1. Department of Neuropharmacology, Institute of Experimental Medicine, St. Petersburg, Russia; St. Petersburg State Pediatric Medical University, St. Petersburg, Russia 2. Department of Neuropharmacology, Institute of Experimental Medicine, St. Petersburg, Russia; Research and Training Center of Molecular and Cellular Technologies, St. Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia 3. Department of Plant Physiology, M.V. Lomonosov Moscow State University, Moscow, Russia; Timiryazev Institute of Plant Physiology of RAS, Moscow, Russia 4. Department of Neuropharmacology, Institute of Experimental Medicine, St. Petersburg, Russia 5. Department of Neuropharmacology, Institute of Experimental Medicine, St. Petersburg, Russia; Department of Pharmacology, Kirov Military Medical Academy, St. Petersburg, Russia
Long-term alcohol consumption causes the development of neuroinflammation in various brain structures. One of the mechanisms involved in this process is the increased activity of TLR-signaling intracellular pathways. Studies confirm the ability of ginseng extract or its individual ginsenosides to reduce the increased activity of TLR-signaling pathways. The aim of our study was to study the effect of the amount of ginsenosides obtained from the extract of the Panax japonicus cell line on the state of the TLR-signaling system in the nucleus accumbens and hippocampus of the rat brain in a model of long-term alcohol consumption during alcohol withdrawal. The results of the study showed that ginsenosides were able to make changes in the TLR signaling system, which has been altered by long-term alcohol consumption. A significant effect of ginsenosides on the level of TLR3 and TLR4 mRNA in the nucleus accumbens was found, while in the hippocampus, ginsenosides significantly affected the level of TLR7 mRNA. The effect of ginsenosides on the level of mRNA of transcription factors and cytokines involved in TLR-signaling was evaluated. Thus, results of our study confirm that ginsenosides are able to influence the state of TLR-signaling pathways, but this effect is multidirectional in relation to different brain structures. In the future, it seems interesting to evaluate the role of individual ginsenosides in relation to genes of TLR-signaling, as well as the effect of ginsenosides on other brain structures.
Airapetov M.I., Eresko S.O., Kochkin D.V., Bychkov E.R., Lebedev A.A., Shabanov P.D. (2022) Ginsenosides affect the system of Toll-like receptors in the brain of rats under conditions of long-term alcohol withdrawal. Biomeditsinskaya Khimiya, 68(6), 459-469.
Airapetov M.I. et al. Ginsenosides affect the system of Toll-like receptors in the brain of rats under conditions of long-term alcohol withdrawal // Biomeditsinskaya Khimiya. - 2022. - V. 68. -N 6. - P. 459-469.
Airapetov M.I. et al., "Ginsenosides affect the system of Toll-like receptors in the brain of rats under conditions of long-term alcohol withdrawal." Biomeditsinskaya Khimiya 68.6 (2022): 459-469.
Airapetov, M. I., Eresko, S. O., Kochkin, D. V., Bychkov, E. R., Lebedev, A. A., Shabanov, P. D. (2022). Ginsenosides affect the system of Toll-like receptors in the brain of rats under conditions of long-term alcohol withdrawal. Biomeditsinskaya Khimiya, 68(6), 459-469.
