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Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System

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Abstract

Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500 μg/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200 mg/kg/day, for 30 days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (α7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect.

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References

  1. Anaeigoudari A, Soukhtanloo M, Shafei MN, Sadeghnia HR, Reisi P, Beheshti F et al (2016) Neuronal nitric oxide synthase has a role in the detrimental effects of lipopolysaccharide on spatial memory and synaptic plasticity in rats. Pharmacol Rep 68:243–249

    Article  CAS  PubMed  Google Scholar 

  2. Dehkordi NG, Noorbakhshnia M, Ghaedi K, Esmaeili A, Dabaghi M (2015) Omega-3 fatty acids prevent LPS-induced passive avoidance learning and memory and CaMKII-α gene expression impairments in hippocampus of rat. Pharmacol Rep 67:370–375

    Article  CAS  PubMed  Google Scholar 

  3. Belarbi K, Jopson T, Tweedie D, Arellano C, Luo W, Greig NH et al (2012) TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflamm 9:23

    Article  CAS  Google Scholar 

  4. Zhou T, Zu G, Zhang X, Wang X, Li S, Gong X et al (2016) Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson’s disease. Neuropharmacology 101:480–489

    Article  CAS  PubMed  Google Scholar 

  5. Zhang Y, Zhang Z, Wang H, Cai N, Zhou S, Zhao Y et al (2016) Neuroprotective effect of ginsenoside Rg1 prevents cognitive impairment induced by isoflurane anesthesia in aged rats via antioxidant, anti-inflammatory and anti-apoptotic effects mediated by the PI3K/AKT/GSK-3β pathway. Mol Med Rep 14:2778–2784

    CAS  PubMed  Google Scholar 

  6. Leung KW, Cheng YK, Mak NK, Chan KK, Fan TP, Wong RN (2006) Signaling pathway of ginsenoside-Rg1 leading to nitric oxide production in endothelial cells. FEBS Lett 580:3211–3216

    Article  CAS  PubMed  Google Scholar 

  7. Wu CF, Bi XL, Yang JY, Zhan JY, Dong YX, Wang JH et al (2007) Differential effects of ginsenosides on NO and TNF-α production by LPS-activated N9 microglia. Int Immunopharmacol 7:313–320

    Article  CAS  PubMed  Google Scholar 

  8. Bao S, Zou Y, Wang B, Li Y, Zhu J, Luo Y et al (2015) Ginsenoside Rg1 improves lipopolysaccharide-induced acute lung injury by inhibiting inflammatory responses and modulating infiltration of M2 macrophages. Int Immunopharmacol 28:429–434

    Article  CAS  PubMed  Google Scholar 

  9. Song X-Y, Hu J-F, Chu S-F, Zhang Z, Xu S, Yuan Y-H et al (2013) Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3β/tau signaling pathway and the Aβ formation prevention in rats. Eur J Pharmacol 710:29–38

    Article  CAS  PubMed  Google Scholar 

  10. Shi YQ, Huang TW, Chen LM, Pan XD, Zhang J, Zhu YG et al (2010) Ginsenoside Rg1 attenuates amyloid-beta content, regulates PKA/CREB activity, and improves cognitive performance in SAMP8 mice. J Alzheimers Dis 19:977–989

    Article  CAS  PubMed  Google Scholar 

  11. Zhu G, Wang Y, Li J, Wang J (2015) Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice. Neuroscience 292:81–89

    Article  CAS  PubMed  Google Scholar 

  12. Robinson L, Platt B, Riedel G (2011) Involvement of the cholinergic system in conditioning and perceptual memory. Behav Brain Res 221:443–465

    Article  CAS  PubMed  Google Scholar 

  13. Takase K, Mitsushima D, Masuda J, Mogi K, Funabashi T, Endo Y et al (2005) Feeding with powdered diet after weaning affects sex difference in acetylcholine release in the hippocampus in rats. Neuroscience 136:593–599

    Article  CAS  PubMed  Google Scholar 

  14. Kart E, Jocham G, Müller CP, Schlömer C, Brandão ML, Huston JP et al (2004) Neurokinin-1 receptor antagonism by SR140333: enhanced in vivo ACh in the hippocampus and promnestic post-trial effects. Peptides 25:1959–1969

    Article  CAS  PubMed  Google Scholar 

  15. Xu Q-Q, Xu Y-J, Yang C, Tang Y, Li L, Cai H-B et al (2016) Sodium tanshinone IIA sulfonate attenuates scopolamine-induced cognitive dysfunctions via improving cholinergic system. BioMed Res Int 2016:9852536

    PubMed  PubMed Central  Google Scholar 

  16. Shen J-x, Tu B, Yakel JL (2009) Inhibition of α7-containing nicotinic ACh receptors by muscarinic M(1) ACh receptors in rat hippocampal CA1 interneurones in slices. J Physiol 587:1033–1042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li D-J, Tang Q, Shen F-M, Su D-F, Duan J-L, Xi T (2009) Overexpressed α7 nicotinic acetylcholine receptor inhibited proinflammatory cytokine release in NIH3T3 cells. J Biosci Bioeng 108:85–91

