Skip to main content
SpringerLink
Log in

Therapeutic Potential of Ursolic Acid to Manage Neurodegenerative and Psychiatric Diseases

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Ursolic acid is a pentacyclic triterpenoid found in several plants. Despite its initial use as a pharmacologically inactive emulsifier in pharmaceutical, cosmetic and food industries, several biological activities have been reported for this compound so far, including anti-tumoural, anti-diabetic, cardioprotective and hepatoprotective properties. The biological effects of ursolic acid have been evaluated in vitro, in different cell types and against several toxic insults (i.e. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, amyloid-β peptides, kainic acid and others); in animal models of brain-related disorders (Alzheimer disease, Parkinson disease, depression, traumatic brain injury) and ageing; and in clinical studies with cancer patients and for muscle atrophy. Most of the protective effects of ursolic acid are related to its ability to prevent oxidative damage and excessive inflammation, common mechanisms associated with multiple brain disorders. Additionally, ursolic acid is capable of modulating the monoaminergic system, an effect that might be involved in its ability to prevent mood and cognitive dysfunctions associated with neurodegenerative and psychiatric conditions. This review presents and discusses the available evidence of the possible beneficial effects of ursolic acid for the management of neurodegenerative and psychiatric disorders. We also discuss the chemical features, major sources and potential limitations of the use of ursolic acid as a pharmacological treatment for brain-related diseases.

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

Similar content being viewed by others

References

  1. Chin JH, Vora N. The global burden of neurologic diseases. Neurology. 2014;83(4):349–51.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Whiteford HA, Ferrari AJ, Degenhardt L, Feigin V, Vos T. The global burden of mental, neurological and substance use disorders: an analysis from the Global Burden of Disease Study 2010. PLoS One. 2015;10(2):e0116820.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Tang SW, Helmeste DM, Leonard BE. Neurodegeneration, neuroregeneration, and neuroprotection in psychiatric disorders. Mod Trends Pharmacopsychiatry. 2017;31:107–23.

    Article  PubMed  Google Scholar 

  4. Liu J. Oleanolic acid and ursolic acid: research perspectives. J Ethnopharmacol. 2005;100(1–2):92–4.

    Article  CAS  PubMed  Google Scholar 

  5. Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G, Bishayee A. Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol. 2013;85(11):1579–87.

    Article  CAS  PubMed  Google Scholar 

  6. Wozniak L, Skapska S, Marszalek K. Ursolic acid: a pentacyclic triterpenoid with a wide spectrum of pharmacological activities. Molecules. 2015;20(11):20614–41.

    Article  CAS  PubMed  Google Scholar 

  7. Kashyap D, Tuli HS, Sharma AK. Ursolic acid (UA): a metabolite with promising therapeutic potential. Life Sci. 2016;146:201–13.

    Article  CAS  PubMed  Google Scholar 

  8. Liby KT, Yore MM, Sporn MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer. 2007;7(5):357–69.

    Article  CAS  PubMed  Google Scholar 

  9. Dzubak P, Hajduch M, Vydra D, Hustova A, Kvasnica M, Biedermann D, et al. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat Prod Rep. 2006;23(3):394–411.

    Article  CAS  PubMed  Google Scholar 

  10. Gao LP, Wei HL, Zhao HS, Xiao SY, Zheng RL. Antiapoptotic and antioxidant effects of rosmarinic acid in astrocytes. Pharmazie. 2005;60(1):62–5.

    CAS  PubMed  Google Scholar 

  11. Szakiel A, Paczkowski C, Pensec F, Bertsch C. Fruit cuticular waxes as a source of biologically active triterpenoids. Phytochem Rev. 2012;11(2–3):263–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Szakiel A, Pączkowski C, Huttunen S. Triterpenoid content of berries and leaves of bilberry Vaccinium myrtillus from Finland and Poland. J Agric Food Chem. 2012;60(48):11839–49.

