Skip to main content

Advertisement

SpringerLink
Log in

Bulbocodin D ameliorate cognitive impairment in APP/PS1 transgenic mice by modulating amyloid-beta burden, oxidative status and neuroinflammation

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Amyloid β peptide (Aβ) triggers a series of pathological events including microglial activation, oxidative stress, and inflammation-causing neuronal death and typical pathological changes in Alzheimer’s disease (AD).

Objectives

This study aimed to investigate the therapeutic effects and mechanism of bulbocodin D for AD in vivo.

Methods

In this study, Morris water maze (MWM) analysis was used to detect the cognitive ability of APP/PS1 mice after gavage with bulbocodin D for 2 months. Levels of Aβ40, Aβ42, IL-1β, and TNF-α were evaluated by ELISA. Aβ plaques and biomarkers of neuroinflammation were also investigated through histological analysis.

Results

We established that bulbocodin D significantly improved cognitive deficits in APP/PS1 transgenic mice and reduced the levels of amyloid plaque, Aβ40, and Aβ42. Bulbocodin D also reduced levels of microglial markers IbA1, GFAP, and antioxidant enzymes and reduced the products of lipid peroxidation and proinflammatory cytokines.

Conclusion

In summary, the present study provides preclinical evidence that oral bulbocodin D can reduce AD pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

CNS:

central nervous system

Aβ:

β-amyloid

BACE1:

beta-secretase

APP:

amyloid precursor protein

SOD:

superoxide dismutase

GSH-PX:

glutathione peroxidase

MDA:

malondialdehyde

ROS:

reactive oxygen damages

TNF-α:

tumor necrosis factor α

IL-1β:

interleukin 1β

NF-κB:

nuclear factor-κb

ThT:

thioflavin T

IbA1:

ionized calcium binding adapter molecule 1

GFAP:

glial fibrillary acidic protein

References

  • Alkadhi KA (2019) Cellular and molecular differences between area CA1 and the dentate gyrus of the hippocampus. Mol Neurobiol 56:6566–6580

    Article  CAS  Google Scholar 

  • Association (2019) Alzheimer's disease facts and figures. Alzheimers Dement 15:321–387

    Article  Google Scholar 

  • Browne TC, Mcquillan K, Mcmanus RM, O'Reilly JA, Mills KHG, Lynch MA (2013) IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol 190:2241–2251

    Article  CAS  Google Scholar 

  • Chen MF, Liou SS, Kao ST, Liu IM (2019) Erianin protects against high glucose-induced oxidative injury in renal tubular epithelial cells. Food Chem Toxicol 126:97–105

    Article  CAS  Google Scholar 

  • Chen Z, Zhong C (2014) Oxidative stress in Alzheimer’s disease. Neurosci Bull 30:271–281

    Article  CAS  Google Scholar 

  • Cummings JL, Vinters HV, Cole GM, Khachaturian ZS (1998) Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 51:S2–S17 discussion S65-7

    Article  CAS  Google Scholar 

  • Dao AT, Zagaar MA, Levine AT, Alkadhi KA (2016) Comparison of the effect of exercise on late-phase LTP of the dentate gyrus and CA1 of Alzheimer's disease model. Mol Neurobiol 53:6859–6868

    Article  CAS  Google Scholar 

  • Deane R, Singh I, Sagare AP, Bell RD, Zlokovic BV (2012) A multimodal RAGE-specific inhibitor reduces amyloid ??-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Investig 122:1377–1392

    Article  CAS  Google Scholar 

  • Geldenhuys WJ, Van der Schyf CJ (2013) Rationally designed multi-targeted agents against neurodegenerative diseases. Curr Med Chem 20:1662–1672

