Table 1.

Signal transduction pathways of acupuncture in treating cerebral ischemic injury.

Subjects	Location	Acupoint	Intervention	Time of intervention	Signal pathway	Main results	Author, reference
Male, SD rats, MCAO	brain	GV20	EA, 3mA, 2/20Hz	30min, QOD for 14 days	increase expression of BDNF/TrkB	elevation of BDNF neuron proliferation	Kim MW, et al. 2012[28]
Male, postnatal SD rats, MCAO	hippocampus	GV20, GV14	EA, 2Hz	20min, QD for 10 days	increase VEGF and BDNF levels	proliferation and differentiation of neuronal stem cells	Kim YR, et al. 2014[27]
Male, postnatal SD rats, CCAO	hippocampus	GV20, Ex-HN 1	MA, 2Hz for 15 sec	30min/time, 3 times	increase GDNF and BDNF levels	antiapoptosis	Zhang Y, et al. 2015[19]
Either sex, SD rats, CCAO combination with hypoxic treatment	cerebral cortex	MA: GV 20, GV 14, LI 11, KI 1 EA: GV 14, LI 11	MA and EA, 1mA, 1/20 Hz	10 min, QD	activation of GDNF/RET/Akt pathway	neuroprotection	Xu T, et al. 2016[25]
Male, SD rats, MCAO	brain	GV20	EA, 1 mA, 2/15 Hz	30min	activation of ERK1/2 pathway	elevation of CB1 neuroprotection	Du J et al. 2010[32]
Male, SD rats, MCAO	brain	ST36, LI11	EA, 1/20 Hz	30 min, QD	activation of the ERK pathway	elevation of Ras, cyclin D1 and CDK4 neural cell proliferation	Xie G, et al. 2013[33]
Male, SD rats, MCAO	brain	GV 20, GV14	EA,2.7-3.0 mA, 5Hz	25min, QD for 2 days	activation of MAPK/ERK kinase, ERK1/2 pathway	elevation of BDNF, pRaf-1, pp90RSK, pBad depression of caspase-3 protein neuroprotection	Cheng CY, et al. 2014[34]
Male, SD rats, MCAO	brain	LI11, ST36	EA, 1-20 Hz	30min, QD for 3 days	activation of the ERK1/2 pathway	elevation of p21 or p27 depression of cyclin D1, CDK4, cyclin E and CDK2 neural cell proliferation	Huang J, et al. 2014[29]
Male, SD rats, MCAO	hippocampus	LU5, LI4, ST36, SP6	EA, 2mA, 2/15 Hz	20 min, QD for 3 days	activation of the ERK pathway	antiapoptosis	Wu C, et al. 2015[35]
Male, SD rats, MCAO	brain	LU5, LI4, ST36, SP6	EA,2 mA, 2/15Hz	20min, QD for 3 days and 7 days	activation of ERK pathway	antiapoptosis	Wu C, et al. 2017[36]
Male, SD rats, ligation of common carotid artery and external carotid artery	hippocampus	LU5, LI4, ST36, SP6	EA, 2/50 Hz	20 min, QD	regulation of p38 MAPK signal pathway	depression of phosphorylated p38 MAPK antiapoptosis	Lan X, et al. 2017[41]
Male, SD rats, MCAO	brain	GV20, GV14, GV26	MA	30min/time, 7 times	Inactivation of MAPK/ERK pathway	elevation of Bcl-2 depression of Bax anti-apoptosis	Lin Y, et al. 2017[42]
Male, SD rats, MCAO	brain	LI11, ST36	EA, 1mA, 4/20 Hz	30min, QD for 3 days	modulation of ERK/JNK/p38 signal pathway	elevation of caspase-3, growth factor midkine depression of Bcl-2 anti-apoptosis	Xing Y, et al. 2018[43]
Male, SD rats, MCAO	brain	GV20, GV24	EA, 1mA, 1/20 Hz	30 min, QD for 10 days	modulation of p38MAPK/ERK1/2/JNK pathway	elevation of ERK1/2, Bcl-2/Bax ratio depression of JNK, p38 MAPK anti-apoptosis	Liu J, et al. 2018[44]
Male, SD rats, MCAO	sensorimotor cortex	LI11, ST36	EA, 0.2mA, 1/20Hz	30 min, QD for 3 days	inactivation of NF-κB, p38 MAPK and MYD88 pathway	depression of TNF-α, IL-1β, IL-6 inhibition of microglia-mediated neuroinflammation	Liu W, et al. 2016[45]
Male, SD rats, MCAO	brain	GV20, GV16	EA, 5 Hz and 25Hz	25 min, QD	activation of p38 MAPK/CREB pathway	decrease reactive astrocytosis	Cheng CY, et al. 2015[46]
Male, Wistar rats, homologous blood emboli injection of internal carotid artery	hippocampus	ST36	MA	QD for 14 days	activation of cAMP/PKA/CREB pathway	activation of long-term potentiation	Li QQ, et al. 2015[47]
Male, SD rats, MCAO	hippocampus	GV24, GV20	EA, 1-3mA, 5/20Hz	30min, QD	increase expression of p-CREB	elevation of superoxide dismutase and glutathione peroxidase, Bcl-2 depression of malondialdehyde, Bcl2-xl anti-oxidase anti-apoptosis	Lin R, et al. 2015[48]
Male C57BL/6 mice, bilateral stenosis of the common carotid artery	corpus callosum	GV20, GV14	EA, 2Hz	20min, QD for 7 days	p-CREB pathway	oligodendrocyte regeneration	Ahn SM, et al. 2016[49]
Female, SD rats, MCAO	hippocampus	GV20, GV24	EA, 1/20Hz	30min, QD for 7 days	inactivation of CaM-CaMKIV-CREB pathway	inactivation of CaM-CaMKIV-CREB pathway	Zhang Y, et al. 2016[50]
