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, 41 (6), 3307-3315

Effect of Electro-Acupuncture on the BDNF-TrkB Pathway in the Spinal Cord of CCI Rats

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Effect of Electro-Acupuncture on the BDNF-TrkB Pathway in the Spinal Cord of CCI Rats

Wen-Zhan Tu et al. Int J Mol Med.

Abstract

Microglia, which comprise a sensor for pathological events in the central nervous system, may be triggered by nerve injury and transformed from a quiescent state into an activated state; ionised calcium binding adaptor molecule 1 (Iba1) is a sensitive marker associated with activated microglia. Accumulated evidence suggests that spinal activated microglia and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signalling pathway play major roles in the production and development of neuropathic pain. Electro-acupuncture (EA) has a positive effect on relieving chronic neuropathic pain; however, the underlying mechanisms remain unclear. To determine the significance of EA in the treatment of neuropathic pain mediated by activated microglia and the BDNF-TrkB signalling pathway in the spinal cord, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values were recorded to assess hyperalgesia and allodynia. In addition, the amount of activated microglia and BDNF were assessed via immunofluorescence. Iba1, BDNF and TrkB mRNA expression levels were examined using qPCR; the protein levels of BDNF, p-TrkB and TrkB in the spinal cord were analysed via western blotting. The present study demonstrated that EA treatment increased the MWT and TWL values. EA significantly inhibited the proportion of activated microglia and BDNF expression in the spinal cord after chronic constrictive injury (CCI). Furthermore, EA decreased the expression of BDNF and TrkB at both the mRNA and protein levels in the spinal cord of CCI rats. These findings suggest that the analgesic effect of EA may be achieved by inhibiting the activation of spinal microglia and subsequently blocking the BDNF-TrkB signalling pathway.

Figures

Figure 1
Figure 1
(A and B) Showed the locations of the 'Zusanli' (ST-36) and 'Yanglingquan' (GB-34) acupoints.
Figure 2
Figure 2
Rat immobilization apparatus designed by our laboratory was comfortable to experimental animals which can reduce stress and is very convenient for acupuncture research.
Figure 3
Figure 3
Analgesic effects of electro-acupuncture (EA) treatment on mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in rats with chronic sciatic nerve constriction (n=15). The (A) MWT and (B) TWL in each group were recorded and compared among groups. There was no significance among the four groups before surgery; ***P<0.001 vs. the sham group; &&&P<0.001 vs. the chronic constrictive injury (CCI) group.
Figure 4
Figure 4
Chronic constrictive injury (CCI) induces microglia activation subsequent to the release of microglia brain-derived neurotrophic factor (BDNF). (A) White rectangle was the dorsal horn of the injured side of the spinal cord, immunofluorescence showed the amount of ionised calcium binding adaptor molecule 1 ionised calcium binding adaptor molecule 1 (Iba1) in the injured ipsilateral side relative to the contralateral, Iba1 was the marker for microglia. Scale bar, 200 µm. (B) Compare the expression of Iba1 in the injury ipsilateral side among the four groups, Scale bar, 100 µm. (C) Representative photomicrographs of immunofluorescence showed colocalization of Iba1 (green, the arrows stand for Iba1+ cells, represent activated microglia) and BDNF (red, the arrows represent BDNF+ cells released from activated microglia, the white triangle represent the BDNF expressed in neurons in the spinal dorsal horns). Scale bar, 20 µm. The right side of the column; scale bar, 10 µm.
Figure 5
Figure 5
Increased ionised calcium binding adaptor molecule 1 (Iba1) and brain-derived neurotrophic factor (BDNF) expression in the spinal cord of chronic constrictive injury (CCI) rats. (A) The qPCR results showed the expression of Iba1 mRNA in the spinal cord. (B) The qPCR results showed the expression of BDNF mRNA in the spinal cord. (C) Protein expression of BDNF in the spinal cord segments. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the loading control and for band density normalization. (D) Optical density analysis of BDNF proteins. Values are expressed as the mean ± SD, n=5/group. ***P<0.001 vs. the sham group; ***P<0.001 vs. the CCI group.
Figure 6
Figure 6
Effect of electro-acupuncture (EA) on the expression of tyrosine kinase receptor B (TrkB) in the spinal cord of chronic constrictive injury (CCI) rats. (A) The qPCR results showed the expression of TrkB mRNA in the spinal cord. (B) Protein expression of p-TrkB and TrkB in the spinal cord segments. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the loading control and for band density normalization. (C) Optical density analysis of p-TrkB proteins. (D) Optical density analysis of TrkB proteins. Values are expressed as the mean ± SD, n=5/group. ***P<0.001 vs. the sham group; **P<0.05 vs. the CCI group.
Figure 7
Figure 7
A schematic of the effect of electro-acupuncture on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) pathway in the spinal cord. After peripheral nerve injury, spinal microglia could transform from a quiescent state into an activated state, which activated the BDNF-TrkB signalling pathway and maintained the pathophysiological processes. Electro-acupuncture (EA) could relieve neuropathic pain by inhibiting the activation of spinal microglia and disrupting the BDNF-TrkB signalling pathway.

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