: brain-derived neurotrophic factor; VTA: ventral tegmental area; GDNF: glial cell-derived neurotrophic factor; SNpr: substantia nigra pars reticulata; GP: globus pallidus; LI11: Quchi; TrkB: tyrosine kinase receptor B; GV29: Yintang; PKB/Akt: protein kinase B; p-Akt: phosphorylated Akt; pERK: phosphorylated extracellular-regulated protein kinase; TrkB FL: full-length TrkB; TrkB T1: splicing truncated isoforms TrkB; pIκBα: phosphorylated inhibitor kappa B alpha; pGSK3β: phosphorylated glycogen synthase kinase 3β; pCREB: phosphorylated cAMP-response element-binding protein; HT7: Shenmen; BrdU: 5-bromo-2-deoxyuridine; SVZ: subventricular zone; DCX: doublecortin; SP10: Xuehai; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; DOPAC: dihydroxyphenylacetic acid; SI3: Houxi; CAT: catalase; MAC-1: macrophage antigen complex-1; CV12: Zhongwan; ST25: Tianshu; Fpn1: ferroportin1; DMT1: recombinant divalent metal transporter 1; NS: no significance; L-DOPA: levodopa; AIM: abnormal involuntary movement; Pmch: pro-melanin-concentrating hormone; Tac2: tachykinin 2; Lcn2: lipocalin 2; CA3: the CA3 region of the hippocampus; AChE: acetyl cholinesterase; MAO-B: monoamine oxidase-B; MCH: melanin-concentrating hormone; pAMPK: phosphorylated cAMP-response phosphorylated adenosine 5-monophosphate-activated protein kinase.