Electroacupuncture (EA) pretreatment alleviates cerebral ischemic injury through α7 nicotinic acetylcholine receptor (α7nAChR). We attempted to investigate whether the phenotypic conversion of microglia was involved in the therapeutic effect of EA pretreatment in cerebral ischemia through α7nAChR. Adult male Sprague–Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) after EA or α7nAChR agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide hydrochloride (PHA-543,613 hydrochloride) and antagonist α-bungarotoxin (α-BGT) pretreatment. Primary microglia were subjected to drug pretreatment and oxygen-glucose deprivation (OGD). The expressions of the classical activated phenotype (M1) microglia markers induced nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and cluster of differentiation 86 (CD86); the alternative activated phenotype (M2) microglia markers arginase-1 (Arg-1), transforming growth factor-β1 (TGF-β1), and cluster of differentiation 206 (CD206); and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) in the ischemic penumbra or in the supernatant of primary microglia were analyzed. The infarction volume and neurological scores were assessed 72 h after reperfusion. The cell viability and lactate dehydrogenase (LDH) release of neurons co-cultured with microglia were analyzed using cell counting kit-8 (CCK-8) and LDH release assays. EA pretreatment decreased the expressions of M1 markers (iNOS, IL-1β, and CD86) and pro-inflammatory cytokines (TNF-α and IL-6), whereas it increased the expressions of M2 markers (Arg-1, TGF-β1, and CD206) and anti-inflammatory cytokines (IL-4 and IL-10) by activating α7nAChR. EA pretreatment also significantly reduced the infarction volume and improved the neurological deficit. The activation of α7nAChR in microglia relieved the inflammatory response of primary microglia subjected to OGD and attenuated the injury of neurons co-cultured with microglia. In conclusion, EA pretreatment alleviates cerebral ischemic injury through α7nAChR-mediated phenotypic conversion of microglia, which may be a new mechanism for the EA pretreatment-induced neuroprotection against cerebral ischemia.

Xingnao Kaiqiao (XNKQ) acupuncture is an acupuncture technique used for stroke patients. In 24 healthy volunteers, we applied this complex acupuncture intervention, which consists of a manual needle-stimulation on five acupuncture points (DU26 unilaterally, PC6, and SP6 bilaterally). XNKQ was compared to three control conditions: (1) insertion of needles on the XNKQ acupuncture points without stimulation, (2) manual needle-stimulation on five nearby non-acupuncture points, and (3) insertion of needles on the non-acupuncture points without stimulation. In a within-subject design, we investigated functional connectivity changes in resting-state functional magnetic resonance imaging (fMRI) by means of the data-driven eigenvector centrality (EC) approach. With a 2 × 2 factorial within-subjects design with two-factor stimulation (stimulation vs. non-stimulation) and location (acupuncture points vs. non-acupuncture points), we found decreased EC in the precuneus after needle-stimulation (stimulation<non-stimulation), whereas the factor location showed no statistically significant EC differences. XNKQ acupuncture compared with needle-stimulation on non-acupuncture points showed decreased EC primarily in subcortical structures such as the caudate nucleus, subthalamic nucleus, and red nucleus. Post-hoc seed-based analysis revealed that the decrease in EC was mainly driven by reduced temporal correlation to primary sensorimotor cortices. The comparison of XNKQ acupuncture with the other two (non-stimulation) interventions showed no significant differences in EC. Our findings support the importance of the stimulation component of the acupuncture intervention and hint toward the modulation of functional connectivity by XNKQ acupuncture, especially in areas involved in motor function. As a next step, similar mechanisms should be validated in stroke patients suffering from motor deficits.

ClinicalTrials.gov ID: NCT02453906

Acupuncture is widely applied all over the world. Although the neurobiological underpinnings of acupuncture still remain unclear, accumulating evidence indicates significant alteration of brain activities in response to acupuncture. In particular, activities of brain regions in the default mode network (DMN) are modulated by acupuncture. DMN is crucial for maintaining physiological homeostasis and its functional architecture becomes disrupted in various disorders. But how acupuncture modulates brain functions and whether such modulation constitutes core mechanisms of acupuncture treatment are far from clear. This Perspective integrates recent literature on interactions between acupuncture and functional networks including the DMN, and proposes a back-translational research strategy to elucidate brain mechanisms of acupuncture treatment.