Breviscapine restores sevoflurane-induced cognitive dysfunction by activating the PI3K/Akt pathway and inhibiting NF-κB

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Qingju Mao
Ke Cheng
Zhen Zhang


cognitive dysfunction, breviscapine, sevoflurane, PI3K/Akt pathway, NF-κB pathway


Postoperative cognitive dysfunction (POCD) is featured by cognitive impairments in patients with high morbidity and mortality. Sevoflurane (SEV) is one of the main drugs used to maintain clinical general anesthesia and has been found to cause cognitive dysfunction. Breviscapine has various pharmacological effects. However, the effects of breviscapine on sevoflurane-induced cognitive dysfunction is unclear. The sevoflurane-induced cognitive dysfunction rat model was established. Morris water maze task was conducted to detect time in target quadrant, number of platform crossings, and the distance covered in the quadrant. Hematoxylin and eosin (H&E) staining was used to examine cell morphology. Cell apoptosis was analyzed through terminal deoxynucleotidyl transferase (TdT)-mediated dUTP Nick-End Labeling (TUNEL) staining. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected the messenger RNA (mRNA) levels. Western blot assay was conducted to measure the protein level. Enzyme-linked immunosorbent serologic assay examined tumor necrosis factor-α, interleukin (IL)-6, IL-1β, malondialdehyde, superoxide dismutase, plasma glutathione peroxidase, and catalase levels. Breviscapine improved sevoflurane-induced cognitive dysfunctioning in rats. Breviscapine could play a suppressive role in apoptosis in the brain tissues of sevoflurane-induced rats. Further functional analysis showed that sevoflurane increased inflammation and oxidative stress in the brain tissues of sevoflurane-induced rats whereas breviscapine exerted apposite effects on sevoflurane-induced inflammation and oxidative stress. Additionally, we demonstrated that breviscapine promoted sevoflurane-induced phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) (PI3K/Akt) pathway and inhibited sevoflurane-induced nuclear factor kappa B (NF-κB) pathway in the brain tissues of rats. These results indicate that breviscapine could improve sevoflurane-induced cognitive dysfunction through activating the PI3K/Akt pathway and suppressing NF-κB pathway, which provides a therapeutic method for patients with sevoflurane-induced cognitive dysfunction.


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Abeyrathna, P. and Su, Y., 2015. The critical role of Akt in cardiovascular function. Vascul Pharmacol 74: 38–48. 10.1016/j.vph.2015.05.008

Akbarzadeh, M., Mihanfar, A., Akbarzadeh, S., Yousefi, B. and Majidinia, M., 2021. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci 285: 119984. 10.1016/j.lfs.2021.119984

Berger, M., Nadler, J.W., Browndyke, J., Terrando, N., Ponnusamy, V., Cohen, H.J., et al. 2015. Postoperative Cognitive Dysfunction: Minding the Gaps in Our Knowledge of a Common Postoperative Complication in the Elderly. Anesthesiol Clin 33: 517–550. 10.1016/j.anclin.2015.05.008

Chen, Z., Wang, C., Liu, Y., Liang, X., Yang, C., Zhang, X., et al. 2020. Protective effects of medicinal plant breviscapine on postcerebral hemorrhage in rats. J Integr Neurosci 19: 101–109. 10.31083/j.jin.2020.01.1253

Chen, Z.Q., Zhou, Y., Chen, F., Huang, J.W., Zheng, J., Li, H.L., et al. 2021. Breviscapine Pretreatment Inhibits Myocardial Inflammation and Apoptosis in Rats After Coronary Microembolization by Activating the PI3K/Akt/GSK-3beta Signaling Pathway. Drug Des Devel Ther 15: 843–855. 10.2147/DDDT.S293382

Fu, Y., Wei, J., Li, B., Gao, L., Xia, P., Wen, Y., et al. 2020. CGA ameliorates cognitive decline by regulating the PI3K/AKT signaling pathway and neurotransmitter systems in rats with multi-infarct dementia. Exp Ther Med 20: 70. 10.3892/etm.2020.9198

Gu, X., Wang, Y., Wang, H., Ni, Q., Zhang, C., Zhu, J., et al. 2015. Upregulated PFTK1 promotes tumor cell proliferation, migration, and invasion in breast cancer. Medical Oncology 32: 195.

Huang, X., Huang, K., Li, Z., Bai, D., Hao, Y., Wu, Q., et al. 2020. Electroacupuncture improves cognitive deficits and insulin resistance in an OLETF rat model of Al/D-gal induced aging model via the PI3K/Akt signaling pathway. Brain Res 1740: 146834. 10.1016/j.brainres.2020.146834

Jiang, L., Hu, Y., He, X., Lv, Q., Wang, T.H. and Xia, Q.J., 2017. Breviscapine reduces neuronal injury caused by traumatic brain injury insult: partly associated with suppression of interleukin-6 expression. Neural Regen Res 12: 90–95. 10.4103/1673-5374.198990

Knox, D., Della Valle, R., Mohammadmirzaei, N., Shultz, B., Biddle, M., et al. 2021. PI3K-Akt Signaling in the Basolateral Amygdala Facilitates Traumatic Stress Enhancements in Fear Memory. Int J Neuropsychopharmacol 24: 229–238. 10.1093/ijnp/pyaa083