    Article  CAS  PubMed  Google Scholar 

  18. Lykhmus O, Voytenko L, Koval L, Mykhalskiy S, Kholin V, Peschana K et al (2015) α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β(42) accumulation in the mouse brain to impair memory. PLoS ONE 10:e0122706

    Article  PubMed  PubMed Central  Google Scholar 

  19. Marubio LM, Paylor R (2004) Impaired passive avoidance learning in mice lacking central neuronal nicotinic acetylcholine receptors. Neuroscience 129:575–582

    Article  CAS  PubMed  Google Scholar 

  20. de Oliveira P, Gomes AQ, Pacheco TR, Vitorino de Almeida V, Saldanha C, Calado A (2012) Cell-specific regulation of acetylcholinesterase expression under inflammatory conditions. Clin Hemorheol Microcirc 51:129–137

    PubMed  Google Scholar 

  21. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J et al (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343

    Article  CAS  PubMed  Google Scholar 

  22. Lykhmus O, Gergalova G, Zouridakis M, Tzartos S, Komisarenko S, Skok M (2015) Inflammation decreases the level of alpha7 nicotinic acetylcholine receptors in the brain mitochondria and makes them more susceptible to apoptosis induction. Int Immunopharmacol 29:148–151

    Article  CAS  PubMed  Google Scholar 

  23. Lee Y-J, Choi D-Y, Choi IS, Kim KH, Kim YH, Kim HM et al (2012) Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflammation 9:35

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Watson C, Paxinos G (2014) The rat brain in stereotaxic coordinates. Seventh Edition, Elsevier Academic Press, San Diego

  25. Sarter M, Bodewitz G, Stephens DN (1988) Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines. Psychopharmacology 94:491–495

    Article  CAS  PubMed  Google Scholar 

  26. Lee Y, Oliynyk S, Jung J-C, Han JJ, Oh S (2013) Administration of glucosylceramide ameliorated the memory impairment in aged mice. Evid-based Complementary Alter Med 824120:10

    Google Scholar 

  27. Hasan W, Woodward WR, Habecker BA (2012) Altered atrial neurotransmitter release in transgenic p75 –/– and gp130 KO mice. Neurosci Lett 529:55–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  29. Wang X, Yan S, Wang A, Li Y, Zhang F (2014) Gastrodin ameliorates memory deficits in 3,3′-iminodipropionitrile-induced rats: possible involvement of dopaminergic system. Neurochem Res 39:1458–1466

    Article  CAS  PubMed  Google Scholar 

  30. Hritcu L, Foyet HS, Stefan M, Mihasan M, Asongalem AE, Kamtchouing P (2011) Neuroprotective effect of the methanolic extract of Hibiscus asper leaves in 6-hydroxydopamine-lesioned rat model of Parkinson’s disease. J Ethnopharmacol 137:585–591

    Article  PubMed  Google Scholar 

  31. Sasaki-Hamada S, Hoshi M, Niwa Y, Ueda Y, Kokaji A, Kamisuki S et al (2016) Neoechinulin A induced memory improvements and antidepressant-like effects in mice. Prog Neuropsychopharmacol Biol Psychiatry 71:155–161

    Article  CAS  PubMed  Google Scholar 

  32. Joshi R, Garabadu D, Teja GR, Krishnamurthy S (2014) Silibinin ameliorates LPS-induced memory deficits in experimental animals. Neurobiol Learn Mem 116:117–131

    Article  CAS  PubMed  Google Scholar 

  33. Lynch G, Palmer LC, Gall CM (2011) The likelihood of cognitive enhancement. Pharmacol Biochem Behav 99:116–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nizri E, Hamra-Amitay Y, Sicsic C, Lavon I, Brenner T (2006) Anti-inflammatory properties of cholinergic up-regulation: a new role for acetylcholinesterase inhibitors. Neuropharmacology 50:540–547

    Article  CAS  PubMed  Google Scholar 

  35. Silva-Herdade AS, Saldanha C (2013) Effects of acetylcholine on an animal mode of inflammation. Clin Hemorheol Microcirc 53:209–216

    CAS  PubMed  Google Scholar 

  36. Tyagi E, Agrawal R, Nath C, Shukla R (2008) Influence of LPS-induced neuroinflammation on acetylcholinesterase activity in rat brain. J Neuroimmunol 205:51–56

    Article  CAS  PubMed  Google Scholar 

  37. Taepavarapruk P, Song C (2010) Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment. J Neurochem 112:1054–1064

    Article  CAS  PubMed  Google Scholar 

  38. Zong Y, Ai QL, Zhong LM, Dai JN, Yang P, He Y et al (2012) Ginsenoside Rg1 attenuates lipopolysaccharide-induced inflammatory responses via the phospholipase Cγ signaling pathway in murine BV-2 microglial cells. Curr Med Chem 19:770–779

    Article  CAS  PubMed  Google Scholar 

  39. Wang Q, Sun LH, Jia W, Liu XM, Dang HX, Mai WL et al (2010) Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine-induced learning and memory impairment in mice. Phytother Res 24:1748–1754