    Article  CAS  Google Scholar 

  • Guan ZF, Tao YH, Zhang XM, Guo QL, Liu YC, Zhang Y, Wang YM, Ji G, Wu GF, Wang NN, Yang H, Yu ZY, Guo JC, Zhou HG (2017) G-CSF and cognitive dysfunction in elderly diabetic mice with cerebral small vessel disease: preventive intervention effects and underlying mechanisms. CNS Neurosci Therapeut 23:462–474

    Article  CAS  Google Scholar 

  • Hao F, Feng Y (2020) Biological evaluation of naturally occurring bulbocodin D as a potential multi-target agent for Alzheimer's disease. Brain Res Bull 165:48–55

    Article  CAS  Google Scholar 

  • Jiang XW, Bai JP, Zhang Q, Hu XL, Tian X, Zhu J, Liu J, Meng WH, Zhao QC (2017) Caffeoylquinic acid derivatives protect SH-SY5Y neuroblastoma cells from hydrogen peroxide-induced injury through modulating oxidative status. Cell Mol Neurobiol 37:499–509

    Article  CAS  Google Scholar 

  • Kuter KOL, Glowacka U, Paleczna M (2019) Astrocyte support is important for the compensatory potential of the nigrostriatal system neurons during early neurodegeneration. J Neurochem 148:63–79

    CAS  PubMed  Google Scholar 

  • Li C, Guo XD, Lei M, Wu JY, Jin JZ, Shi XF, Zhu ZY, Rukachaisirikul V, Hu LH, Wen TQ, Shen X (2017) Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aβ and Tau pathologies. Acta Pharmacol Sin 38:9–28

    Article  Google Scholar 

  • Li Y, Tan MS, Jiang T, Tan L (2014) Microglia in Alzheimer's disease. Biomed Res Int 2014:437483

    PubMed  PubMed Central  Google Scholar 

  • Liu R, Li JZ, Song JK, Zhou D, Huang C, Bai XY, Xie T, Zhang X, Li YJ, Wu CX, Zhang L, Li L, Zhang TT, Du GH (2014) Pinocembrin improves cognition and protects the neurovascular unit in Alzheimer related deficits. Neurobiol Aging 35(6):1275–1285

  • Ma Y, Ma B, Shang Y, Yin Q, Liu X (2017) Flavonoid-rich ethanol extract from the leaves of Diospyros kaki attenuates cognitive deficits, amyloid-beta production, oxidative stress, and neuroinflammation in APP/PS1 transgenic mice. Brain Res 1678:85–93

    Article  Google Scholar 

  • McGrath LT, McGleenon BM, Brennan S, McColl D, Mc IS, Passmore AP (2001) Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM : Monthly J Assoc Phys 94:485–490

    Article  CAS  Google Scholar 

  • Navarro VS-ME, Jimenez S, Munoz-Castro C, Sanchez-Varo R, Davila JC, Vizuete M, Gutierrez A, Vitorica J (2018) Microglia in Alzheimer's disease: activated, dysfunctional or degenerative. Front Aging Neurosci 10:140

    Article  Google Scholar 

  • Orhan IE, Senol FS (2016) Designing multi-targeted therapeutics for the treatment of Alzheimer's disease. Curr Top Med Chem 16:1889–1896

    Article  CAS  Google Scholar 

  • Peng-Xin Xu S-WW, Yu X-L, Ya-Jing S, Wang T, Zhou W-W, He Z, Wang Y-J, Liu R-T (2014) Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing Abeta oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res 264:173–180

    Article  Google Scholar 

  • Rad SK, Arya A, Karimian H, Madhavan P, Rizwan F, Koshy S, Prabhu G (2018) Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer's disease. Drug Design Develop Ther 12:3999–4021

    Article  CAS  Google Scholar 

  • Sala Frigerio C, De Strooper B (2016) Alzheimer's disease mechanisms and emerging roads to novel therapeutics. Annu Rev Neurosci 39:57–79

    Article  CAS  Google Scholar 

  • Sharma P, Srivastava P, Seth A, Tripathi PN, Banerjee AG, Shrivastava SK (2019a) Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies. Prog Neurobiol 174:53–89

