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Objective <p>To explore the effects of early electroacupuncture (EA) intervention on the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4) signaling pathway-related protein expression and oligodendrocytes in mice with amyotrophic lateral sclerosis (ALS), and uncover the potential molecular mechanisms underlying the improvement of motor function in ALS mice by early EA intervention.</p> Methods <p>ALS mice carrying the SOD1G93A gene were randomly divided into a model group and an EA group, with 10 mice in each group; 10 littermate mice with a negative SOD1G93A genotype served as the control group. In the EA group, Baihui (GV20), Tianzhu (BL10), and Tianshu (ST25) were selected with needles retained for 10 min, 5 consecutive days per week, with 2 d of rest. One week constituted a course of treatment, and a total of 3 consecutive courses were performed. The other groups were grasped and fixed similarly but without intervention. Motor function was assessed using the open field test (OFT) and Morris water maze (MWM). Subsequently, hematoxylin-eosin staining was used to observe neuron morphology in the M1 region of the cerebral cortex. Immunofluorescence was performed to detect the positive cell rate of TAR DNA-binding protein 43 (TDP-43), and double immunofluorescence staining was used to observe the positive cell rate and cell states of ionized calcium-binding adaptor molecule 1 (Iba-1) and myelin basic protein (MBP) in the M1 region of the cerebral cortex. Western blotting was used to detect the relative expression levels of TDP-43, tumor necrosis factor (TNF)-α, HMGB1, and TLR4 proteins.</p> Results <p>Compared to the control group, the model group exhibited a reduced total movement distance in the OFT, and an increased escape latency, and fewer platform crossings in the MWM, with statistically significant differences (<i>P</i>&lt;0.01). In the model group, the number of degenerated and necrotic neurons in the M1 region of the ALS mouse cerebral cortex increased, with significant nuclear shrinkage and cytoplasmic vacuolization; the percentage of TDP-43 immunofluorescence positive cells in the M1 region of the cerebral cortex increased (<i>P</i>&lt;0.01), and the relative expression level of TDP-43 protein in the cerebral cortex showed a significant increase (<i>P</i>&lt;0.01); the Iba-1 positive cell percentage increased, while the MBP positive cell percentage decreased (<i>P</i>&lt;0.01); the relative expression levels of TNF-α, HMGB1, and TLR4 proteins increased (<i>P</i>&lt;0.05). Compared to the model group, the EA group showed an increased total movement distance (<i>P</i>&lt;0.01), and a reduced escape latency, and more platform crossings in the MWM, with statistically significant differences (<i>P</i>&lt;0.05). In the EA group, neurons showed improvement, with reduced degeneration and necrosis, and larger, clearer nuclei; the percentage of TDP-43 immunofluorescence positive cells in the M1 region of the cerebral cortex decreased (<i>P</i>&lt;0.05), and the relative expression level of TDP-43 protein also decreased (<i>P</i>&lt;0.05); the percentage of Iba-1 positive cells in the M1 region of the cerebral cortex decreased, while the percentage of MBP positive cells increased (<i>P</i>&lt;0.01); the relative expression levels of TNF-α, HMGB1, and TLR4 proteins decreased (<i>P</i>&lt;0.05).</p> Conclusion <p>EA intervention can suppress microglial activation, improve the state of oligodendrocytes, and reduce abnormal TDP-43 aggregation in the M1 region of the cerebral cortex in ALS model mice; its mechanism of action may be related to the HMGB1/TLR4 signaling pathway.</p>

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Effects of electroacupuncture on the HMGB1/TLR4 pathway and oligodendrocytes in the cerebral cortex of mice with amyotrophic lateral sclerosis

  • 期刊论文

  • 发表日期：

    2025年5月30日

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  • Jiawei Zeng,
  • Weijia Zhao,
  • Junyang Liu,
  • Shanshan Liu,
  • Le Li,
  • Weixing Feng,
  • Yingqian Zhao,
  • Qiang Wang,
  • Chao Jiang

摘要

Objective

To explore the effects of early electroacupuncture (EA) intervention on the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4) signaling pathway-related protein expression and oligodendrocytes in mice with amyotrophic lateral sclerosis (ALS), and uncover the potential molecular mechanisms underlying the improvement of motor function in ALS mice by early EA intervention.

Methods

ALS mice carrying the SOD1G93A gene were randomly divided into a model group and an EA group, with 10 mice in each group; 10 littermate mice with a negative SOD1G93A genotype served as the control group. In the EA group, Baihui (GV20), Tianzhu (BL10), and Tianshu (ST25) were selected with needles retained for 10 min, 5 consecutive days per week, with 2 d of rest. One week constituted a course of treatment, and a total of 3 consecutive courses were performed. The other groups were grasped and fixed similarly but without intervention. Motor function was assessed using the open field test (OFT) and Morris water maze (MWM). Subsequently, hematoxylin-eosin staining was used to observe neuron morphology in the M1 region of the cerebral cortex. Immunofluorescence was performed to detect the positive cell rate of TAR DNA-binding protein 43 (TDP-43), and double immunofluorescence staining was used to observe the positive cell rate and cell states of ionized calcium-binding adaptor molecule 1 (Iba-1) and myelin basic protein (MBP) in the M1 region of the cerebral cortex. Western blotting was used to detect the relative expression levels of TDP-43, tumor necrosis factor (TNF)-α, HMGB1, and TLR4 proteins.

Results

Compared to the control group, the model group exhibited a reduced total movement distance in the OFT, and an increased escape latency, and fewer platform crossings in the MWM, with statistically significant differences (P<0.01). In the model group, the number of degenerated and necrotic neurons in the M1 region of the ALS mouse cerebral cortex increased, with significant nuclear shrinkage and cytoplasmic vacuolization; the percentage of TDP-43 immunofluorescence positive cells in the M1 region of the cerebral cortex increased (P<0.01), and the relative expression level of TDP-43 protein in the cerebral cortex showed a significant increase (P<0.01); the Iba-1 positive cell percentage increased, while the MBP positive cell percentage decreased (P<0.01); the relative expression levels of TNF-α, HMGB1, and TLR4 proteins increased (P<0.05). Compared to the model group, the EA group showed an increased total movement distance (P<0.01), and a reduced escape latency, and more platform crossings in the MWM, with statistically significant differences (P<0.05). In the EA group, neurons showed improvement, with reduced degeneration and necrosis, and larger, clearer nuclei; the percentage of TDP-43 immunofluorescence positive cells in the M1 region of the cerebral cortex decreased (P<0.05), and the relative expression level of TDP-43 protein also decreased (P<0.05); the percentage of Iba-1 positive cells in the M1 region of the cerebral cortex decreased, while the percentage of MBP positive cells increased (P<0.01); the relative expression levels of TNF-α, HMGB1, and TLR4 proteins decreased (P<0.05).

Conclusion

EA intervention can suppress microglial activation, improve the state of oligodendrocytes, and reduce abnormal TDP-43 aggregation in the M1 region of the cerebral cortex in ALS model mice; its mechanism of action may be related to the HMGB1/TLR4 signaling pathway.