    Article  CAS  PubMed  Google Scholar 

  13. Jäger S, Trojan H, Kopp T, Laszczyk MN, Scheffler A. Pentacyclic triterpene distribution in various plants: rich sources for a new group of multi-potent plant extracts. Molecules. 2009;14(6):2016–31.

    Article  PubMed  CAS  Google Scholar 

  14. Lee S, Kim BK, Cho SH, Shin KH. Phytochemical constituents from the fruits of Acanthopanax sessiliflorus. Arch Pharm Res. 2002;25(3):280–4.

    Article  CAS  PubMed  Google Scholar 

  15. González-Trujano ME, Ventura-Martínez R, Chávez M, Díaz-Reval I, Pellicer F. Spasmolytic and antinociceptive activities of ursolic acid and acacetin identified in Agastache mexicana. Planta Med. 2012;78(8):793–6.

    Article  PubMed  CAS  Google Scholar 

  16. Verano J, González-Trujano ME, Déciga-Campos M, Ventura-Martínez R, Pellicer F. Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism. Pharmacol Biochem Behav. 2013;110:255–64.

    Article  CAS  PubMed  Google Scholar 

  17. Caligiani A, Malavasi G, Palla G, Marseglia A, Tognolini M, Bruni R. A simple GC-MS method for the screening of betulinic, corosolic, maslinic, oleanolic and ursolic acid contents in commercial botanicals used as food supplement ingredients. Food Chem. 2013;136(2):735–41.

    Article  CAS  PubMed  Google Scholar 

  18. Hong SY, Jeong WS, Jun M. Protective effects of the key compounds isolated from Corni fructus against β-amyloid-induced neurotoxicity in PC12 cells. Molecules. 2012;17(9):10831–45.

    Article  CAS  PubMed  Google Scholar 

  19. Tapondjou LA, Lontsi D, Sondengam BL, Choi J, Lee KT, Jung HJ, et al. In vivo anti-nociceptive and anti-inflammatory effect of the two triterpenes, ursolic acid and 23-hydroxyursolic acid, from Cussonia bancoensis. Arch Pharm Res. 2003;26(2):143–6.

    Article  CAS  PubMed  Google Scholar 

  20. Rollinger JM, Kratschmar DV, Schuster D, Pfisterer PH, Gumy C, Aubry EM, et al. 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches. Bioorg Med Chem. 2010;18(4):1507–15.

    Article  CAS  PubMed  Google Scholar 

  21. Kim JH, Kim GH, Hwang KH. Monoamine oxidase and dopamine β-hydroxylase inhibitors from the fruits of Gardenia jasminoides. Biomol Ther (Seoul). 2012;20(2):214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Prediger RD, Fernandes MS, Rial D, Wopereis S, Pereira VS, Bosse TS, et al. Effects of acute administration of the hydroalcoholic extract of mate tea leaves (Ilex paraguariensis) in animal models of learning and memory. J Ethnopharmacol. 2008;120(3):465–73.

    Article  PubMed  Google Scholar 

  23. Chattopadhyay D, Arunachalam G, Mandal SC, Bhadra R, Mandal AB. CNS activity of the methanol extract of Mallotus peltatus (Geist) Muell Arg. leaf: an ethnomedicine of Onge. J Ethnopharmacol. 2003;85(1):99–105.

    Article  PubMed  Google Scholar 

  24. Ibarra A, Feuillere N, Roller M, Lesburgere E, Beracochea D. Effects of chronic administration of Melissa officinalis L. extract on anxiety-like reactivity and on circadian and exploratory activities in mice. Phytomedicine. 2010;17(6):397–403.

    Article  CAS  PubMed  Google Scholar 

  25. Shen D, Pan MH, Wu QL, Park CH, Juliani HR, Ho CT, et al. A rapid LC/MS/MS method for the analysis of nonvolatile antiinflammatory agents from Mentha spp. J Food Sci. 2011;76(6):C900–8.

