Abstract
Sleep deprivation (SD) is prevalent throughout the world, which has negative effects on cognitive abilities, and causing mood alterations. 8-O-acetyl shanzhiside methylester (8-OaS), a chief component in Lamiophlomis rotata (L. rotata) Kudo, possesses potent neuroprotective properties and analgesic effects. Here, we evaluated the alleviative effects of 8-OaS on memory impairment and anxiety in mice subjected to SD (for 72-h). Our results demonstrated that 8-OaS (0.2, 2, 20 mg/kg) administration dose-dependently ameliorated behavioral abnormalities in SD mice, accompanied with restored synaptic plasticity and reduced shrinkage and loss of hippocampal neurons. 8-OaS reduced the inflammatory response and oxidative stress injury in hippocampus caused by SD, which may be related to inhibition of NLRP3 inflammasome-mediated inflammatory process and activation of the Nrf2/HO-1 pathway. SD also led to increases in the expressions of TLR-4/MyD88, active NF-κB, pro-IL-1β, TNFα and MDA, as well as a decrease in the level of SOD in mice hippocampus, which were reversed by 8-OaS administration. Moreover, our molecular docking analyses showed that 8-OaS also has good affinity for NLRP3 and Nrf2 signaling pathways. These results suggested that 8-OaS could be used as a novel herbal medicine for the treatment of sleep loss and for use as a structural base for developing new drugs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Datasets from this study are available from the corresponding author on reasonable request.
References
Alhowail A, Alsikhan R, Alsaud M, Aldubayan M, Rabbani SI (2022) Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature. Drug Des Devel Ther 16:2919–2931. https://doi.org/10.2147/DDDT.S367229
Alomar SY, Gentili A, Zaibi MS, Kepczynska MA, Trayhurn P (2016) IL-1beta (interleukin-1beta) stimulates the production and release of multiple cytokines and chemokines by human preadipocytes. Arch Physiol Biochem 122(3):117–122. https://doi.org/10.3109/13813455.2016.1156706
Anacker C, Hen R (2017) Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci 18(6):335–346. https://doi.org/10.1038/nrn.2017.45
Atrooz F, Salim S (2020) Sleep deprivation, oxidative stress and inflammation. Adv Protein Chem Struct Biol 119:309–336. https://doi.org/10.1016/bs.apcsb.2019.03.001
Besedovsky L, Lange T, Haack M (2019) The Sleep-Immune Crosstalk in Health and Disease. Physiol Rev 99(3):1325–1380. https://doi.org/10.1152/physrev.00010.2018
Chidambaram SB, Rathipriya AG, Bolla SR, Bhat A, Ray B, Mahalakshmi AM, Manivasagam T, Thenmozhi AJ, Essa MM, Guillemin GJ, Chandra R, Sakharkar MK (2019) Dendritic spines: Revisiting the physiological role. Prog Neuropsychopharmacol Biol Psychiatry 92:161–193. https://doi.org/10.1016/j.pnpbp.2019.01.005
Cui ZH, Qin SS, Zang EH, Li C, Gao L, Li QC, Wang YL, Huang XZ, Zhang ZY, Li MH (2020). Traditional uses, phytochemistry, pharmacology and toxicology of Lamiophlomis rotata (Benth.) Kudo: a review. RSC Adv 10(19): 11463–74. https://doi.org/10.1039/D0RA01050B
Cunningham TJ, Kishore D, Guo M, Igue M, Malhotra A, Stickgold R, Djonlagic I (2022) The Effect of Obstructive Sleep Apnea on Sleep-Dependent Emotional Memory Consolidation. Ann Am Thorac Soc. https://doi.org/10.1513/AnnalsATS.202204-315OC
Dai Y, Liu S, Chen J, Liu L, Zhou C, Zuo Y (2022) Microglial responses and pain behaviors are exacerbated by chronic sleep deprivation in rats with chronic pain via neuroinflammatory pathways. Neuroscience 503:83–94. https://doi.org/10.1016/j.neuroscience.2022.09.004
Fan K, Yang J, Gong WY, Pan YC, Zheng P, Yue XF (2021) NLRP3 inflammasome activation mediates sleep deprivation-induced pyroptosis in mice. PeerJ 9:e11609. https://doi.org/10.7717/peerj.11609