References
He Y., Yang J., Lv Y., Chen J., Yin F., Huang J., Zheng Q. (2018) A review of ginseng clinical trials registered in the WHO international clinical trials registry platform. Biomed. Res. Int., 2018, 1843142. CrossRef Scholar google search
Mahady G.B., Gyllenhaal C., Fong H.H.S., Farnsworth N.R. (2000) Ginsengs: A review of safety and efficacy. Nutr. Clin. Care, 3(2), 90-101. CrossRef Scholar google search
Cui L., Wu S.Q., Zhao C.A., Yin C.R. (2016) Microbial conversion of major ginsenosides in ginseng total saponins by endophytes. J. Ginseng Res., 40(4), 366-374. CrossRef Scholar google search
Nguyen N.H., Nguyen C.T. (2019) Pharmacological effects of ginseng on infectious diseases. Inflammopharmacology, 27(5), 871-883. CrossRef Scholar google search
Tam D.N.H., Truong D.H., Nguyen T.T.H., Quynh L.N., Tran L., Nguyen H.D., Shamandy B.E., Le T.M.H., Tran D.K., Sayed D., Vu V.V., Mizukami S., Hirayama K., Huy N.T. (2018) Ginsenoside Rh1: A systematic review of its pharmacological properties. Planta Med., 84(3), 139-152. CrossRef Scholar google search
Fan S., Zhang Z., Su H., Xu P., Qi H., Zhao D., Li X. (2020) Panax ginseng clinical trials: Current status and future perspectives. Biomed. Pharmacother., 132, 110832. CrossRef Scholar google search
González-Burgos E., Fernandez-Moriano C., Gómez-Serranillos M.P. (2015) Potential neuroprotective activity of ginseng in Parkinson's disease: A review. J. Neuroimmune Pharmacol., 10(1), 14-29. CrossRef Scholar google search
Wang X., Wang S., Wang J., Guo H., Dong Z., Chai L., Hu L., Zhang Y., Wang H., Chen L. (2015) Neuroprotective effect of Xueshuantong for injection (lyophilized) in transient and permanent rat cerebral ischemia model. Evid. Based. Complement. Alternat. Med., 2015, 134685. CrossRef Scholar google search
Xu X., Jin L., Jiang T., Lu Y., Aosai F., Piao H.N., Xu G.H., Jin C.H., Jin X.J., Ma J., Piao L.X. (2020) Ginsenoside Rh2 attenuates microglial activation against toxoplasmic encephalitis via TLR4/NF-κB signaling pathway. J Ginseng Res., 44(5), 704-716. CrossRef Scholar google search
Li J., Huang Q., Chen J., Qi H., Liu J., Chen Z., Zhao D., Wang Z., Li X. (2021) Neuroprotective potentials of Panax ginseng against Alzheimer's disease: A review of preclinical and clinical evidences. Front. Pharmacol., 12, 688490. CrossRef Scholar google search
Cai L., Hu F., Fu W., Yu X., Zhong W., Liu F., Wang T., Sui D. (2021) Ginsenoside Rg2 ameliorates brain injury after intracerebral hemorrhage in a rat model of preeclampsia. Reprod. Sci., 28(12), 3431-3439. CrossRef Scholar google search
Sun Y., Yang Y., Liu S., Yang S., Chen C., Lin M., Zeng Q., Long J., Yao J., Yi F., Meng L., Ai Q., Chen N. (2022) New therapeutic approaches to and mechanisms of ginsenoside Rg1 against neurological diseases. Cells, 11(16), 2529. CrossRef Scholar google search
Gong L., Yin J., Zhang Y., Huang R., Lou Y., Jiang H., Sun L., Jia J., Zeng X. (2022) Neuroprotective mechanisms of ginsenoside Rb1 in central nervous system diseases. Front. Pharmacol., 13, 914352. CrossRef Scholar google search
Zheng Z., Liang S., Sun S., Liu P., Yu L. (2022) Clinical observation of salvianolic acid combined with Panax notoginseng saponins combined with basic nursing intervention on cerebral ischemia-reperfusion injury in rats. J. Healthc. Eng., 30, 8706730. CrossRef Scholar google search