    Article  CAS  Google Scholar 

  • Sharma P, Tripathi A, Tripathi PN, Prajapati SK, Seth A, Tripathi MK, Srivastava P, Tiwari V, Krishnamurthy S, Shrivastava SK (2019b) Design and development of multitarget-directed N-Benzylpiperidine analogs as potential candidates for the treatment of Alzheimer's disease. Eur J Med Chem 167:510–524

    Article  CAS  Google Scholar 

  • Sharma P, Tripathi A, Tripathi PN, Singh SS, Singh SP, Shrivastava SK (2019c) Novel molecular hybrids of N-benzylpiperidine and 1,3,4-oxadiazole as multitargeted therapeutics to treat Alzheimer's disease. ACS Chem Neurosci 10:4361–4384

    Article  CAS  Google Scholar 

  • Tian XGL-P, Hu X-L, Huang J, Fan Y-H, Ren T-S, Zhao Q-C (2014) Protective effects of Arctium lappa L. roots against hydrogen peroxide-induced cell injury and potential mechanisms in SH-SY5Y cells. Cell Mol Neurobiol 35:335–344

    Article  Google Scholar 

  • Tripathi A, Choubey PK, Sharma P, Seth A, Saraf P, Shrivastava SK (2020) Design, synthesis, and biological evaluation of ferulic acid based 1,3,4-oxadiazole hybrids as multifunctional therapeutics for the treatment of Alzheimer's disease. Bioorg Chem 95:103506

    Article  CAS  Google Scholar 

  • Wang Q, Jiang H, Wang L, Yi H, Li Z, Liu R (2019a) Vitegnoside mitigates neuronal injury, mitochondrial apoptosis, and inflammation in an Alzheimer's disease cell model via the p38 MAPK/JNK Pathway. J Alzheimers Dis 72:199–214

    Article  CAS  Google Scholar 

  • Wang X, Wang Y, Zhu Y, Yan L, Zhao L (2019b) Neuroprotective EFFECT of S-trans, trans-farnesylthiosalicylic acid via inhibition of RAS/ERK pathway for the treatment of Alzheimer's disease. Drug Design Develop Ther 13:4053–4063

    Article  CAS  Google Scholar 

  • Xiao-wen Jiang W-wL, Wu Y-t, Wu Q, Lu H-y, Xu Z-h, Gao H-y, Zhao Q-c (2020) Notopterygium incisum extract (NRE) rescues cognitive deficits in APP/PS1 Alzheimer’s disease mice by attenuating amyloid-beta, tau, and neuroinflammation pathology. J Ethnopharmacol 249:112433

    Article  Google Scholar 

  • Xu PX, Wang SW, Yu XL, Su YJ, Wang T, Zhou WW, Zhang H, Wang YJ, Liu RT (2014) Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res 264:173–180

    Article  CAS  Google Scholar 

  • Zhou Y, Ning X, Li L, Yu Z, Zhang X, Dong M (2014) Puerarin alleviates cognitive impairment and oxidative stress in APP/PS1 transgenic mice. Int J Neuropsychopharmacol 17:635–644

    Article  Google Scholar 

  • Zhu Z, Yan J, Jiang W, Yao XG, Chen J, Chen L, Li C, Hu L, Jiang H, Shen X (2013) Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance. J Neurosci 33:13138–13149

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, 110122, Liaoning, China

    Fengjin Hao

  2. Department of Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, China

    Yueqin Feng

Authors
  1. Fengjin Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yueqin Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yueqin Feng.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 145 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hao, F., Feng, Y. Bulbocodin D ameliorate cognitive impairment in APP/PS1 transgenic mice by modulating amyloid-beta burden, oxidative status and neuroinflammation. Psychopharmacology 238, 2073–2082 (2021). https://doi.org/10.1007/s00213-021-05832-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-021-05832-9

Keywords

Search

Navigation