Farajdokht F, Vatandoust SM, Hosseini L, Fekri K, RahighAghsan S, Majdi A, Sadigh-Eteghad S, Mahmoudi J (2021) Sericin protects against acute sleep deprivation-induced memory impairment via enhancement of hippocampal synaptic protein levels and inhibition of oxidative stress and neuroinflammation in mice. Brain Res Bull 174:203–211. https://doi.org/10.1016/j.brainresbull.2021.06.013
Feng H, Xue M, Deng H, Cheng S, Hu Y, Zhou C (2022) Ginsenoside and Its therapeutic potential for cognitive Impairment. Biomolecules 12(9):1310. https://doi.org/10.3390/biom12091310
Gaine ME, Chatterjee S, Abel T (2018) Sleep Deprivation and the Epigenome. Front Neural Circuits 12:14. https://doi.org/10.3389/fncir.2018.00014
Gisabella B, Scammell T, Bandaru SS, Saper CB (2020) Regulation of hippocampal dendritic spines following sleep deprivation. J Comp Neurol 528(3):380–388. https://doi.org/10.1002/cne.24764
Gugliandolo A, Bramanti P, Mazzon E (2020) Activation of Nrf2 by natural bioactive compounds: a promising approach for stroke? Int J Mol Sci 21(14):4875. https://doi.org/10.3390/ijms21144875
Hanamsagar R, Hanke ML, Kielian T (2012) Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol 33(7):333–342. https://doi.org/10.1016/j.it.2012.03.001
Hennig P, Garstkiewicz M, Grossi S, Di Filippo M, French LE, Beer HD (2018) The Crosstalk between Nrf2 and Inflammasomes. Int J Mol Sci 19(2):562. https://doi.org/10.3390/ijms19020562
Hou J, Shen Q, Wan X, Zhao B, Wu Y, Xia Z (2019) REM sleep deprivation-induced circadian clock gene abnormalities participate in hippocampal-dependent memory impairment by enhancing inflammation in rats undergoing sevoflurane inhalation. Behav Brain Res 364:167–176. https://doi.org/10.1016/j.bbr.2019.01.038
Huang X, Fei GQ, Liu WJ, Ding J, Wang Y, Wang H, Ji JL, Wang X (2020) Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-kappaB signaling pathways. Acta Pharmacol Sin 41(5):612–619. https://doi.org/10.1038/s41401-019-0317-6
Irwin MR, Olmstead R, Carroll JE (2016) Sleep Disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry 80(1):40–52. https://doi.org/10.1016/j.biopsych.2015.05.014
Iwasaki S, Sasaki T, Ikegaya Y (2021) Hippocampal beta oscillations predict mouse object-location associative memory performance. Hippocampus 31(5):503–511. https://doi.org/10.1002/hipo.23311
Jiang WL, Fu FH, Zheng SG, Zhang DL, Zhu HB, Jian H (2010) 8-O-acetyl shanzhiside methylester attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons exposed to oxygen-glucose deprivation. Eur J Pharmacol 629(1–3):20–24. https://doi.org/10.1016/j.ejphar.2009.11.065
Jiang WL, Zhang SP, Zhu HB, Hou J (2011) Effect of 8-O-acetyl shanzhiside methylester increases angiogenesis and improves functional recovery after stroke. Basic Clin Pharmacol Toxicol 108(1):21–27. https://doi.org/10.1111/j.1742-7843.2010.00620.x
Jiao Q, Dong X, Guo C, Wu T, Chen F, Zhang K, Ma Z, Sun Y, Cao H, Tian C, Hu Q, Liu N, Wang Y, Ji L, Yang S, Zhang X, Li J, Shen H (2022) Effects of sleep deprivation of various durations on novelty-related object recognition memory and object location memory in mice. Behav Brain Res 418:113621. https://doi.org/10.1016/j.bbr.2021.113621
Kelley N, Jeltema D, Duan Y, He Y (2019) The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci 20(13):3328. https://doi.org/10.3390/ijms20133328
Li YJ, Zhang K, Sun T, Wang J, Guo YY, Yang L, Yang Q, Li YJ, Liu SB, Zhao MG, Wu YM (2019) Epigenetic suppression of liver X receptor beta in anterior cingulate cortex by HDAC5 drives CFA-induced chronic inflammatory pain. J Neuroinflammation 16(1):132. https://doi.org/10.1186/s12974-019-1507-3