    Article  CAS  PubMed  Google Scholar 

  40. Kim JM, Park SK, Guo TJ, Kang JY, Ha JS, Lee DS et al (2016) Anti-amnesic effect of Dendropanax morbifera via JNK signaling pathway on cognitive dysfunction in high-fat diet-induced diabetic mice. Behav Brain Res 312:39–54

    Article  CAS  PubMed  Google Scholar 

  41. Pehrson AL, Hillhouse TM, Haddjeri N, Rovera R, Porter JH, Mørk A et al (2016) Task- and treatment length-dependent effects of vortioxetine on scopolamine-induced cognitive dysfunction and hippocampal extracellular acetylcholine in rats. J Pharmacol Exp Ther 358:472–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Deibel SH, Weishaupt N, Regis AM, Hong NS, Keeley RJ, Balog RJ et al (2016) Subtle learning and memory impairment in an idiopathic rat model of Alzheimer’s disease utilizing cholinergic depletions and β-amyloid. Brain Res 1646:12–24

    Article  CAS  PubMed  Google Scholar 

  43. Yakel JL (2014) Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity. J Physiol 592:4147–4153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cao G, Zhu J, Zhong Q, Shi C, Dang Y, Han W et al (2013) Distinct roles of methamphetamine in modulating spatial memory consolidation, retrieval, reconsolidation and the accompanying changes of ERK and CREB activation in hippocampus and prefrontal cortex. Neuropharmacology 67:144–154

    Article  CAS  PubMed  Google Scholar 

  45. Churchwell JC, Kesner RP (2011) Hippocampal-prefrontal dynamics in spatial working memory: Interactions and independent parallel processing. Behav Brain Res 225:389–395

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE et al (2000) Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci 20:149–155

    PubMed  Google Scholar 

  47. Ming Z, Wotton CA, Appleton RT, Ching JC, Loewen ME, Sawicki G et al (2015) Systemic lipopolysaccharide-mediated alteration of cortical neuromodulation involves increases in monoamine oxidase-A and acetylcholinesterase activity. J Neuroinflamm 12:37

    Article  Google Scholar 

  48. Chiapinotto Spiazzi C, Bucco Soares M, Pinto Izaguirry A, Musacchio Vargas L, Zanchi MM, Frasson Pavin N et al (2015) Selenofuranoside ameliorates memory loss in Alzheimer-like sporadic dementia: AChE activity, oxidative stress, and inflammation involvement. Oxid Med Cell Longev 2015:976908

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kim E-J, Jung I-H, Van Le TK, Jeong J-J, Kim N-J, Kim D-H (2013) Ginsenosides Rg5 and Rh3 protect scopolamine-induced memory deficits in mice. J Ethnopharmacol 146:294–299

    Article  CAS  PubMed  Google Scholar 

  50. Ming Z, Sawicki G, Bekar LK (2015) Acute systemic LPS-mediated inflammation induces lasting changes in mouse cortical neuromodulation and behavior. Neurosci Lett 590:96–100

    Article  CAS  PubMed  Google Scholar 

  51. Chu S, Gu J, Feng L, Liu J, Zhang M, Jia X et al (2014) Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses. Int Immunopharmacol 19:317–326

    Article  CAS  PubMed  Google Scholar 

  52. Foyet HS, Ngatanko Abaïssou HH, Wado E, Asongalem Acha E, Alin C (2015) Emilia coccinae (SIMS) G Extract improves memory impairment, cholinergic dysfunction, and oxidative stress damage in scopolamine-treated rats. BMC Complement Altern Med 15:333

    Article  PubMed  PubMed Central  Google Scholar 

  53. Tyagi E, Agrawal R, Nath C, Shukla R (2010) Inhibitory role of cholinergic system mediated via α7 nicotinic acetylcholine receptor in LPS-induced neuro-inflammation. Innate. Immunity 16:3–13

    CAS  Google Scholar 

  54. Lykhmus O, Mishra N, Koval L, Kalashnyk O, Gergalova G, Uspenska K et al (2016) Molecular mechanisms regulating LPS-Induced inflammation in the brain. Front Mol Neurosci 9:19

    Article  PubMed  PubMed Central  Google Scholar 

  55. Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology 184:523–539

    Article  CAS  PubMed  Google Scholar 

  56. Chen T, Wang C, Sha S, Zhou L, Chen L, Chen L (2016) Simvastatin enhances spatial memory and long-term potentiation in hippocampal CA1 via upregulation of α7 nicotinic acetylcholine receptor. Mol Neurobiol 53:4060–4072

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Provincial Natural Science Foundation of Shandong [Grant Number ZR2015HQ002], the National Natural Science Foundation of China [Grant Numbers 81572534 and 81602226], the Provincial Projects of Medical and Technology Development Program of Shandong [Grant Numbers 2014WS0091 and 2014WS0347], the Key Research and Development Program of Shandong Province [Grant Number 2015GSF118096], and a China Postdoctoral Science Foundation Funded Project [Grant Number 2016M590641].

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Correspondence to Tianyin Wang.

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Jin, Y., Peng, J., Wang, X. et al. Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System. Neurochem Res 42, 1299–1307 (2017). https://doi.org/10.1007/s11064-016-2171-y

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