Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder in which superior brain functions, such as memory and cognition, are impaired. Currently, no effective treatment is available for AD. Although andrographolide (ANDRO), a compound extracted from the herb Andrographis paniculata, has shown interesting effects in models of several diseases, including AD, its effects on other molecular changes observed in AD, such as neuroinflammation and oxidative stress, have not yet been studied. To evaluate the impact of ANDRO-based intervention on the levels of amyloid-β (Aβ) and neuroinflammatory and oxidative stress markers in the brains of aged Octodon degus, a Chilean rodent, fifty-six-month-old O. degus were treated intraperitoneally with 2 or 4 mg/kg ANDRO. Vehicle-injected and 12-month-old O. degus were used as positive controls. Then, the protein levels of selected markers were assessed via immunohistochemistry and immunoblotting. ANDRO significantly reduced the total Aβ burden as well as astrogliosis and interleukin-6 levels. Moreover, ANDRO significantly reduced the levels of 4-hydroxynonenal and N-tyrosine adducts, suggesting a relevant reduction in oxidative stress within aged O. degus brain. Considering that O. degus has been proposed as a potential “natural” model for sporadic AD due to the development of neuropathological markers that resemble this pathology, our results suggest that ANDRO should be further studied to establish its potential as a therapeutic drug for AD.
KeywordsAndrographolide Amyloid-β Neuroinflammation Oxidative stress Alzheimer’s disease Octodon degus
We thank the “Lithium in Health and Disease” project from the Sociedad Química y Minera de Chile (SQM).
CL contributed to the western blot analyses and the drafting of this work; JMZ prepared and critically revised the final draft of this manuscript; DSR administered the ANDRO and vehicle solution and manuscript revision; PC contributed to the immunofluorescence analysis and to manuscript revision; NCI and FB contributed to the conception and design of this work as well as the revision of the final manuscript.
This work was supported by a postdoctoral grant from FONDECYT (N° 3,140,395 to DSR and N° 11,160,651 to PC) and by grants from the Basal Center of Excellence in Science and Technology (CONICYT PIA/BASAL FB0002 to FB 0002–2014 (Line 3), CONICYT-AFB 170005 and FONDECYT N° 1,160,724 to NCI).
Compliance with Ethical Standards
Conflict of Interest
The authors have no conflicts of interest to disclose.
- 11.Inestrosa NC, Rios JA, Cisternas P, Tapia-Rojas C, Rivera DS, Braidy N, Zolezzi JM, Godoy JA et al (2015) Age progression of neuropathological markers in the brain of the Chilean rodent Octodon degus, a natural model of Alzheimer's disease. Brain Pathol 25(6):679–691. https://doi.org/10.1111/bpa.12226 CrossRefGoogle Scholar
- 12.Ardiles AO, Tapia-Rojas CC, Mandal M, Alexandre F, Kirkwood A, Inestrosa NC, Palacios AG (2012) Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease. Proc Natl Acad Sci U S A 109(34):13835–13840. https://doi.org/10.1073/pnas.1201209109 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Rivera DS, Lindsay CB, Codocedo JF, Morel I, Pinto C, Cisternas P, Bozinovic F, Inestrosa NC (2016) Andrographolide recovers cognitive impairment in a natural model of Alzheimer’s disease (Octodon degus). Neurobiol Aging 46:204–220. https://doi.org/10.1016/j.neurobiolaging.2016.06.0 CrossRefPubMedGoogle Scholar
- 14.Cisternas P, Zolezzi JM, Lindsay C, Rivera DS, Martinez A, Bozinovic F, Inestrosa NC (2018) New insights into the spontaneous human Alzheimer's disease-like model Octodon degus: Unraveling amyloid-beta peptide aggregation and age-related amyloid pathology. J Alzheimers Dis 66(3):1145–1163. https://doi.org/10.3233/JAD-180729 CrossRefPubMedGoogle Scholar
- 15.Panossian A, Hovhannisyan A, Mamikonyan G, Abrahamian H, Hambardzumyan E, Gabrielian E, Goukasova G, Wikman G et al (2000) Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine 7(5):351–364CrossRefGoogle Scholar
- 20.Toledo EM, Inestrosa NC (2010) Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Mol Psychiatry 15(3):272–285. https://doi.org/10.1038/mp.2009.72 CrossRefPubMedGoogle Scholar