    Article  CAS  PubMed  Google Scholar 

  26. Vasconcelos MA, Royo VA, Ferreira DS, Crotti AE, Andrade e Silva ML, Carvalho JC, et al. In vivo analgesic and anti-inflammatory activities of ursolic acid and oleanoic acid from Miconia albicans (Melastomataceae). Z Naturforsch C. 2006;61(7–8):477–82.

    CAS  PubMed  Google Scholar 

  27. Taviano MF, Miceli N, Monforte MT, Tzakou O, Galati EM. Ursolic acid plays a role in Nepeta sibthorpii Bentham CNS depressing effects. Phytother Res. 2007;21(4):382–5.

    Article  CAS  PubMed  Google Scholar 

  28. Jothie Richard E, Illuri R, Bethapudi B, Anandhakumar S, Bhaskar A, Chinampudur Velusami C, et al. Anti-stress activity of Ocimum sanctum: possible effects on hypothalamic-pituitary-adrenal axis. Phytother Res. 2016;30(5):805–14.

    Article  PubMed  CAS  Google Scholar 

  29. Chung YK, Heo HJ, Kim EK, Kim HK, Huh TL, Lim Y, et al. Inhibitory effect of ursolic acid purified from Origanum majorana L. on the acetylcholinesterase. Mol Cells. 2001;11(2):137–43.

    PubMed  Google Scholar 

  30. Heo HJ, Cho HY, Hong B, Kim HK, Heo TR, Kim EK, et al. Ursolic acid of Origanum majorana L. reduces Abeta-induced oxidative injury. Mol Cells. 2002;13(1):5–11.

    CAS  PubMed  Google Scholar 

  31. Jetter R, Schäffer S. Chemical composition of the Prunus laurocerasus leaf surface. Dynamic changes of the epicuticular wax film during leaf development. Plant Physiol. 2001;126(4):1725–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Machado DG, Cunha MP, Neis VB, Balen GO, Colla A, Bettio LE, et al. Antidepressant-like effects of fractions, essential oil, carnosol and betulinic acid isolated from Rosmarinus officinalis L. Food Chem. 2013;136(2):999–1005.

    Article  CAS  PubMed  Google Scholar 

  33. Machado DG, Neis VB, Balen GO, Colla A, Cunha MP, Dalmarco JB, et al. Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: evidence for the involvement of the dopaminergic system. Pharmacol Biochem Behav. 2012;103(2):204–11.

    Article  CAS  PubMed  Google Scholar 

  34. Çulhaoğlu B, Yapar G, Dirmenci T, Topçu G. Bioactive constituents of Salvia chrysophylla Stapf. Nat Prod Res. 2013;27(4–5):438–47.

    Article  PubMed  CAS  Google Scholar 

  35. González-Cortazar M, Maldonado-Abarca AM, Jiménez-Ferrer E, Marquina S, Ventura-Zapata E, Zamilpa A, et al. Isosakuranetin-5-O-rutinoside: a new flavanone with antidepressant activity isolated from Salvia elegans Vahl. Molecules. 2013;18(11):13260–70.

    Article  PubMed  CAS  Google Scholar 

  36. Bahadori MB, Dinparast L, Valizadeh H, Farimani MM, Ebrahimi SN. Bioactive constituents from roots of Salvia syriaca L.: acetylcholinesterase inhibitory activity and molecular docking studies. S Afr J Bot. 2016;106:1–4.

    Article  CAS  Google Scholar 

  37. Kowalski R. Studies of selected plant raw materials as alternative sources of triterpenes of oleanolic and ursolic acid types. J Agric Food Chem. 2007;55(3):656–62.

    Article  CAS  PubMed  Google Scholar 

  38. Novotny L, Abdel-Hamid ME, Hamza H, Masterova I, Grancai D. Development of LC-MS method for determination of ursolic acid: application to the analysis of ursolic acid in Staphylea holocarpa Hemsl. J Pharm Biomed Anal. 2003;31(5):961–8.