Lima DD, Cyrino LAR, Ferreira GK, Magro DDD, Calegari CR, Cabral H, Cavichioli N, Ramos SA, Ullmann OM, Mayer Y, Pscheidt LC, Schramm MA, Tomasi MC, Stammerjohann FLS, Delmonego L, Packer MH, Fiamoncini H (2022) Neuroinflammation and neuroprogression produced by oxidative stress in euthymic bipolar patients with different onset disease times. Sci Rep 12(1):16742. https://doi.org/10.1038/s41598-022-21170-y
Long X, Hu X, Pan C, Xiang H, Chen S, Qi B, Liu S, Yang X (2022) Antioxidant activity of gracilaria lemaneiformis polysaccharide degradation based on Nrf-2/Keap-1 signaling pathway in HepG2 cells with oxidative stress induced by H2O2. Mar Drugs 20(9):545. https://doi.org/10.3390/md20090545
Lu C, Lv J, Jiang N, Wang H, Huang H, Zhang L, Li S, Zhang N, Fan B, Liu X, Wang F (2020) Protective effects of Genistein on the cognitive deficits induced by chronic sleep deprivation. Phytother Res 34(4):846–858. https://doi.org/10.1002/ptr.6567
Manchanda S, Singh H, Kaur T, Kaur G (2018) Low-grade neuroinflammation due to chronic sleep deprivation results in anxiety and learning and memory impairments. Mol Cell Biochem 449(1–2):63–72. https://doi.org/10.1007/s11010-018-3343-7
Merikanto I, Partonen T (2021) Eveningness increases risks for depressive and anxiety symptoms and hospital treatments mediated by insufficient sleep in a population-based study of 18,039 adults. Depress Anxiety 38(10):1066–1077. https://doi.org/10.1002/da.23189
Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16(1):22–34. https://doi.org/10.1038/nri.2015.5
Nikkar R, Esmaeili-Bandboni A, Badrikoohi M, Babaei P (2022) Effects of inhibiting astrocytes and BET/BRD4 chromatin reader on spatial memory and synaptic proteins in rats with Alzheimer’s disease. Metab Brain Dis 37(4):1119–1131. https://doi.org/10.1007/s11011-022-00940-7
Qiu C, Wang M, Yu W, Rong Z, Zheng HS, Sun T, Liu SB, Zhao MG, Wu YM (2021) Activation of the Hippocampal LXRbeta Improves Sleep-Deprived Cognitive Impairment by Inhibiting Neuroinflammation. Mol Neurobiol 58(10):5272–5288. https://doi.org/10.1007/s12035-021-02446-2
Raven F, Van der Zee EA, Meerlo P, Havekes R (2018) The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function. Sleep Med Rev 39:3–11. https://doi.org/10.1016/j.smrv.2017.05.002
Shavit-Stein E, Dori A, Shimon MB, Gofrit SG, Maggio N (2021) Prolonged Systemic Inflammation Alters Muscarinic Long-Term Potentiation (mLTP) in the Hippocampus. Neural Plast 2021:8813734. https://doi.org/10.1155/2021/8813734
Sun T, Luo L, Tian QQ, Wang WJ, Liu QQ, Yang L, Zhang K, Zhang W, Zhao MG, Yang Q (2020) Anxiolytic Effects of 8-O-Acetyl shanzhiside methylester on acute and chronic anxiety via inflammatory response inhibition and excitatory/inhibitory transmission Imbalance. Neurotox Res 38(4):979–991. https://doi.org/10.1007/s12640-020-00203-2
Tai F, Wang C, Deng X, Li R, Guo Z, Quan H, Li S (2020) Treadmill exercise ameliorates chronic REM sleep deprivation-induced anxiety-like behavior and cognitive impairment in C57BL/6J mice. Brain Res Bull 164:198–207. https://doi.org/10.1016/j.brainresbull.2020.08.025
Tang H, Li K, Dou X, Zhao Y, Huang C, Shu F (2020) The neuroprotective effect of osthole against chronic sleep deprivation (CSD)-induced memory impairment in rats. Life Sci 263:118524. https://doi.org/10.1016/j.lfs.2020.118524
Turan I, SayanOzacmak H, Ozacmak VH, Ergenc M, Bayraktaroglu T (2021) The effects of glucagon-like peptide 1 receptor agonist (exenatide) on memory impairment, and anxiety- and depression-like behavior induced by REM sleep deprivation. Brain Res Bull 174:194–202. https://doi.org/10.1016/j.brainresbull.2021.06.011
