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Acupuncture Alleviates Chronic Ischemic White Matter Injury in SHR Rats via JNK-NMDAR Circuit

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Abstract

To study the protective mechanism of acupuncture at “Jiangya Recipe” on chronic ischemic white matter injury in spontaneously hypertensive rats (SHR) and the regulation of Jun N-terminal kinase-N-methyl-D-aspartate receptor (JNK-NMDAR) loop. A hypertensive white matter injury model was established in 46 male SHR rats aged 11 weeks by bilateral common carotid artery tapering (SHR-2VGO). In the SHR sham operation group, only bilateral common carotid arteries were isolated and in the SHR-2VGO modeling group, 36 rats were used for microcoil spring clip implantation to narrow the common carotid arteries and then, after 2 weeks of modeling, rats with impaired motor function were removed, and SHR-2VGO rats with successful final models were randomly divided into the model group, JNK blocking group, and acupuncture group. The sham operation group, model group, and JNK blocking group underwent the same grasping fixation, and the acupuncture group received acupuncture at acupoints “Jiangya Fang” once daily. In the JNK blocker group, an injection cannula was implanted into the lateral ventricle and sp600125 was injected into the lateral ventricle at 4.5 ul/day for 4 weeks. One week after the end of the intervention, white matter lesions were detected by MRI DWI and T2 imaging, and the learning and memory ability of rats was tested by Y-Maze and Passive Avoidance. Myelin density was detected by luxol fast blue (LFB) staining, also axon arrangement, myelin integrity, and thickness of neurons were detected by electron microscopy; neuronal morphology and the number of Nissl bodies in the hippocampus were detected by Nissl staining, dendritic spine density changes were detected by Golgi staining, and JNK, NMDAR1, and N-methyl-D-receptor 2B (NMDAR2B) in DG, CA3 region of hippocampus were detected by immunohistochemistry, protein expression of p-JNK/JNK, p-NMDAR1/NMDAR1, NMDAR2B, GSK3β protein expression in the fimbria of hippocampus was detected by Western blot. The Y maze test of SHR-2VGO+Acu and SHR-2VGO+ sp600125 group showed that the spontaneous alternating reaction rate increased significantly. At the same time, the incubation period increased significantly and the number of errors decreased significantly in Passive Avoidance. MRI T2WI showed that the white matter high signal of the corpus callosum, internal capsule and hippocampal fimbria in the SHR-2VGO+ sp600125 and SHR-2VGO+Acu groups was significantly lower than that in the SHR-2VGO model group, and the striatum and anterior commissure were not obvious. DWI showed that the SHR-2VGO model group had scattered high signal and limited diffusion movement in both the internal capsule and striatum, but the difference between groups was not obvious. Compared with SHR-2VGO rats, LFB staining of SHR-2VGO + sp600125 and SHR-2VGO +Acu groups showed significant relaxation of myelin porosity in corpus callosum, striatum, inner capsule, anterior commissure and hippocampal fimbria, and electron microscopy showed improved axonal myelin integrity and thickness in corpus callosum region. Also, the number of blue patchy Nissl bodies increased, and the number and complexity of dendritic spines increased significantly in Golgi staining. Immunohistochemical detection showed that JNK levels in DG and CA3 region were increased and NMDAR1 and NMDAR2B levels were decreased in SHR-2VGO+Acu and SHR-2VGO+ sp600125 groups. Meanwhile, protein expressions of GSK3β, NMDAR1/p-NMDAR1 and NMDAR2B in fimbria of hippocampus were increased, and JNK/P-JNK protein expression decreased. Acupuncture can increase the density and thickness of myelin sheath in white matter areas of corpus callosum, anterior commissure and hippocampal fimbria, increase the number and length of hippocampal neuronal dendrites, and improve hypertensive white matter injury and cognitive decline through JNK-NMDAR pathway.

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All data generated or analysed during this study are included in this published article.

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Acknowledgements

Funded Project : Education Department of Shanxi Province Project (2020L0410); Natural Science Youth Project of Shanxi Province (20210302124006); Shanxi Province Platform Foundation and Talent Special (2021BKS05); National Natural Science Foundation of China (81673887); Science and Technology Innovation Team of Shanxi University of Traditional Chinese Medicine (2022TD2002); Research and Development Innovation Team of Chinese Medicine for Immune Regulation (2022TD1017)

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Authors and Affiliations

  1. Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China

    Aiai Dong, Zhen Gao, Haijun Wang, Ronglin Wu, Xiaofei Jin, Yufang Ji, Ziwen Jiang, Yongrong Xu, Jilong Guo & Laixi Ji

  2. Shanxi University of Traditional Chinese Medicine Affiliated Hospital of Acupuncture and Massage, Taiyuan, 030006, China

    Weifeng Wang & Faming Yang

  3. Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China

    Tao Zhu

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Contributions

DA, GZ, WH, WR, WW, JX, JY, YF, ZT, JZ, XY, GJ and JL participated the draft and design, supervision and editing, and resources, writing of original draft, experimental implementation, and data statistics and analysis. All authors read and approved final manuscript.

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Correspondence to Laixi Ji.

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This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Animal Ethics and Management Committee of Shanxi University of Traditional Chinese Medicine (2021DW034) and adhered to the 3R principle. All methods are reported following ARRIVE guidelines (https://arriftguidelines.org) for the reporting of animal experiments.

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Aiai Dong and Zhen Gao made equal contributions to the manuscript they are co first authors.

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Dong, A., Gao, Z., Wang, H. et al. Acupuncture Alleviates Chronic Ischemic White Matter Injury in SHR Rats via JNK-NMDAR Circuit. Mol Neurobiol 61, 3144–3160 (2024). https://doi.org/10.1007/s12035-023-03759-0

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