    Article  CAS  PubMed  Google Scholar 

  39. Rowe EJ, Orr JE. Isolation of oleanolic acid and ursolic acid from Thymus vulgaris L. J Am Pharm Assoc Am Pharm Assoc. 1949;38(3 Pt. 1):122–4.

  40. Chandramu C, Manohar RD, Krupadanam DG, Dashavantha RV. Isolation, characterization and biological activity of betulinic acid and ursolic acid from Vitex negundo L. Phytother Res. 2003;17(2):129–34.

    Article  CAS  PubMed  Google Scholar 

  41. Leal AS, Wang R, Salvador JA, Jing Y. Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells. Bioorg Med Chem. 2012;20(19):5774–86.

    Article  CAS  PubMed  Google Scholar 

  42. Dar BA, Lone AM, Shah WA, Qurishi MA. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents. Eur J Med Chem. 2016;111:26–32.

    Article  CAS  PubMed  Google Scholar 

  43. Wojciak-Kosior M. Separation and determination of closely related triterpenic acids by high performance thin-layer chromatography after iodine derivatization. J Pharm Biomed Anal. 2007;45(2):337–40.

    Article  CAS  PubMed  Google Scholar 

  44. Shanmugam MK, Ong TH, Kumar AP, Lun CK, Ho PC, Wong PT, et al. Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating pro-inflammatory pathways. PLoS One. 2012;7(3):e32476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen Q, Luo S, Zhang Y, Chen Z. Development of a liquid chromatography-mass spectrometry method for the determination of ursolic acid in rat plasma and tissue: application to the pharmacokinetic and tissue distribution study. Anal Bioanal Chem. 2011;399(8):2877–84.

    Article  CAS  PubMed  Google Scholar 

  46. Wang XH, Zhou SY, Qian ZZ, Zhang HL, Qiu LH, Song Z, et al. Evaluation of toxicity and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy adult volunteers and patients with advanced solid tumors. Expert Opin Drug Metab Toxicol. 2013;9(2):117–25.

    Article  CAS  PubMed  Google Scholar 

  47. Zhu Z, Qian Z, Yan Z, Zhao C, Wang H, Ying G. A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors. Int J Nanomedicine. 2013;8:129–36.

    PubMed  PubMed Central  Google Scholar 

  48. Qian Z, Wang X, Song Z, Zhang H, Zhou S, Zhao J, et al. A phase I trial to evaluate the multiple-dose safety and antitumor activity of ursolic acid liposomes in subjects with advanced solid tumors. Biomed Res Int. 2015;2015:809714.

    PubMed  PubMed Central  Google Scholar 

  49. Shanmugam MK, Manu KA, Ong TH, Ramachandran L, Surana R, Bist P, et al. Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model. Int J Cancer. 2011;129(7):1552–63.

    Article  CAS  PubMed  Google Scholar 

  50. Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, et al. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res. 2007;5(9):943–55.

    Article  CAS  PubMed  Google Scholar 

  51. Shan JZ, Xuan YY, Ruan SQ, Sun M. Proliferation-inhibiting and apoptosis-inducing effects of ursolic acid and oleanolic acid on multi-drug resistance cancer cells in vitro. Chin J Integr Med. 2011;17(8):607–11.

    Article  CAS  PubMed  Google Scholar 

  52. Prasad S, Yadav VR, Sung B, Reuter S, Kannappan R, Deorukhkar A, et al. Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine. Clin Cancer Res. 2012;18(18):4942–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tokuda H, Ohigashi H, Koshimizu K, Ito Y. Inhibitory effects of ursolic and oleanolic acid on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Lett. 1986;33(3):279–85.

    Article  CAS  PubMed  Google Scholar 

  54. De Angel RE, Smith SM, Glickman RD, Perkins SN, Hursting SD. Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutr Cancer. 2010;62(8):1074–86.

