Skip to content
2000
Volume 24, Issue 5
  • ISSN: 1871-5273
  • E-ISSN: 1996-3181

Abstract

Introduction

Neuroinflammation derived from the activation of the microglia is considered a vital pathogenic factor of Alzheimer's Disease (AD). T-006, a tetramethylpyrazine derivative, has been found to alleviate cognitive deficits inhibiting tau expression and phosphorylation in AD transgenic mouse models. Recently, T-006 has been proven to dramatically decrease the levels of total Amyloid β (Aβ) peptide and Glial Fibrillary Acidic Protein (GFAP) and suppress the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in APP/PS1 mice. Therefore, we have further investigated the effects of T-006 on neuroinflammation in AD-like pathology.

Methods

The anti-inflammatory effects of T-006 and its underlying mechanisms were evaluated in Lipopolysaccharide (LPS)-induced AD rats. The potential protective effects against LPS-activated microglia-mediated neurotoxicity were also measured.

Results

T-006 significantly improved the cognitive impairment in LPS-induced AD rats by inhibiting the microglia/astrocyte activation. Further cellular assays found that T-006 significantly reserved the anomalous elevation of inflammatory cytokines in LPS-induced BV2 microglial cells in a concentration-dependent manner, while T-006 treatment alone showed no effects on the normal cultured cells. T-006 also reduced the levels of Toll-like Receptor 4 (TLR4)/Myeloid Differentiation protein-88 (MyD88)/NF-κB signaling-related proteins in BV2 cells exposed to LPS stimulation. TAK242, which selectively inhibits TLR4, slightly lessened the effects of T-006 in LPS-treatment BV2 cells without significance. Importantly, T-006 protected neurons against LPS-induced neuroinflammation by inhibiting the Reactive Oxygen Species (ROS) production and maintaining mitochondrial function.

Conclusion

T-006 inhibited TLR4-mediated MyD88/NF-κB signaling pathways to suppress neuroinflammation in the LPS-induced AD rat model.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cnsnddt/10.2174/0118715273337232241121113048
2025-01-08
2025-09-02