Xu X., Lu Y.N., Cheng J.H., Lan H.W., Lu J.M., Jin G.N., Xu G.H., Jin C.H., Ma J., Piao H.N., Jin X., Piao L.X. (2022) Ginsenoside Rh2 reduces depression in offspring of mice with maternal toxoplasma infection during pregnancy by inhibiting microglial activation via the HMGB1/TLR4/NF-κB signaling pathway. J. Ginseng Res., 46(1), 62-70. CrossRef Scholar google search
Ramos A., Joshi R.S., Szabo G. (2022) Innate immune activation: Parallels in alcohol use disorder and Alzheimer's disease. Front. Mol. Neurosci., 15, 910298. CrossRef Scholar google search
Coleman L.G.J., Crews F.T., Vetreno R.P. (2021) The persistent impact of adolescent binge alcohol on adult brain structural, cellular, and behavioral pathology: A role for the neuroimmune system and epigenetics. Int. Rev. Neurobiol., 160, 1-44. CrossRef Scholar google search
Airapetov M., Eresko S., Lebedev A., Bychkov E., Shabanov P. (2021) The role of Toll-like receptors in neurobiology of alcoholism. Biosci. Trends, 15(2), 74-82. CrossRef Scholar google search
Becker H.C., Mulholland P.J. (2014) Neurochemical mechanisms of alcohol withdrawal. Handb. Clin. Neurol., 125, 133-156. CrossRef Scholar google search
Gano A., Lebonville C.L., Becker H.C. (2022) TLR3 activation with polyI:C exacerbates escalated alcohol consumption in dependent male C57BL/6J mice. Am. J. Drug Alcohol Abuse, 12, 1-12. CrossRef Scholar google search
Griffin W.C., Lopez M.F., Woodward J.J., Becker H.C. (2022) Alcohol dependence and the ventral hippocampal influence on alcohol drinking in male mice. Alcohol, 2022, DOI: 10.1016/j.alcohol.2022.10.004. CrossRef Scholar google search
Femenia T., Qian Y., Arentsen T., Forssberg H., Diaz Heijtz R. (2018) Toll-like receptor-4 regulates anxiety-like behavior and DARPP-32 phosphorylation. Brain Behav. Immun., 69, 273-282. CrossRef Scholar google search
Tripathi A.S., Bansod P., Swathi K.P. (2021) Activation of 5-HT 1b/d receptor restores the cognitive function by reducing glutamate release, deposition of β-amyloid and TLR-4 pathway in the brain of scopolamine-induced dementia in rat. J. Pharm. Pharmacol., 73(12), 1592-1598. CrossRef Scholar google search
Shirayama Y., Iwata M., Fujita Y., Oda Y., Hashimoto K. (2022) The Toll-like receptor 4 antagonist TAK-242 induces antidepressant-like effects in a rat learned helplessness model of depression through BDNF-TrkB signaling and AMPA receptor activation. Behav. Brain Res., 423, 113769. CrossRef Scholar google search
Pannacci M., Lucini V., Colleoni F., Martucci C., Grosso S., Sacerdote P., Scaglione F. (2006) Panax ginseng C.A. Mayer G115 modulates pro-inflammatory cytokine production in mice throughout the increase of macrophage Toll-like receptor 4 expression during physical stress. Brain Behav. Immun., 20(6), 546-551. CrossRef Scholar google search
Rhule A., Rase B., Smith J.R., Shepherd D.M. (2008) Toll-like receptor ligand-induced activation of murine DC2.4 cells is attenuated by Panax notoginseng. J. Ethnopharmacol., 116(1), 179-186. CrossRef Scholar google search
Beamer C.A., Shepherd D.M. (2012) Inhibition of TLR ligandand interferon gamma-induced murine microglial activation by Panax notoginseng. J. Neuroimmune Pharmacol., 7(2), 465-476. CrossRef Scholar google search
Kim T.W., Joh E.H., Kim B., Kim D.H. (2012) Ginsenoside Rg5 ameliorates lung inflammation in mice by inhibiting the binding of LPS to toll-like receptor-4 on macrophages. Int. Immunopharmacol., 12(1), 110-116. CrossRef Scholar google search
