Eucommia ulmoides extract alleviated spinal cord injury in rats by inhibiting endoplasmic reticulum stress and oxidative stress

Main Article Content

Hongjuan Cheng
Haoyu Dong
Jie Wei
Guopeng You

Keywords

endoplasmic reticulum stress, eucommia ulmoides extract (EUE), MAPK pathway, oxidative stress, spinal cord injury

Abstract

Spinal cord injury (SCI) is the major cause of severe disability worldwide, which leads to neuron death, neuronal degeneration, and functional changes in the spinal cord. Eucommia ulmoides extract (EUE) is composed of multiple iridoids and phenols and possesses anti-oxidative and anti-inflammatory effects in various pathologies. This study aims to evaluate the effects of EUE on SCI and the underlying mechanisms. Male adult Sprague-Dawley rats (250–280 g) were applied to mimic SCI in vivo. Western blot and ELISA kits assessed the expressions of apoptosis, oxidative stress, and endoplasmic reticulum stress (ER stress)-relevant proteins. The apoptosis rate of neurons in spinal cord specimens was measured by TUNEL assay. Finally, our data indicated that EUE inhibited SCI-induced apoptosis, oxidative stress, and ER stress through the suppression of mitogen-activated protein kinase (MAPK) pathway. Our data manifest EUE as a potential therapeutic target in SCI.

Abstract 323 | PDF Downloads 411 HTML Downloads 91 XML Downloads 6

References

Abbasi, J. Patients With Complete Paralysis Walk With Spinal Cord Implant. JAMA 2022;327:909. 10.1001/jama.2022.2565

Anjum, A., Yazid, M. D., Fauzi Daud, M., Idris, J., Ng, A. M. H., Selvi Naicker, A., et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21. 10.3390/ijms21207533

Camilloni, A., Nati, G., Maggiolini, P., Romanelli, A., Latina, R. Chronic non-cancer pain in primary care: an Italian cross-sectional study. Signa Vitae 2021;7:54–62.

Chen, S., Ye, J., Chen, X., Shi, J., Wu, W., Lin, W., et al. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-kappaB pathway dependent of HDAC3. J Neuroinflammation. 2018;15:150. 10.1186/s12974-018-1193-6

Chen, Z., Guo, H., Lu, Z., Sun, K., Jin, Q. Hyperglycemia aggravates spinal cord injury through endoplasmic reticulum stress mediated neuronal apoptosis, gliosis and activation. Biomed Pharmac-other. 2019;112:108672. 10.1016/j.biopha.2019.108672

Fan, S., Yin, Q., Li, D., Ma, J., Li, L., Chai, S., et al. Anti-neuroinflammatory effects of Eucommia ulmoides Oliv. In a Parkinson's mouse model through the regulation of p38/JNK-Fosl2 gene expression. J Ethnopharmacol. 2020;260: 113016. 10.1016/j.jep.2020.113016

Hotamisligil, G. S., Davis, R. J. Cell Signaling and Stress Responses. Cold Spring Harb Perspect Biol. 2016;8. 10.1101/cshperspect.a006072

Ishimitsu, A., Tojo, A., Satonaka, H., Ishimitsu, T. Eucommia ulmoides (Tochu) and its extract geniposidic acid reduced blood pressure and improved renal hemodynamics. Biomed Pharmac-other. 2021;141:111901. 10.1016/j.biopha.2021111901

Kwon, S. H., Kim, M. J., Ma, S. X., You, I. J., Hwang, J. Y., Oh, J. H., et al. Eucommia ulmoides Oliv. Bark. protects against hydrogen peroxide--induced neuronal cell death in SH-SY5Y cells. J Ethnopharmacol. 2012;142:337–45. 10.1016/j.jep.2012.04.010

Kwon, S. H., Ma, S. X., Hong, S. I., Kim, S. Y., Lee, S. Y., Jang, C. G. Eucommia ulmoides Oliv. bark. attenuates 6--hydroxydopamine-induced neuronal cell death through inhibition of oxidative stress in SH-SY5Y cells. J Ethnopharmacol. 2014;152:173–82. 10.1016/j.jep.2013.12.048