Wadhwa M, Prabhakar A, Ray K, Roy K, Kumari P, Jha PK, Kishore K, Kumar S, Panjwani U (2017) Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation. J Neuroinflammation 14(1):222. https://doi.org/10.1186/s12974-017-0998-z
Wang J, Wu X, Liang W, Chen M, Zhao C, Wang X (2020a) Objective short sleep duration is related to the peripheral inflammasome dysregulation in patients with chronic insomnia. Nat Sci Sleep 12:759–766. https://doi.org/10.2147/NSS.S270045
Wang W, Yang L, Liu T, Ma Y, Huang S, He M, Wang J, Wen A, Ding Y (2020b) Corilagin ameliorates sleep deprivation-induced memory impairments by inhibiting NOX2 and activating Nrf2. Brain Res Bull 160:141–149. https://doi.org/10.1016/j.brainresbull.2020.03.010
Wang W, Yang L, Liu T, Wang J, Wen A, Ding Y (2020c). Ellagic acid protects mice against sleep deprivation-induced memory impairment and anxiety by inhibiting TLR4 and activating Nrf2. Aging (Albany NY) 12(11): 10457–72. https://doi.org/10.18632/aging.103270
Wang X, Wang Z, Cao J, Dong Y, Chen Y (2021) Melatonin alleviates acute sleep deprivation-induced memory loss in mice by suppressing hippocampal ferroptosis. Front Pharmacol 12:708645. https://doi.org/10.3389/fphar.2021.708645
Yu R, Jiang S, Tao Y, Li P, Yin J, Zhou Q (2019) Inhibition of HMGB1 improves necrotizing enterocolitis by inhibiting NLRP3 via TLR4 and NF-kappaB signaling pathways. J Cell Physiol 234(8):13431–13438. https://doi.org/10.1002/jcp.28022
Zhang L, Kan ZC, Zhang XL, Fang H, Jiang WL (2014) 8-O-acetyl shanzhiside methylester attenuates cerebral ischaemia/reperfusion injury through an anti-inflammatory mechanism in diabetic rats. Basic Clin Pharmacol Toxicol 115(6):481–487. https://doi.org/10.1111/bcpt.12266
Zhang Q-LMX-H, Qiu J-G, Jia Z-P (2018a) Major pharmacodynamics and acute toxicity of iridoid glycosides capsules of Lamiophlomis rotata. Chinese Traditional Patent Medicine 40(9):2048–2051. https://doi.org/10.3969/j.issn.1001-1528.2018.09.034
Zhang W, Bai Y, Qiao Y, Wang J, Li MY, Wang JW, Jia N, Chen T, Li YQ, Wen AD (2018b) 8-O-Acetyl shanzhiside methylester from lamiophlomis rotata reduces neuropathic pain by inhibiting the ERK/TNF-alpha pathway in spinal astrocytes. Front Cell Neurosci 12:54. https://doi.org/10.3389/fncel.2018.00054
Zhou H, Wu J, Gong Y, Zhou Z, Wang J (2022) Isoquercetin alleviates sleep deprivation dependent hippocampal neurons damage by suppressing NLRP3-induced pyroptosis. Immunopharmacol Immunotoxicol 44(5):766–772. https://doi.org/10.1080/08923973.2022.2082976
Zhu B, Gong N, Fan H, Peng CS, Ding XJ, Jiang Y, Wang YX (2014) Lamiophlomis rotata, an orally available Tibetan herbal painkiller, specifically reduces pain hypersensitivity states through the activation of spinal glucagon-like peptide-1 receptors. Anesthesiology 121(4):835–851. https://doi.org/10.1097/ALN.0000000000000320
Zhu X, Liu J, Huang S, Zhu W, Wang Y, Chen O, Xue J (2019) Neuroprotective effects of isoliquiritigenin against cognitive impairment via suppression of synaptic dysfunction, neuronal injury, and neuroinflammation in rats with kainic acid-induced seizures. Int Immunopharmacol 72:358–366. https://doi.org/10.1016/j.intimp.2019.04.028
Zielinski MR, Gerashchenko D, Karpova SA, Konanki V, McCarley RW, Sutterwala FS, Strecker RE, Basheer R (2017) The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide. Brain Behav Immun 62:137–150. https://doi.org/10.1016/j.bbi.2017.01.012
Funding
This study was funded by National Natural Science Foundation of China (No. 82001422 for Dr. Li), The Natural Science Foundation of Jiangsu Province for Dr. Li (Grants No BK. 20200274), and National Natural Science Foundation of China (No. 81901890 for Dr. Zhou).