Zhao B.S., Liu Y., Gao X.Y., Zhai H.Q., Guo J.Y., Wang X.Y. (2014) Effects of ginsenoside Rg1 on the expression of Toll-like receptor 3, 4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line. Molecules, 19(10), 16925-16936. CrossRef Scholar google search
Nosov A.M., Popova E.V., Kochkin D.V. (2014) Isoprenoid production via plant cell cultures: biosynthesis, accumulation and scaling-up to bioreactors. In: Production of Biomass and Bioactive Compounds Using Bioreactor Technology. Springer, Netherlands, p. 563-623. CrossRef Scholar google search
Murashige T., Skoog F.A. (1962) Revised medium for rapid growth and bio assays with tobacco tissue cultures. Physiologia Plantarum, 15, 473-497. CrossRef Scholar google search
Smolenskaya I.N., Reshetnyak O.V., Nosov A.V., Zoriniants S.E., Chaiko A.L., Smirnova Y.N., Nosov A.M. (2007) Ginsenoside production, growth and cytogenetic characteristics of sustained Panax japonicus var. repens cell suspension culture. Biologia Plantarum, 51, 235-241. CrossRef Scholar google search
Koob G.F. (2014) Neurocircuitry of alcohol addiction: synthesis from animal models. Handb. Clin. Neurol., 125, 33-54. CrossRef Scholar google search
Sobstyl M., Kupryjaniuk A., Mierzejewski P. (2021) Nucleus accumbens as a stereotactic target for the treatment of addictions in humans: A literature review. Neurol. Neurochir. Pol., 55(5), 440-449. CrossRef Scholar google search
Airapetov M.I., Eresko S.O., Skabelkin D.A., Iskalieva A.R., Lebedev A.A., Bychkov E.R., Shabanov P.D. (2022) The effect of rifampicin on the system of Toll-like receptors in the nucleus accumbens of the brain of long-term alcoholized rats during alcohol withdrawal. Biomeditsinskaya Khimiya, 68(4), 279-287. CrossRef Scholar google search
Edith V.S., Anjali D., Eve R., Margaret J.R., Adolf P. (2005) Striatal and forebrain nuclei volumes: Contribution to motor function and working memory deficits in alcoholism. Biol. Psychiatry, 57(7), 768-776. CrossRef Scholar google search
McClintick J.N., Xuei X., Tischfield J.A., Goate A., Foroud T., Wetherill L., Ehringer M.A., Edenberg H.J. (2013) Stress-response pathways are altered in the hippocampus of chronic alcoholics. Alcohol, 47(7), 505-515. CrossRef Scholar google search
Shabani Z., Jafarzadeh Gharehziaaddin M. (2020) Effects and potential mechanisms of alcohol use disorder on the fate determination of newly born neurons in the hippocampus. Alcohol Alcohol., 55(6), 598-602. CrossRef Scholar google search
Xia T., Fang B., Kang C., Zhao Y., Qiang X., Zhang X., Wang Y., Zhong T., Xiao J., Wang M. (2022) Hepatoprotective mechanism of ginsenoside Rg1 against alcoholic liver damage based on gut microbiota and network pharmacology. Oxid. Med. Cell Longev., 2022, 5025237. CrossRef Scholar google search
Kim G.O., Kim N., Song G.Y., Bae J.S. (2022) Inhibitory activities of rare ginsenoside Rg4 on cecal ligation and puncture-induced sepsis. Int. J. Mol. Sci. 23(18), 10836. CrossRef Scholar google search
Zhou P., Xie W., Sun Y., Dai Z., Li G., Sun G., Sun X. (2019) Ginsenoside Rb1 and mitochondria: A short review of the literature. Molecular Cellular Probes, 43, 1-5. CrossRef Scholar google search
McCarthy G.M., Warden A.S., Bridges C.R., Blednov Y.A., Harris R.A. (2017) Chronic ethanol consumption: Role of TLR3/TRIF-dependent signaling. Addiction Biology, 23(3), 889-903. CrossRef Scholar google search