Lan, T., Jiang, S., Zhang, J., Weng, Q., Yu, Y., Li, H., et al. 2022. Breviscapine alleviates NASH by inhibiting TGF-beta-activated kinase 1-dependent signaling. Hepatology 76: 155–171. 10.1002/hep.32221

Lee, H.K., Kumar, P., Fu, Q., Rosen, K.M. and Querfurth, H.W., 2009. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell 20: 1533–1544. 10.1091/mbc.E08-07-0777

Li, Y., Li, S. and Li, D., 2020. Breviscapine Alleviates Cognitive Impairments Induced by Transient Cerebral Ischemia/Reperfusion through Its Anti-Inflammatory and Anti-Oxidant Properties in a Rat Model. ACS Chem Neurosci 11: 4489–4498. 10.1021/acschemneuro.0c00697

Li, Z., Zhang, X.B., Gu, J.H., Zeng, Y.Q. and Li, J.T., 2020. Breviscapine exerts neuroprotective effects through multiple mechanisms in APP/PS1 transgenic mice. Mol Cell Biochem 468: 1–11. 10.1007/s11010-020-03698-7

Lin, L.L., Liu, A.J., Liu, J.G., Yu, X.H., Qin, L.P. and Su, D.F., 2007. Protective effects of scutellarin and breviscapine on brain and heart ischemia in rats. J Cardiovasc Pharmacol 50: 327–332. 10.1097/FJC.0b013e3180cbd0e7

Liu, S., Zheng, M., Li, Y., He, L. and Chen, T., 2020. The protective effect of Geniposide on diabetic cognitive impairment through BTK/TLR4/NF-kappaB pathway. Psychopharmacology (Berl) 237: 465–477. 10.1007/s00213-019-05379-w

Palanca, B.J.A., Avidan, M.S. and Mashour, G.A., 2017. Human neural correlates of sevoflurane-induced unconsciousness. Br J Anaesth 119: 573–582. 10.1093/bja/aex244

Peng, S., Li, P., Liu, P., Yan, H., Wang, J., Lu, W., et al. 2020. Cistanches alleviates sevoflurane-induced cognitive dysfunction by regulating PPAR-gamma-dependent antioxidant and anti-inflammatory in rats. J Cell Mol Med 24: 1345–1359. 10.1111/jcmm.14807

Qian, L.H., Li, N.G., Tang, Y.P., Zhang, L., Tang, H., Wang, Z.J., et al. 2011. Synthesis and bio-activity evaluation of scutellarein as a potent agent for the therapy of ischemic cerebrovascular disease. Int J Mol Sci 12: 8208–8216. 10.3390/ijms12118208

Qin, J., Ma, Q. and Ma, D., 2020. Low-dose Sevoflurane Attenuates Cardiopulmonary Bypass (CPB)-induced Postoperative Cognitive Dysfunction (POCD) by Regulating Hippocampus Apoptosis via PI3K/AKT Pathway. Curr Neurovasc Res 17: 232–240. 10.2174/1567202617666200513085403

Saggu, R., Schumacher, T., Gerich, F., Rakers, C., Tai, K., Delekate, A., et al. 2016. Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta Neuropathol Commun 4: 76. 10.1186/s40478-016-0350-3

Shoair, O.A., Grasso Ii, M.P., Lahaye, L.A., Daniel, R., Biddle, C.J. and Slattum, P.W., 2015. Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study. J Anaesthesiol Clin Pharmacol 31: 30–36. 10.4103/0970-9185.150530

Shu, Q., Zhao, X., Geng, X. and Wang, X., 2020. CD82 Aggravates Sevoflurane-Induced Neurotoxicity by Regulating TRPM7 in Developing Neurons. Signa Vitae 16: 142–147.

Steinmetz, J., Christensen, K.B., Lund, T., Lohse, N. and Rasmussen, L.S., 2009. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110: 548–555. 10.1097/ALN.0b013e318195b569

Tewari, D., Patni, P., Bishayee, A. and Sah, A.N., 2022. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy. Semin Cancer Biol 80: 1–17. 10.1016/j.semcancer.2019.12.008

Wang, C., Li, Y., Gao, S., Cheng, D., Zhao, S. and Liu, E., 2015. Breviscapine Injection Improves the Therapeutic Effect of Western Medicine on Angina Pectoris Patients. PLoS One 10: e0129969. 10.1371/journal.pone.0129969

Wang, L. and Ma, Q., 2018. Clinical benefits and pharmacology of scutellarin: A comprehensive review. Pharmacol Ther 190: 105–127. 10.1016/j.pharmthera.2018.05.006

Yan, L., Huang, H., Tang, Q.Z., Zhu, L.H., Wang, L., Liu, C., Bian, Z.Y. and Li, H., 2010. Breviscapine protects against cardiac hypertrophy through blocking PKC-alpha-dependent signaling. J Cell Biochem 109: 1158–1171. 10.1002/jcb.22495

Yang, B., Tan, X., Xiong, X., Wu, D., Zhang, G., Wang, M., et al. 2017. Effect of CD40/CD40L signaling on IL-10-producing regulatory B cells in Chinese children with Henoch-Schönlein purpura nephritis. Immunologic research 65: 592–604.

Yang, W., Cheng, H., Xie, Y.M., Yang, H. and Zhuang, Y., 2012. [Dengzhanxixin injection using character analysis in clinical based on real world HIS database]. Zhongguo Zhong Yao Za Zhi 37: 2718–2722.