Skip to main content

Advertisement

SpringerLink
Log in

Andrographolide enhances hippocampal BDNF signaling and suppresses neuronal apoptosis, astroglial activation, neuroinflammation, and spatial memory deficits in a rat model of chronic cerebral hypoperfusion

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Andrographolide is a medical herbal compound with documented anti-inflammatory activity and therapeutic efficacy in animal models of Alzheimer’s disease, traumatic brain injury, and ischemic stroke. The present study examined the potential therapeutic effects of andrographolide on chronic cerebral hypoperfusion (CCH)–induced hippocampal neuronal damage and cognitive dysfunction. A CCH model was established in male Sprague Dawley (SD) rats using 2-vessel occlusion (2VO). After 4 weeks of CCH, spatial learning and memory were assessed in the Morris water maze and structural damage to the hippocampus by hematoxylin and eosin (HE) staining. Astrocyte activation was examined by immunohistochemical staining and Western blotting for glial fibrillary acid protein (GFAP), while expression levels of the pro-inflammatory cytokine-tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), the apoptosis effector cysteinyl aspartate specific proteinase-3 (caspase-3), and the neuroprotectant brain-derived neurotrophic factor (BDNF) and the TrkB receptor were estimated by Western blotting. After 4 weeks of CCH, the hippocampus of 2VO rats exhibited marked neurodegeneration as well as elevated GFAP, TNF-α, IL-1β, and caspase-3 compared to Sham controls. In addition, spatial learning was impaired compared to Sham controls. Andrographolide treatment during CCH suppressed astrocyte activation as evidenced by reduced GFAP expression, enhanced expression of BDNF and TrkB, improved impaired spatial learning and memory, and reversed upregulated TNF-α, IL-1β, and caspase-3 expression. These results reveal a potential neuroprotective effect of andrographolide on hippocampal neuronal damage and cognitive impairment from CCH due to suppression of astrocyte activation and enhancement of BDNF-TrkB signaling.

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

Similar content being viewed by others

References

  • Bertoglio JC, Baumgartner M, Palma R, Ciampi E, Carcamo C, Cáceres DD, Acosta-Jamett G, Hancke JL, Burgos RA (2016) Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study. BMC Neurol 16:77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan SJ, Wong WS, Wong PT et al (2010) Neuroprotective effects of andrographolide in a rat model of permanent cerebral ischaemia. Br J Pharmacol 161(3):668–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chern CM, Liou KT, Wang YH, Liao JF, Yen JC, Shen YC (2011) Andrographolide inhibits PI3K/AKT-dependent NOX2 and iNOS expression protecting mice against hypoxia/ischemia-induced oxidative brain injury. Planta Med 77(15):1669–1679

    Article  CAS  PubMed  Google Scholar 

  • Das S, Mishra KP, Ganju L, Singh SB (2017) Andrographolide - a promising therapeutic agent, negatively regulates glial cell derived neurodegeneration of prefrontal cortex, hippocampus and working memory impairment. J Neuroimmunol 313:161–175

    Article  CAS  PubMed  Google Scholar 

  • de Pins B, Cifuentes-Diaz C, Thamila Farah A et al (2019) Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease. J Neurosci

  • Du J, Zhang C, Na X et al (2018) Andrographolide protects mouse astrocytes against hypoxia injury by promoting autophagy and S100B expression. Braz J Med Biol Res 51(6):e7061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duncombe J, Kitamura A, Hase Y, Ihara M, Kalaria RN, Horsburgh K (2017) Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin Sci (Lond) 131(19):2451–2468

    Article  CAS  Google Scholar 

  • El Hayek L, Khalifeh M, Zibara V et al (2019) Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J Neurosci

  • Fletcher JL, Murray SS, Xiao J (2018) Brain-derived neurotrophic factor in central nervous system myelination: a new mechanism to promote myelin plasticity and repair. Int J Mol Sci 19(12)

  • Geng J, Liu W, Xiong Y, Ding H, Jiang C, Yang X, Li X, Elgehama A, Sun Y, Xu Q, Guo W, Gao J (2018) Andrographolide sulfonate improves Alzheimer-associated phenotypes and mitochondrial dysfunction in APP/PS1 transgenic mice. Biomed Pharmacother 97:1032–1039

    Article  CAS  PubMed  Google Scholar 

  • Goncalves CA, Rodrigues L, Bobermin LD et al (2018) Glycolysis-derived compounds from astrocytes that modulate synaptic communication. Front Neurosci 12:1035

    Article  PubMed  Google Scholar 

  • Graverini G, Piazzini V, Landucci E, Pantano D, Nardiello P, Casamenti F, Pellegrini-Giampietro DE, Bilia AR, Bergonzi MC (2018) Solid lipid nanoparticles for delivery of andrographolide across the blood-brain barrier: in vitro and in vivo evaluation. Colloids Surf B Biointerfaces 161:302–313