  • From This Site

    /content/journals/cnsnddt/10.2174/0118715273337232241121113048
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. VenegasC. HenekaM.T. Inflammasome-mediated innate immunity in Alzheimer’s disease.FASEB J.20193312130751308410.1096/fj.201900439 31702392
     [Google Scholar]
  2. Loera-ValenciaR. Cedazo-MinguezA. KenigsbergP.A. Current and emerging avenues for Alzheimer’s disease drug targets.J. Intern. Med.2019286439843710.1111/joim.12959 31286586
     [Google Scholar]
  3. LongJ.M. HoltzmanD.M. Alzheimer disease: an update on pathobiology and treatment strategies.Cell2019179231233910.1016/j.cell.2019.09.001 31564456
     [Google Scholar]
  4. OzbenT. OzbenS. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease.Clin. Biochem.201972878910.1016/j.clinbiochem.2019.04.001 30954437
     [Google Scholar]
  5. ColonnaM. ButovskyO. Microglia function in the central nervous system during health and neurodegeneration.Annu. Rev. Immunol.201735144146810.1146/annurev‑immunol‑051116‑052358 28226226
     [Google Scholar]
  6. LymanM. LloydD.G. JiX. VizcaychipiM.P. MaD. Neuroinflammation: The role and consequences.Neurosci. Res.20147911210.1016/j.neures.2013.10.004 24144733
     [Google Scholar]
  7. HammondT.R. MarshS.E. StevensB. Immune signaling in neurodegeneration.Immunity201950495597410.1016/j.immuni.2019.03.016 30995509
     [Google Scholar]
  8. ZhaoY. LiQ. NiuJ. Neutrophil membrane-camouflaged polyprodrug nanomedicine for inflammation suppression in ischemic stroke therapy.Adv. Mater.20243621231180310.1002/adma.202311803 38519052
     [Google Scholar]
  9. WangR. CaoS. BashirM.E.H. Treatment of peanut allergy and colitis in mice via the intestinal release of butyrate from polymeric micelles.Nat. Biomed. Eng.202271385510.1038/s41551‑022‑00972‑5 36550307
     [Google Scholar]
  10. ThakurS. DhapolaR. SarmaP. MedhiB. ReddyD.H. Neuroinflammation in Alzheimer’s disease: current progress in molecular signaling and therapeutics.Inflammation202346111710.1007/s10753‑022‑01721‑1 35986874
     [Google Scholar]
  11. DhapolaR. HotaS.S. SarmaP. BhattacharyyaA. MedhiB. ReddyD.H. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer’s disease.Inflammopharmacology20212961669168110.1007/s10787‑021‑00889‑6 34813026
     [Google Scholar]
  12. WeekmanE.M. SudduthT.L. AbnerE.L. Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice.J. Neuroinflammation201411112710.1186/1742‑2094‑11‑127 25062954
     [Google Scholar]
  13. MaphisN. XuG. Kokiko-CochranO.N. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.Brain201513861738175510.1093/brain/awv081 25833819
     [Google Scholar]
  14. LuC. ZhangJ. ShiX. Neuroprotective effects of tetramethylpyrazine against dopaminergic neuron injury in a rat model of Parkinson’s disease induced by MPTP.Int. J. Biol. Sci.201410435035710.7150/ijbs.8366 24719552
     [Google Scholar]
  15. ZhaoH. XuM.L. ZhangQ. Tetramethylpyrazine alleviated cytokine synthesis and dopamine deficit and improved motor dysfunction in the mice model of Parkinson’s disease.Neurol. Sci.201435121963196710.1007/s10072‑014‑1871‑9 25030124
     [Google Scholar]
  16. ZhangG. WuJ. HuangC. The tetramethylpyrazine analogue T-006 alleviates cognitive deficits by inhibition of Tau expression and phosphorylation in transgenic mice modeling Alzheimer’s disease.J. Mol. Neurosci.20217171456146610.1007/s12031‑020‑01762‑x 33403592
     [Google Scholar]
  17. ZengZ. ChangX. ZhangD. Structural elucidation and anti-neuroinflammatory activity of Polygala tenuifolia polysaccharide.Int. J. Biol. Macromol.20222191284129610.1016/j.ijbiomac.2022.08.161 36037912
     [Google Scholar]
  18. AbbateA. ToldoS. MarchettiC. KronJ. Van TassellB.W. DinarelloC.A. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease.Circ. Res.202012691260128010.1161/CIRCRESAHA.120.315937 32324502
     [Google Scholar]
  19. ChenH.Y. XuD.P. TanG.L. A potent multi-functional neuroprotective derivative of tetramethylpyrazine.J. Mol. Neurosci.201556497798710.1007/s12031‑015‑0566‑x 25982925