- 23.Braidy N, Munoz P, Palacios AG, Castellano-Gonzalez G, Inestrosa NC, Chung RS, Sachdev P, Guillemin GJ (2012) Recent rodent models for Alzheimer's disease: Clinical implications and basic research. J Neural Transm 119(2):173–195. https://doi.org/10.1007/s00702-011-0731-5 CrossRefPubMedGoogle Scholar
- 26.van Groen T, Kadish I, Popovic N, Popovic M, Caballero-Bleda M, Bano-Otalora B, Vivanco P, Rol MA et al (2011) Age-related brain pathology in Octodon degu: Blood vessel, white matter and Alzheimer-like pathology. Neurobiol Aging 32(9):1651–1661. https://doi.org/10.1016/j.neurobiolaging.2009.10.008 CrossRefGoogle Scholar
- 34.McDonald CL, Hennessy E, Rubio-Araiz A, Keogh B, McCormack W, McGuirk P, Reilly M, Lynch MA (2016) Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease. Brain Behav Immun 58:191–200. https://doi.org/10.1016/j.bbi.2016.07.143 CrossRefPubMedGoogle Scholar
- 39.Zhou X, Li J, Yang W (2014) Calcium/calmodulin-dependent protein kinase II regulates cyclooxygenase-2 expression and prostaglandin E2 production by activating cAMP-response element-binding protein in rat peritoneal macrophages. Immunology 143(2):287–299. https://doi.org/10.1111/imm.12309 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Chiou WF, Lin JJ, Chen CF (1998) Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide. Br J Pharmacol 125(2):327–334. https://doi.org/10.1038/sj.bjp.0702073 CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Hidalgo MA, Hancke JL, Bertoglio JC, Burgos R (2013) Andrographolide a new potential drug for the long term treatment of rheumatoid arthritis disease. In: Hiroaki M (ed) Innovative Rheumatology First Edn. IntehOpen Limited, LondonGoogle Scholar
- 45.Wang X, Ye P, Cao R, Yang X, Xiao W, Zhang Y, Bai Y, Wu H (2014) The association of homocysteine with metabolic syndrome in a community-dwelling population: Homocysteine might be concomitant with metabolic syndrome. PLoS One 9(11):e113148. https://doi.org/10.1371/journal.pone.0113148 CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Wong SY, Tan MG, Banks WA, Wong WS, Wong PT, Lai MK (2016) Andrographolide attenuates LPS-stimulated up-regulation of C-C and C-X-C motif chemokines in rodent cortex and primary astrocytes. J Neuroinflammation 13:34. https://doi.org/10.1186/s12974-016-0498-6 CrossRefPubMedPubMedCentralGoogle Scholar
- 56.Gill R, Tsung A, Billiar T (2010) Linking oxidative stress to inflammation: Toll-like receptors. Free Radic Biol Med 48(9):1121–1132. https://doi.org/10.1016/j.freeradbiomed.2010.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
- 64.Gemma C, Vila J, Bachstetter A, Bickford PC (2007) Oxidative stress and the aging brain: From theory to prevention. In DR Riddle (ed) Brain aging: Models, methods, and mechanisms, CRC Press/Taylor & Francis, Boca RatónGoogle Scholar
- 65.Bradley MA, Markesbery WR, Lovell MA (2010) Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease. Free Radic Biol Med 48(12):1570–1576. https://doi.org/10.1016/j.freeradbiomed.2010.02.016 CrossRefPubMedPubMedCentralGoogle Scholar
- 68.Wang DP, Yin H, Lin Q, Fang SP, Shen JH, Wu YF, Su SH, Hai J (2019) 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. https://doi.org/10.1007/s00210-019-01672-9 CrossRefGoogle Scholar
- 69.Tapia-Rojas C, Schuller A, Lindsay CB, Ureta RC, Mejias-Reyes C, Hancke J, Melo F, Inestrosa NC (2015) Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3beta: Autoregulation of GSK-3beta in vivo. Biochem J 466(2):415–430. https://doi.org/10.1042/BJ20140207 CrossRefPubMedGoogle Scholar
- 71.Cisternas P, Oliva CA, Torres VI, Barrera DP, Inestrosa NC (2019) Presymptomatic treatment with Andrographolide improves brain metabolic markers and cognitive behavior in a model of early-onset Alzheimer’s disease. Front Cell Neurosci. https://doi.org/10.3389/fncel.2019.00295
- 75.Peng S, Hang N, Liu W, Guo W, Jiang C, Yang X, Xu Q, Sun Y (2016) Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-kappaB pathways. Acta Pharm Sin B 6(3):205–211. https://doi.org/10.1016/j.apsb.2016.02.002 CrossRefPubMedPubMedCentralGoogle Scholar