    Article  CAS  PubMed  Google Scholar 

  • Gu L, Yu Q, Li Q, Zhang L, Lu H, Zhang X (2018) Andrographolide protects PC12 cells against beta-amyloid-induced autophagy-associated cell death through activation of the Nrf2-mediated p62 signaling pathway. Int J Mol Sci 19(9)

  • Hancke JL, Srivastav S, Caceres DD et al (2019) A double-blind, randomized, placebo-controlled study to assess the efficacy of andrographis paniculata standardized extract (ParActin(R)) on pain reduction in subjects with knee osteoarthritis. Phytother Res 33:1469–1479

    Article  CAS  PubMed  Google Scholar 

  • Hase Y, Ding R, Harrison G, Hawthorne E, King A, Gettings S, Platten C, Stevenson W, Craggs LJL, Kalaria RN (2019) White matter capillaries in vascular and neurodegenerative dementias. Acta Neuropathol Commun 7(1):16

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang L, Nakamura Y, Lo EH, Hayakawa K (2019) Astrocyte signaling in the neurovascular unit after central nervous system injury. Int J Mol Sci 20(2)

  • Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 96(1):17–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JH, Ko PW, Lee HW, Jeong JY, Lee MG, Kim JH, Lee WH, Yu R, Oh WJ, Suk K (2017) Astrocyte-derived lipocalin-2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia. Glia. 65(9):1471–1490

    Article  PubMed  Google Scholar 

  • Lin HC, Li CC, Yang YC, Chiu TH, Liu KL, Lii CK, Chen HW (2019) Andrographis paniculata diterpenoids and ethanolic extract inhibit TNFalpha-induced ICAM-1 expression in EA.hy926 cells. Phytomedicine. 52:157–167

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Fassbender K (2018) Deficiency of TLR4 ameliorates hypoperfusion-induced brain pathology. Theranostics. 8(22):6355–6356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu W, Li R, Yin J, Guo S, Chen Y, Fan H, Li G, Li Z, Li X, Zhang X, He X, Duan C (2019) Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch. J Neuroinflammation 16(1):8

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–250

    Article  CAS  PubMed  Google Scholar 

  • Mansour A, Niizuma K, Rashad S, Sumiyoshi A, Ryoke R, Endo H, Endo T, Sato K, Kawashima R, Tominaga T (2018) A refined model of chronic cerebral hypoperfusion resulting in cognitive impairment and a low mortality rate in rats. J Neurosurg:1–11

  • Ojha CR, Rodriguez M, Karuppan MKM, Lapierre J, Kashanchi F, el-Hage N (2019) Toll-like receptor 3 regulates Zika virus infection and associated host inflammatory response in primary human astrocytes. PLoS One 14(2):e0208543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paemanee A, Hitakarun A, Wintachai P, Roytrakul S, Smith DR (2019) A proteomic analysis of the anti-dengue virus activity of andrographolide. Biomed Pharmacother 109:322–332

    Article  CAS  PubMed  Google Scholar 

  • Piazzini V, Landucci E, Graverini G, Pellegrini-Giampietro D, Bilia A, Bergonzi M (2018) Stealth and cationic nanoliposomes as drug delivery systems to increase andrographolide BBB permeability. Pharmaceutics 10(3)

  • Ray AK, DuBois JC, Gruber RC et al (2017) Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure. Glia. 65(12):2051–2069

    Article  PubMed  PubMed Central  Google Scholar 

  • Seo EJ, Klauck SM, Efferth T, Panossian A (2019) Adaptogens in chemobrain (part I): plant extracts attenuate cancer chemotherapy-induced cognitive impairment - transcriptome-wide microarray profiles of neuroglia cells. Phytomedicine. 55:80–91

    Article  CAS  PubMed  Google Scholar 

  • Serrano FG, Tapia-Rojas C, Carvajal FJ, Hancke J, Cerpa W, Inestrosa NC (2014) Andrographolide reduces cognitive impairment in young and mature AbetaPPswe/PS-1 mice. Mol Neurodegener 9:61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siuda J, Patalong-Ogiewa M, Zmuda W et al (2017) Cognitive impairment and BDNF serum levels. Neurol Neurochir Pol 51(1):24–32

    Article  PubMed  Google Scholar 

  • Trias E, Barbeito L, Yamanaka K (2018) Phenotypic heterogeneity of astrocytes in motor neuron disease. Clin Exp Neuroimmunol 9(4):225–234

    Article  PubMed  PubMed Central  Google Scholar 

  • Varela-Nallar L, Arredondo SB, Tapia-Rojas C et al (2015) Andrographolide stimulates neurogenesis in the adult hippocampus. Neural Plast 2015:935403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wan Q, Ma X, Zhang ZJ, Sun T, Xia F, Zhao G, Wu YM (2017) Ginsenoside reduces cognitive impairment during chronic cerebral hypoperfusion through brain-derived neurotrophic factor regulated by epigenetic modulation. Mol Neurobiol 54(4):2889–2900

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Liu B, Zhang W, Wilson B, Hong JS (2004) Andrographolide reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation. J Pharmacol Exp Ther 308(3):975–983