    Article  PubMed  CAS  Google Scholar 

  55. Monteiro MC, Coleman MD, Hill EJ, Prediger RD, Maia CS. Neuroprotection in neurodegenerative disease: from basic science to clinical applications. Oxid Med Cell Longev. 2017;2017:2949102.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Shimohama S, Sawada H, Kitamura Y, Taniguchi T. Disease model: Parkinson’s disease. Trends Mol Med. 2003;9(8):360–5.

    Article  CAS  PubMed  Google Scholar 

  57. Falkenburger BH, Saridaki T, Dinter E. Cellular models for Parkinson’s disease. J Neurochem. 2016;139(Suppl. 1):121–30.

    Article  CAS  PubMed  Google Scholar 

  58. Tsai SJ, Yin MC. Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. J Food Sci. 2008;73(7):H174–8.

    Article  CAS  PubMed  Google Scholar 

  59. Keeney PM, Xie J, Capaldi RA, Bennett JP. Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26(19):5256–64.

    Article  CAS  PubMed  Google Scholar 

  60. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, et al. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol. 2008;64(5):555–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yealland G, Battaglia G, Bandmann O, Mortiboys H. Rescue of mitochondrial function in parkin-mutant fibroblasts using drug loaded PMPC-PDPA polymersomes and tubular polymersomes. Neurosci Lett. 2016;630:23–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zheng XY, Zhang HL, Luo Q, Zhu J. Kainic acid-induced neurodegenerative model: potentials and limitations. J Biomed Biotechnol. 2011;2011:457079.

    Article  PubMed  CAS  Google Scholar 

  63. Shih YH, Chein YC, Wang JY, Fu YS. Ursolic acid protects hippocampal neurons against kainate-induced excitotoxicity in rats. Neurosci Lett. 2004;362(2):136–40.

    Article  CAS  PubMed  Google Scholar 

  64. Santos CY, Snyder PJ, Wu WC, Zhang M, Echeverria A, Alber J. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement (Amst). 2017;7:69–87.

    PubMed  PubMed Central  Google Scholar 

  65. Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol. 2017;13(4):217–31.

    Article  PubMed  Google Scholar 

  66. Bredesen DE. Neurodegeneration in Alzheimer’s disease: caspases and synaptic element interdependence. Mol Neurodegener. 2009;4:27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Takahashi RH, Nagao T, Gouras GK. Plaque formation and the intraneuronal accumulation of β-amyloid in Alzheimer’s disease. Pathol Int. 2017;67(4):185–93.

    Article  CAS  PubMed  Google Scholar 

  68. Hane FT, Lee BY, Leonenko Z. Recent progress in Alzheimer’s disease research. Part 1: pathology. J Alzheimers Dis. 2017;57(1):1–28.

    Article  PubMed  Google Scholar 

  69. Snow WM, Albensi BC. Neuronal gene targets of NF-κB and their dysregulation in Alzheimer’s disease. Front Mol Neurosci. 2016;9:118.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wilkinson K, Boyd JD, Glicksman M, Moore KJ, El Khoury J. A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J Biol Chem. 2011;286(40):34914–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yoon JH, Youn K, Ho CT, Karwe MV, Jeong WS, Jun M. p-Coumaric acid and ursolic acid from Corni fructus attenuated β-amyloid(25-35)-induced toxicity through regulation of the NF-κB signaling pathway in PC12 cells. J Agric Food Chem. 2014;62(21):4911–6.

    Article  CAS  PubMed  Google Scholar 

  72. Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromol Med. 2010;12(1):1–12.

    Article  CAS  Google Scholar 

  73. Bates KA, Verdile G, Li QX, Ames D, Hudson P, Masters CL, et al. Clearance mechanisms of Alzheimer’s amyloid-beta peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry. 2009;14(5):469–86.