Li, A., Yuan, J. F., Gong, Q., Zhang, N., Chen, L. Y., Luo, Y. Y., et al. Effects of Eucommia ulmoides extract against renal injury caused by long-term high purine diets in rats. Food Funct. 2021;12:5607–20. 10.1039/d0fo02802a

Liu, S., Sarkar, C., Dinizo, M., Faden, A. I., Koh, E. Y., Lipinski, M. M., et al. Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis. 2015;6:e1582. 10.1038/cddis.2014.527

Liu, Z., Yao, X., Jiang, W., Li, W., Zhu, S., Liao, C., et al. Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-kappaB signaling pathway and pyroptosis after secondary spinal cord injury. J Neuroinflammation. 2020;17:90. 10.1186/s12974-020-01751-2

Liu, Z., Yao, X., Sun, B., Jiang, W., Liao, C., Dai, X., et al. Pretreatment with kaempferol attenuates microglia-mediate neuroinflammation by inhibiting MAPKs-NF-kappaB signaling pathway and pyroptosis after secondary spinal cord injury. Free Radic Biol Med. 202;168:142–54. 10.1016/j.freeradbiomed.2021.03.037

Lu, Y., Yang, J., Wang, X., Ma, Z., Li, S., Liu, Z., et al. Research progress in use of traditional Chinese medicine for treatment of spinal cord injury. Biomed Pharmacother. 2020;127:110136. 10.1016/j.biopha.2020.110136

Luan, Y., Luan, Y., Feng, Q., Chen, X., Ren, K. D., Yang, Y. Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases. Oxid Med Cell Longev. 2021:3259963. 10.1155/2021/3259963

Luan, Y., Ren, K. D., Luan, Y., Chen, X., Yang, Y. Mitochondrial Dynamics: Pathogenesis and Therapeutic Targets of Vascular Diseases. Front Cardiovasc Med. 2021;8:770574. 10.3389/fcvm.2021.770574

Ren, K. D., Liu, W. N., Tian, J., Zhang, Y. Y., Peng, J. J., Zhang, D., et al. Mitochondrial E3 ubiquitin ligase 1 promotes brain injury by disturbing mitochondrial dynamics in a rat model of ischemic stroke. Eur J Pharmacol. 2019;861:172617. 10.1016/j.ejphar.2019.172617

Thuret, S., Moon, L. D., Gage, F. H. Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 2006;7:628–43. 10.1038/nrn1955

Wu, J., Chen, H., Li, H., Tang, Y., Yang, L., Cao, S., et al. Antidepressant Potential of Chlorogenic Acid-Enriched Extract from Eucommia ulmoides Oliver Bark with Neuron Protection and Promotion of Serotonin Release through Enhancing Synapsin I Expression. Molecules. 2016;21:260. 10.3390/molecules21030260

Yang, Y., Luan, Y., Feng, Q., Chen, X., Qin, B., Ren, K. D., et al. Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus. Front Pharmacol. 2021;12:807413. 10.3389/fphar.2021.807413

Zhang, J., Wang, L., Xie, W., Hu, S., Zhou, H., Zhu, P., et al. Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway. J Cell Physiol. 2020;235:2847–56. 10.1002/jcp.29190

Zhou, K., Zheng, Z., Li, Y., Han, W., Zhang, J., Mao, Y., et al. TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress. Theranostics. 2020;10:9280–302. 10.7150/thno.46566

Zhou, Z., Hou, J., Mo, Y., Ren, M., Yang, G., Qu, Z., et al. Geniposidic acid ameliorates spatial learning and memory deficits and alleviates neuroinflammation via inhibiting HMGB-1 and downregulating TLR4/2 signaling pathway in APP/PS1 mice. Eur J Pharmacol. 2020;869:172857. 10.1016/j.ejphar.2019.172857