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Wang J, Wang F, Liu C, Yang X, Yang J, Ming D (2017a) VEGF-mediated cognitive and synaptic improvement in chronic cerebral hypoperfusion rats involves autophagy process. NeuroMolecular Med 19(2–3):423–435

    Article  CAS  PubMed  Google Scholar 

  • Wang D, Lin Q, Su S, Liu K, Wu Y, Hai J (2017b) URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy. Neuroscience. 344:293–304

    Article  CAS  PubMed  Google Scholar 

  • Wang DP, Liu KJ, Kasper G, Lin Q, Hai J (2017c) Inhibition of SENP3 by URB597 ameliorates neurovascular unit dysfunction in rats with chronic cerebral hypoperfusion. Biomed Pharmacother 91:872–879

    Article  CAS  PubMed  Google Scholar 

  • Wang DP, Yin H, Kang K, Lin Q, Su SH, Hai J (2018a) The potential protective effects of cannabinoid receptor agonist WIN55,212-2 on cognitive dysfunction is associated with the suppression of autophagy and inflammation in an experimental model of vascular dementia. Psychiatry Res 267:281–288

    Article  CAS  PubMed  Google Scholar 

  • Wang HC, Tsay HS, Shih HN, Chen YA, Chang KM, Agrawal DC, Huang S, Lin YL, Lee MJ (2018b) Andrographolide relieved pathological pain generated by spared nerve injury model in mice. Pharm Biol 56(1):124–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang YH, Yang YL, Cheng X, Zhang J, Li W, du GH (2019) Xiao-Xu-Ming decoction extract regulates differentially expressed proteins in the hippocampus after chronic cerebral hypoperfusion. Neural Regen Res 14(3):470–479

    Article  PubMed  PubMed Central  Google Scholar 

  • Wurzelmann M, Romeika J, Sun D (2017) Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury. Neural Regen Res 12(1):7–12

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie YC, Yao ZH, Yao XL, Pan JZ, Zhang SF, Zhang Y, Hu JC (2018) Glucagon-like peptide-2 receptor is involved in spatial cognitive dysfunction in rats after chronic cerebral hypoperfusion. J Alzheimers Dis 66(4):1559–1576

    Article  CAS  PubMed  Google Scholar 

  • Xu F, Wu H, Zhang K, Lv P, Zheng L, Zhao J (2016) Proneurogenic effects of andrographolide on RSC96 Schwann cells in vitro. Mol Med Rep 14(4):3573–3580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang CH, Yen TL, Hsu CY, Thomas PA, Sheu JR, Jayakumar T (2017) Multi-targeting Andrographolide, a novel NF-kappaB inhibitor, as a potential therapeutic agent for stroke. Int J Mol Sci 18(8)

  • Yen TL, Hsu WH, Huang SK et al (2013) A novel bioactivity of andrographolide from Andrographis paniculata on cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis. Pharm Biol 51(9):1150–1157

    Article  CAS  PubMed  Google Scholar 

  • Yen TL, Chen RJ, Jayakumar T, Lu WJ, Hsieh CY, Hsu MJ, Yang CH, Chang CC, Lin YK, Lin KH, Sheu JR (2016) Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats. Transl Res 170:57–72

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work received funding from the National Nature Science Foundation of China (81771410) and Priority of Shanghai key discipline of medicine (2017ZZ02020).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Postal address: No. 389, Xincun Road, Putuo District, Shanghai, 200065, China

      Da-Peng Wang, Yi-Fang Wu, Shao-Hua Su & Jian Hai

    2. Department of Neurosurgery, Zao Zhuang Municipal Hospital, Zaozhuang, 277000, Shandong, China

      Hang Yin

    3. Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

      Qi Lin

    4. Department of Neurosurgery, Feng Cheng Hospital, Shanghai, 201499, China

      Shu-Ping Fang

    5. Department of Neurosurgery, Affiliated Dongtai Hospital of Nantong University, Nantong, 224200, Jiangsu, China

      Jian-Hua Shen

    Authors
    1. Da-Peng Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Hang Yin
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Qi Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Shu-Ping Fang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jian-Hua Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yi-Fang Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Shao-Hua Su
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jian Hai
      View author publications

      You can also search for this author in PubMed Google Scholar

    Contributions

    DP. W. wrote the manuscript. H.Y., Q.L., SP. F., and JH. S. prepared the experiments and collected the data. YF. W. and SH. S. analyzed and interpreted the data. DP. W. and J.H. designed the study. All authors read and approved the manuscript.

    Corresponding authors

    Correspondence to Da-Peng Wang or Jian Hai.

    Ethics declarations

    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Publisher’s note

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

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Wang, DP., Yin, H., Lin, Q. et al. Andrographolide enhances hippocampal BDNF signaling and suppresses neuronal apoptosis, astroglial activation, neuroinflammation, and spatial memory deficits in a rat model of chronic cerebral hypoperfusion. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1277–1284 (2019). https://doi.org/10.1007/s00210-019-01672-9

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00210-019-01672-9

    Keywords

    Search

    Navigation