    Article  CAS  PubMed  Google Scholar 

  74. Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther. 2014;6(9):89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Youn K, Jun M. Inhibitory effects of key compounds isolated from Corni fructus on BACE1 activity. Phytother Res. 2012;26(11):1714–8.

    Article  CAS  PubMed  Google Scholar 

  76. Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol. 2002;160(1):101–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11(2):155–61.

    Article  CAS  PubMed  Google Scholar 

  78. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;1:CD005593.

  79. Esch T, Stefano GB, Fricchione GL, Benson H. The role of stress in neurodegenerative diseases and mental disorders. Neuro Endocrinol Lett. 2002;23(3):199–208.

    PubMed  Google Scholar 

  80. Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialog Clin Neurosci. 2006;8(4):383–95.

    Google Scholar 

  81. Morgan SA, Sherlock M, Gathercole LL, Lavery GG, Lenaghan C, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle. Diabetes. 2009;58(11):2506–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chapman K, Holmes M, Seckl J. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev. 2013;93(3):1139–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Singla RK, Scotti L, Dubey AK. In silico studies revealed multiple neurological targets for the antidepressant molecule ursolic acid. Curr Neuropharmacol. 2016 (Epub ahead of print).

  84. Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci. 2006;7(4):295–309.

    Article  CAS  PubMed  Google Scholar 

  85. Nyola A, Karpowich NK, Zhen J, Marden J, Reith ME, Wang DN. Substrate and drug binding sites in LeuT. Curr Opin Struct Biol. 2010;20(4):415–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Levin EY, Levenberg B, Kaufman S. The enzymatic conversion of 3,4-dihydroxyphenylethylamine to norepinephrine. J Biol Chem. 1960;235:2080–6.

    CAS  PubMed  Google Scholar 

  87. Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65(4):304–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lu J, Zheng YL, Wu DM, Luo L, Sun DX, Shan Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by d-galactose. Biochem Pharmacol. 2007;74(7):1078–90.

    Article  CAS  PubMed  Google Scholar 

  89. Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF, et al. Ursolic acid improves high fat diet-induced cognitive impairments by blocking endoplasmic reticulum stress and IκB kinase β/nuclear factor-κB-mediated inflammatory pathways in mice. Brain Behav Immun. 2011;25(8):1658–67.

    Article  CAS  PubMed  Google Scholar 

  90. Wang YJ, Lu J, Wu DM, Zheng ZH, Zheng YL, Wang XH, et al. Ursolic acid attenuates lipopolysaccharide-induced cognitive deficits in mouse brain through suppressing p38/NF-κB mediated inflammatory pathways. Neurobiol Learn Mem. 2011;96(2):156–65.

    Article  CAS  PubMed  Google Scholar 

  91. Ennaceur A. Tests of unconditioned anxiety: pitfalls and disappointments. Physiol Behav. 2014;135:55–71.

    Article  CAS  PubMed  Google Scholar 

  92. Vorhees CV, Williams MT. Assessing spatial learning and memory in rodents. ILAR J. 2014;55(2):310–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, et al. Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res. 2013;1497:32–9.

    Article  CAS  PubMed  Google Scholar 

  94. Wang Y, He Z, Deng S. Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury. Drug Des Devel Ther. 2016;10:1663–74.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wei H, Li L, Song Q, Ai H, Chu J, Li W. Behavioural study of the d-galactose induced aging model in C57BL/6J mice. Behav Brain Res. 2005;157(2):245–51.

    Article  CAS  PubMed  Google Scholar 

  96. Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF, Ye Q, et al. Ursolic acid attenuates d-galactose-induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF-κB pathway activation. Cereb Cortex. 2010;20(11):2540–8.

    Article  PubMed  Google Scholar 

  97. Zhang T, Su J, Guo B, Zhu T, Wang K, Li X. Ursolic acid alleviates early brain injury after experimental subarachnoid hemorrhage by suppressing TLR4-mediated inflammatory pathway. Int Immunopharmacol. 2014;23(2):585–91.