     [Google Scholar]
  20. ZhongJ. QiuX. YuQ. ChenH. YanC. A novel polysaccharide from Acorus tatarinowii protects against LPS-induced neuroinflammation and neurotoxicity by inhibiting TLR4-mediated MyD88/NF-κB and PI3K/Akt signaling pathways.Int. J. Biol. Macromol.202016346447510.1016/j.ijbiomac.2020.06.266 32621930
     [Google Scholar]
  21. ChenH. ZhongJ. LiJ. ZengZ. YuQ. YanC. PTP70-2, a novel polysaccharide from Polygala tenuifolia, prevents neuroinflammation and protects neurons by suppressing the TLR4-mediated MyD88/NF-κB signaling pathway.Int. J. Biol. Macromol.202219454655510.1016/j.ijbiomac.2021.11.097 34801584
     [Google Scholar]
  22. ChenX. ChoiI.Y. ChangT.S. Pretreatment with interferon-γ protects microglia from oxidative stress via up-regulation of Mn-SOD.Free Radic. Biol. Med.20094681204121010.1016/j.freeradbiomed.2009.01.027 19439213
     [Google Scholar]
  23. WooP.C.Y. LauS.K.P. MartelliP. Fatal systemic necrotizing infections associated with a novel paramyxovirus, anaconda paramyxovirus, in green anaconda juveniles.J. Clin. Microbiol.201452103614362310.1128/JCM.01653‑14 25078906
     [Google Scholar]
  24. ChenH. CaoJ. ZhaL. Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson’s disease models through activating the MEF2-PGC1α and BDNF/CREB pathways.Aging (Albany NY)20201214148971491710.18632/aging.103551 32710729
     [Google Scholar]
  25. XuD. ChenH. MakS. Neuroprotection against glutamate-induced excitotoxicity and induction of neurite outgrowth by T-006, a novel multifunctional derivative of tetramethylpyrazine in neuronal cell models.Neurochem. Int.20169919420510.1016/j.neuint.2016.07.006 27445088
     [Google Scholar]
  26. HenekaM.T. CarsonM.J. KhouryJ.E. Neuroinflammation in Alzheimer’s disease.Lancet Neurol.201514438840510.1016/S1474‑4422(15)70016‑5 25792098
     [Google Scholar]
  27. SzczepańskaK. BojarskiA.J. PopikP. Malikowska-RaciaN. Novel object recognition test as an alternative approach to assessing the pharmacological profile of sigma-1 receptor ligands.Pharmacol. Rep.20237551291129810.1007/s43440‑023‑00516‑x 37572216
     [Google Scholar]
  28. WangX. WangC. WangJ. Pseudoginsenoside-F11 (PF11) exerts anti-neuroinflammatory effects on LPS-activated microglial cells by inhibiting TLR4-mediated TAK1/IKK/NF-κB, MAPKs and Akt signaling pathways.Neuropharmacology20147964265610.1016/j.neuropharm.2014.01.022 24467851
     [Google Scholar]
  29. MuhammadT. IkramM. UllahR. RehmanS. KimM. Hesperetin, a citrus flavonoid, attenuates LPS-induced neuroinflammation, apoptosis and memory impairments by modulating TLR4/NF-κB Signaling.Nutrients201911364810.3390/nu11030648 30884890
     [Google Scholar]
  30. YangY.L. LiuM. ChengX. Myricitrin blocks activation of NF-κB and MAPK signaling pathways to protect nigrostriatum neuron in LPS-stimulated mice.J. Neuroimmunol.201933757704910.1016/j.jneuroim.2019.577049 31526918
     [Google Scholar]
  31. ZhaoM. ZhouA. XuL. ZhangX. The role of TLR4-mediated PTEN/PI3K/AKT/NF-κB signaling pathway in neuroinflammation in hippocampal neurons.Neuroscience20142699310110.1016/j.neuroscience.2014.03.039 24680857
     [Google Scholar]
  32. ZussoM. LunardiV. FranceschiniD. Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway.J. Neuroinflammation201916114810.1186/s12974‑019‑1538‑9 31319868
     [Google Scholar]
  33. LuY.C. YehW.C. OhashiP.S. LPS/TLR4 signal transduction pathway.Cytokine200842214515110.1016/j.cyto.2008.01.006 18304834
     [Google Scholar]
  34. LiC. ChenT. ZhouH. BHDPC is a novel neuroprotectant that provides anti-neuroinflammatory and neuroprotective effects by inactivating NF-κB and activating PKA/CREB.Front. Pharmacol.2018961410.3389/fphar.2018.00614 29988625
     [Google Scholar]
  35. WestA.P. Mitochondrial dysfunction as a trigger of innate immune responses and inflammation.Toxicology2017391546310.1016/j.tox.2017.07.016 28765055
     [Google Scholar]
  36. MawuenyegaK.G. SigurdsonW. OvodV. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease.Science20103306012177410.1126/science.1197623 21148344