Male, SD rats, MCAO	hippocampus	GV20, HT7	MA LA, 30 mW, 100Hz	14 days	enhance cholinergic system	elevation of CREB, BDNF, and Bcl-2 depression of Bax anti-apoptosis	Yun YC, et al. 2017[51]
Neonatal SD rats, CCAO	brain	GV20, ST36	EA, 1mA, 2Hz	20min	activation of CREB/BDNF pathway	oligodendrogenesis	Pak ME, et al. 2018[52]
Male, Wistar rats, MCAO	forebrain	GV20, GV26	EA, 3mA, 3/20Hz	60min	activation of Akt	depression of caspase-9 anti-apoptosis	Wang SJ, et al. 2002[55]
Male, SD rats, MCAO	brain	GV26, CV 24,	EA,1 mA, 4/16Hz	30min	activation of PI3K pathway	neuroprotection	Sun N, et al. 2005[56]
Male, SD rats, MCAO	brain	GV26, CV24	EA, 4/16Hz	30 min	activation of TrkA-PI3K pathway	neuroprotection	Zhao L, et al. 2007[57]
Rats, modified intravascular suture technique	hippocampus, cerebral cortex	GV26, CV 24	acupuncture	- -	activation of TrkA/PI3K pathway	depression of NO, nNOS and iNOS	Chen SX, et al. 2011[58]
Male, SD rats, MCAO	brain	LI11, ST36	EA, 1mA, 1/20 Hz	30 min, QD	activation of PI3K/Akt pathway	elevation of BDNF, GDNF, Bcl-2/Bax ratio anti-apoptosis	Chen A, et al. 2012[59]
SD rats, left common carotid artery (LCCA) ligation	cerebral cortex	GV 20, GV 14, LI 11, KI 1	MA and EA	- -	activation of PI3K/Akt pathway	neuroprotection	Xu T, et al. 2014[60]
Male, SD rats, MCAO	brain	LI11, ST36	EA, 4/20 Hz	30 min, QD for 3 days	activation of PI3K/Akt pathway	elevation of PI3K, p-Akt, p-Bad and Bcl-2 depression of Bax, caspase-3-positive expression anti-apoptosis	Xue X, et al. 2014[12]
Male, SD rats, MCAO	brain	GV20, CV6	EA,1mA, 2Hz	30min, BID	activation of PI3K/Akt pathway	depression of caspase-3, -8 and -9 anti-apoptosis	Kim YR, et al. 2013[61]
Male, SD rats, MCAO	bone marrow	GV20, LI4, LR3	EA, 3mA, 2/20Hz	30min, QD	increase expression of p-Akt protein	elevation of CD 34+ endothelial progenitor cell	Xie CC, et al. 2014[63]
Male, SD rats, MCAO	brain	LI11, ST36	EA, 0.2 mA, 1/20 Hz	30 min, QD for 3 days	activation of mTORC1-ULK1 complex-beclin1 pathway	depression of microtubule-associated protein 1 light chain 3 beta II/I, ULK1, autophagy related gene 13 and Beclin1 anti-autophagy	Liu W, et al. 2016[62]
Male, SD rats, MCAO	brain	GV20	EA, 1mA, 2/15 Hz	30 min, QD for 3 days	phosphorylation of GSK-3β	anti-apoptosis	Wei H, et al. 2014[64]
Male, SD rats, MCAO	brain	GV20	EA, 1mA, 2/15Hz	30min, QD for 5 days	decrease expression of p-Akt	elevation of claudin-5, occludin decrease blood-brain barrier disruption	Zou R, et al. 2015[65]
Male, SD rats, MCAO	brain	GV20, GV24	EA 1/20Hz	30min, QD for 10 days	inhibition of NF-κB-mediated apoptosis pathway	depression of Bax and Fas anti-apoptosis	Feng X, et al. 2013[66]
Male, SD rats, MCAO	brain	LI11, ST36	EA,0.01mA, 1/20Hz	- -	regulation of TLR4/NF-κB pathway	depression of TNF-α, IL-1β and IL-6 neuroprotection	Lan L, et al. 2013[67]

Abbreviations

- -: not mentioned; Bax: Bcl-2 associated X; Bad: Bcl-2-associated death promoter; Bcl-2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; CaMK: Ca2+/calmodulin-dependent protein kinase; cAMP: cyclic adenosine monophosphate; CB1: cannabinoid receptor type 1; CCAO: occlusion of common carotid artery; CDK: cyclin-dependent kinase; CREB: phosphorylated cyclic AMP response element-binding protein; EA: electroacupuncture; ERK: extracellular signal-regulated kinase; GDNF: glial-derived neurotrophic factor; IL: interleukin; JNK: c-Jun N-terminal kinases; MA: manual acupuncture; MAPK: mitogen-activated protein kinases; MCAO: occlusion of MCA; mTOR: mammalian target of rapamycin; MYD88: myeloid differentiation primary response 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; p38 MAPKs: p38 mitogen-activated protein kinases; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PKA: protein kinase A; pp90RSK: phospho-90 kDa ribosomal S6 kinase; QD: daily; QOD: every other day; SD rat: Sprague Dawley rat; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor-alpha; Trk: tyrosine receptor kinase; ULK: UNC-51-like kinase; VEGF: vascular endothelial growth factor.