    Article  PubMed  CAS  Google Scholar 

  98. Zhang T, Su J, Wang K, Zhu T, Li X. Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage. Neurosci Lett. 2014;579:12–7.

    Article  CAS  PubMed  Google Scholar 

  99. Ding H, Wang H, Zhu L, Wei W. Ursolic acid ameliorates early brain injury after experimental traumatic brain injury in mice by activating the Nrf2 pathway. Neurochem Res. 2017;42(2):337–46.

    Article  CAS  PubMed  Google Scholar 

  100. Chen X, Guo C, Kong J. Oxidative stress in neurodegenerative diseases. Neural Regen Res. 2012;7(5):376–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Wu DM, Lu J, Zhang YQ, Zheng YL, Hu B, Cheng W, et al. Ursolic acid improves domoic acid-induced cognitive deficits in mice. Toxicol Appl Pharmacol. 2013;271(2):127–36.

    Article  CAS  PubMed  Google Scholar 

  102. Rai SN, Yadav SK, Singh D, Singh SP. Ursolic acid attenuates oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in MPTP-induced Parkinsonian mouse model. J Chem Neuroanat. 2016;71:41–9.

    Article  CAS  PubMed  Google Scholar 

  103. Brooks SP, Dunnett SB. Tests to assess motor phenotype in mice: a user’s guide. Nat Rev Neurosci. 2009;10(7):519–29.

    Article  CAS  PubMed  Google Scholar 

  104. Nitta A, Itoh A, Hasegawa T, Nabeshima T. beta-Amyloid protein-induced Alzheimer’s disease animal model. Neurosci Lett. 1994;170(1):63–6.

    Article  CAS  PubMed  Google Scholar 

  105. Takeda S, Sato N, Niisato K, Takeuchi D, Kurinami H, Shinohara M, et al. Validation of Abeta1-40 administration into mouse cerebroventricles as an animal model for Alzheimer disease. Brain Res. 2009;1280:137–47.

    Article  CAS  PubMed  Google Scholar 

  106. Liang W, Zhao X, Feng J, Song F, Pan Y. Ursolic acid attenuates beta-amyloid-induced memory impairment in mice. Arq Neuropsiquiatr. 2016;74(6):482–8.

    Article  PubMed  Google Scholar 

  107. Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–47.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Colla AR, Oliveira A, Pazini FL, Rosa JM, Manosso LM, Cunha MP, et al. Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice. Pharmacol Biochem Behav. 2014;124:108–16.

    Article  CAS  PubMed  Google Scholar 

  109. Marks DM, Pae CU, Patkar AA. Triple reuptake inhibitors: the next generation of antidepressants. Curr Neuropharmacol. 2008;6(4):338–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243–52.

    Article  CAS  PubMed  Google Scholar 

  111. Bodkin JA, Lasser RA, Wines JD Jr, Gardner DM, Baldessarini RJ. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry. 1997;58(4):137–45.

    Article  CAS  PubMed  Google Scholar 

  112. Sharma H, Santra S, Dutta A. Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? Future Med Chem. 2015;7(17):2385–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Skolnick P, Krieter P, Tizzano J, Basile A, Popik P, Czobor P, et al. Preclinical and clinical pharmacology of DOV 216,303, a “triple” reuptake inhibitor. CNS Drug Rev. 2006;12(2):123–34.

    Article  CAS  PubMed  Google Scholar 

  114. Beer B, Stark J, Krieter P, Czobor P, Beer G, Lippa A, et al. DOV 216,303, a “triple” reuptake inhibitor: safety, tolerability, and pharmacokinetic profile. J Clin Pharmacol. 2004;44(12):1360–7.