     [Google Scholar]
  37. ZhangY. ThompsonR. ZhangH. XuH. APP processing in Alzheimer’s disease.Mol. Brain201141310.1186/1756‑6606‑4‑3 21214928
     [Google Scholar]
  38. WhitneyN.P. EidemT.M. PengH. HuangY. ZhengJ.C. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders.J. Neurochem.200910861343135910.1111/j.1471‑4159.2009.05886.x 19154336
     [Google Scholar]
  39. WalkerK.A. FicekB.N. WestbrookR. Understanding the role of systemic inflammation in Alzheimer’s disease.ACS Chem. Neurosci.20191083340334210.1021/acschemneuro.9b00333 31241312
     [Google Scholar]
  40. ZhouJ. DengY. LiF. YinC. ShiJ. GongQ. Icariside II attenuates lipopolysaccharide-induced neuroinflammation through inhibiting TLR4/MyD88/NF-κB pathway in rats.Biomed. Pharmacother.201911131532410.1016/j.biopha.2018.10.201 30590319
     [Google Scholar]
  41. TyagiE. AgrawalR. NathC. ShuklaR. Influence of LPS-induced neuroinflammation on acetylcholinesterase activity in rat brain.J. Neuroimmunol.20082051-2515610.1016/j.jneuroim.2008.08.015 18838174
     [Google Scholar]
  42. FuA.K.Y. HungK.W. YuenM.Y.F. IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline.Proc. Natl. Acad. Sci. USA201611319E2705E271310.1073/pnas.1604032113 27091974
     [Google Scholar]
  43. MerighiS. NigroM. TravagliA. GessiS. Microglia and Alzheimer’s Disease.Int. J. Mol. Sci.202223211299010.3390/ijms232112990 36361780
     [Google Scholar]
  44. ZhongQ. ZouY. LiuH. Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice.Mol. Brain20201312010.1186/s13041‑020‑0559‑8 32059688
     [Google Scholar]
  45. PeriF. CalabreseV. Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update.J. Med. Chem.20145793612362210.1021/jm401006s 24188011
     [Google Scholar]
  46. JinX. LiuM.Y. ZhangD.F. Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP 3 inflammasomes and TLR 4/NF-κB signaling pathway.CNS Neurosci. Ther.201925557559010.1111/cns.13086 30676698
     [Google Scholar]
  47. ZhouY. ChenY. XuC. ZhangH. LinC. TLR4 targeting as a promising therapeutic strategy for Alzheimer disease treatment.Front. Neurosci.20201460250810.3389/fnins.2020.602508 33390886
     [Google Scholar]
  48. LiuF. CaiJ. WangC. Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: a possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway.J. Neuroinflammation201815134710.1186/s12974‑018‑1388‑x 30572907
     [Google Scholar]
  49. WilkinsH.M. SwerdlowR.H. Relationships between mitochondria and neuroinflammation: implications for Alzheimer’s disease.Curr. Top. Med. Chem.201616884985710.2174/1568026615666150827095102 26311426
     [Google Scholar]
  50. KimJ. LeeH. ParkS.K. Donepezil regulates LPS and Aβ-stimulated neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 signaling.Int. J. Mol. Sci.202122191063710.3390/ijms221910637 34638977
     [Google Scholar]
  51. NohH. JeonJ. SeoH. Systemic injection of LPS induces region-specific neuroinflammation and mitochondrial dysfunction in normal mouse brain.Neurochem. Int.201469354010.1016/j.neuint.2014.02.008 24607701
     [Google Scholar]
  52. GubandruM. MarginaD. TsitsimpikouC. Alzheimer’s disease treated patients showed different patterns for oxidative stress and inflammation markers.Food Chem. Toxicol.20136120921410.1016/j.fct.2013.07.013 23871825
     [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273337232241121113048
Loading
Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer’s Disease Models by Modulating TLR4-Mediated MyD88/NF-κB Signaling
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 24, 382 (2025); https://doi.org/10.2174/0118715273337232241121113048
/content/journals/cnsnddt/10.2174/0118715273337232241121113048
/content/journals/cnsnddt/10.2174/0118715273337232241121113048
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): Alzheimer's disease; microglial activation; MyD88/NF-κB signaling pathways; neuroinflammation; T-006; Tetramethylpyrazine derivative; TLR4

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test