Randall P.A., Vetreno R.P., Makhijani V.H., Crews F.T., Besheer J. (2019) The Toll-like receptor 3 agonist poly(I:C) induces rapid and lasting changes in gene expression related to glutamatergic function and increases ethanol self-administration in rats. Alcohol. Clin. Exp. Res., 43(1), 48-60. CrossRef Scholar google search
Kashima D.T., Grueter B.A. (2017) Toll-like receptor 4 deficiency alters nucleus accumbens synaptic physiology and drug reward behavior. Proc. Natl. Acad. Sci. USA., 114(33), 8865-8870. CrossRef Scholar google search
Harris R.A., Bajo M., Bell R.L., Blednov Y.A., Varodayan F.P., Truitt J.M., de Guglielmo G., Lasek A.W., Logrip M.L., Vendruscolo L.F., Roberts A.J., Roberts E., George O., Mayfield J., Billiar T.R., Hackam D.J., Mayfield R.D., Koob G.F., Roberto M., Homanics G.E. (2017) Genetic and pharmacologic manipulation of TLR4 has minimal impact on ethanol consumption in rodents. J Neurosci., 37(5), 1139-1155. CrossRef Scholar google search
Blednov Y.A., Black M., Benavidez J.M., da Costa A., Mayfield J., Harris R.A. (2017) Sedative and motor in coordination effects of ethanol in mice lacking CD14, TLR2, TLR4, or MyD88. Alcohol. Clin. Exp. Res., 41(3), 531-540. CrossRef Scholar google search
Montesinos J., Pascual M., Pla A., Maldonado C., Rodríguez-Arias M., Miñarro J., Guerri C. (2015) TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment. Brain Behav. Immun., 45, 233-344. CrossRef Scholar google search
Alfonso-Loeches S., Pascual-Lucas M., Blanco A.M., Sanchez-Vera I., Guerri C. (2010) Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J. Neurosci., 30(24), 8285-8295. CrossRef Scholar google search
Coleman L.G., Zou J., Crews F.T. (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J. Neuroinflammation, 14(1), 22. CrossRef Scholar google search
Whitman B.A., Knapp D.J., Werner D.F., Crews F.T., Breese G.R. (2013) The cytokine mRNA increase induced by withdrawal from chronic ethanol in the sterile environment of brain is mediated by CRF and HMGB1 release. Alcohol. Clin. Exp. Res., 37(12), 2086-2097. CrossRef Scholar google search
Sanchez-Alavez M., Nguyen W., Mori S., Wills D.N., Otero D., Ehlers C.L., Conti B. (2019) Time course of microglia activation and brain and blood cytokine/chemokine levels following chronic ethanol exposure and protracted withdrawal in rats. Alcohol, 76, 37-45. CrossRef Scholar google search
Lippai D., Bala S., Petrasek J., Csak T., Levin I., Kurt-Jones E.A., Szabo G. (2013) Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J. Leukoc. Biol., 94(1), 171-182. CrossRef Scholar google search
Airapetov M.I., Eresko S.O., Bychkov E.R., Lebedev A.A., Shabanov P.D. (2021) HMGB1 gene expression changes in the striatum and amigdal of the rat's brain under alcoholization and ethanol withdrawal. Biomeditsinskaya Khimiya, 67(1), 95-99. CrossRef Scholar google search
Li Y., Liu H., Zeng Z., Lin H., Chen X., Yuan X., Qiu J., Fu F., Chen Z., Kuang J. (2022) Ginsenoside Rb3 attenuates skin flap ischemia-reperfusion damage by inhibiting STING-IRF3 signaling. J. Mol. Histol. 53(4), 763-772. CrossRef Scholar google search
Choi Y.J., Kang L.J., Lee S.G. (2014) Stimulation of DDX3 expression by ginsenoside Rg3 through the Akt/p53 pathway activates the innate immune response via TBK1/IKKε/IRF3 signalling. Curr. Med. Chem., 21(8), 1050-1060. CrossRef Scholar google search
Cai H.A., Huang L., Zheng L.J., Fu K., Wang J., Hu F.D., Liao R.Y. (2019) Ginsenoside (Rg-1) promoted the wound closure of diabetic foot ulcer through iNOS elevation via miR-23a/IRF-1 axis. Life Sci., 233, 116525. CrossRef Scholar google search