    Article  CAS  PubMed  Google Scholar 

  115. Ramos-Hryb AB, Cunha MP, Pazini FL, Lieberknecht V, Prediger RD, Kaster MP, et al. Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2. Pharmacol Rep. 2017. doi:10.1016/j.pharep.2017.05.009.

  116. Popoli M, Brunello N, Perez J, Racagni G. Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs. J Neurochem. 2000;74(1):21–33.

    Article  CAS  PubMed  Google Scholar 

  117. Hettema JM. What is the genetic relationship between anxiety and depression? Am J Med Genet C Semin Med Genet. 2008;148C(2):140–6.

    Article  PubMed  Google Scholar 

  118. Colla AR, Rosa JM, Cunha MP, Rodrigues AL. Anxiolytic-like effects of ursolic acid in mice. Eur J Pharmacol. 2015;758:171–6.

    Article  CAS  PubMed  Google Scholar 

  119. Jeon SJ, Park HJ, Gao Q, Pena IJ, Park SJ, Lee HE, et al. Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice. Eur J Pharmacol. 2015;762:443–8.

    Article  CAS  PubMed  Google Scholar 

  120. Anderson KN, Bradley AJ. Sleep disturbance in mental health problems and neurodegenerative disease. Nat Sci Sleep. 2013;5:61–75.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drug and cosmetics. 2nd ed. New York: Wiley; 1996.

    Google Scholar 

  122. Xia Y, Wei G, Si D, Liu C. Quantitation of ursolic acid in human plasma by ultra performance liquid chromatography tandem mass spectrometry and its pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879(2):219–24.

    Article  CAS  PubMed  Google Scholar 

  123. Bang HS, Seo DY, Chung YM, Oh KM, Park JJ, Arturo F, et al. Ursolic acid-induced elevation of serum irisin augments muscle strength during resistance training in men. Korean J Physiol Pharmacol. 2014;18(5):441–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Moon HS, Dincer F, Mantzoros CS. Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism. 2013;62(8):1131–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hussain H, Green IR, Ali I, Khan IA, Ali Z, Al-Sadi AM, et al. Ursolic acid derivatives for pharmaceutical use: a patent review (2012–2016). Expert Opin Ther Pat. 2017;27(9):1061–72.

    Article  CAS  PubMed  Google Scholar 

  127. Zhao W, Zhang H, Wang H, Tang X, Wu J. Caffeoyl substituted pentacyclic triterpene derivative and use thereof. Google Patents; 2014.

  128. Ting A, Milne JC, Jirousek MR, Bemis JE, Vu CB. Fatty acid triterpene derivatives and their uses. Google Patents; 2012.

  129. Kuang C, Xiao Y, Hondmann D. Nutritional composition containing a neurologic component of ursolic acid. Google Patents; 2015.

Download references

Acknowledgements

The authors thank Servier Medical Art for providing images for Figs. 2 and 3.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Center for Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Ana B. Ramos-Hryb, Francis L. Pazini, Manuella P. Kaster & Ana Lúcia S. Rodrigues

Authors
  1. Ana B. Ramos-Hryb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francis L. Pazini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuella P. Kaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Lúcia S. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Lúcia S. Rodrigues.

Ethics declarations

Funding

The authors acknowledge funding from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), #308723/2013-9 and #449436/2014-4, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, NENASC Project (PRONEX-FAPESC/CNPq) #1262/2012-9. Manuella P. Kaster and Ana Lúcia S. Rodrigues are CNPq Research Fellows.

Conflict of interest

Ana B. Ramos-Hryb, Francis L. Pazini, Manuella P. Kaster, and Ana Lúcia S. Rodrigues have no conflicts of interest directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramos-Hryb, A.B., Pazini, F.L., Kaster, M.P. et al. Therapeutic Potential of Ursolic Acid to Manage Neurodegenerative and Psychiatric Diseases. CNS Drugs 31, 1029–1041 (2017). https://doi.org/10.1007/s40263-017-0474-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-017-0474-4

Search

Navigation