Author information
Authors and Affiliations
Contributions
Yujiao-Li designed the study and wrote the manuscript. Xiao-Lu He developed the model and performed part of the behavior test. Jie-Yu Zhang participated in the western blot analysis. Xue-jiao Liu was responsible for morphological experiments. Jia-Long Liang carried out the molecular docking analyses. Yu-jiao Li and Qing Zhou analyzed the data. Guo-Hua Zhou supervised whole experiments. All authors approved the final manuscript for submission.
Corresponding authors
Ethics declarations
Ethical approval
This study was approved by the Animal Care Committee of Jinling Hospital (Approval No.: 2020JLHGKJDWLS-106).
Consent to participate
Not applicable. This study does not contain any studies with human participants performed by any of the authors.
Consent for publication
Not applicable.
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
11011_2022_1132_MOESM1_ESM.jpg
Supplementary Fig. 1 The average body weight of mice in each group before and during 72-h SD with or without 8-OaS administration. Data are presented as the means ± SEM. n = 10 in each group, *p < 0.05, **p < 0.01, versus the control group. (JPG 121 KB)
11011_2022_1132_MOESM2_ESM.jpg
Supplementary Fig. 2 The effects of 8-OaS on spatial working memory of SD mice in Y-maze test. (a) Schematic representation of the Y-maze test. (b) The percentage of spontaneous alternation. (c) The total distance traveled of each group. Data are presented as the means ± SEM. n = 10 in each group, **p < 0.01, versus the control group; #p < 0.05, ##p < 0.01, versus the SD group. (JPG 151 KB)
11011_2022_1132_MOESM3_ESM.jpg
Supplementary Fig. 3 The effects of 8-OaS on the pro-inflammatory cytokine levels in the hippocampus of SD mice. (a) Levels of TNF-α and IL-1β in the hippocampus after SD in five groups. 8-OaS treatment significantly reduced the elevated levels of TNF-α (b) and IL-1β (c) in the hippocampus, as shown by ELISA. Data are presented as the means ± SEM, n = 5 in each group, **p < 0.01, versus the control group; #p < 0.05, ##p < 0.01, versus the SD group. (JPG 241 KB)
11011_2022_1132_MOESM4_ESM.jpg
Supplementary Fig. 4 The effects of 8-OaS on the TLR4-induced inflammatory responses in SD mice. (a) Representative western blot images of TLR4, MyD88, p-p65 and p65 are presented. 8-OaS treatment significantly inhibited the increase of TLR4 (b), MyD88 (c) and p-p65/p65 (d) expressions in mice hippocampus after SD normalized to β-actin. Data are presented as the means ± SEM. n = 5 in each group, **p < 0.01, versus the control group; #p < 0.05, ##p < 0.01, versus the SD group. (JPG 328 KB)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Li, YJ., He, XL., Zhang, JY. et al. 8-O-acetyl shanzhiside methylester protects against sleep deprivation-induced cognitive deficits and anxiety-like behaviors by regulating NLRP3 and Nrf2 pathways in mice. Metab Brain Dis 38, 641–655 (2023). https://doi.org/10.1007/s11011-022-01132-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-022-01132-z