Neurochemical Research

, Volume 44, Issue 12, pp 2843–2855 | Cite as

Protective Effects of Ursolic Acid Against Cytotoxicity Induced by Corticosterone: Role of Protein Kinases

  • Ana B. Ramos-Hryb
  • Nicolle Platt
  • Andiara E. Freitas
  • Isabella A. Heinrich
  • Manuela G. López
  • Rodrigo B. Leal
  • Manuella P. Kaster
  • Ana Lúcia S. RodriguesEmail author
Original Paper


Neuronal hippocampal death can be induced by exacerbated levels of cortisol, a condition usually observed in patients with Major depressive disorder (MDD). Previous in vitro and in vivo studies showed that ursolic acid (UA) elicits antidepressant and neuroprotective properties. However, the protective effects of UA against glucocorticoid-induced cytotoxicity have never been addressed. Using an in vitro model of hippocampal cellular death induced by elevated levels of corticosterone, we investigated if UA prevents corticosterone-induced cytotoxicity in HT22 mouse hippocampal derived cells. Concentrations lower than 25 µM UA did not alter cell viability. Co-incubation with UA for 48 h was able to protect HT22 cells from the reduction on cell viability and from the increase in apoptotic cells induced by corticosterone. Inhibition of protein kinase A (PKA), protein kinase C (PKC) and, Ca2+/calmodulin-dependent protein kinase II (CaMKII), but not phosphoinositide 3-kinase(PI3K), by using the pharmacological the inhibitors: H-89, chelerythrine, KN-62, and LY294002, respectively totally abolished the cytoprotective effects of UA. Finally, UA abrogated the reduction in phospho-extracellular signal–regulated kinases 1 and 2 (ERK1/2) but not in phospho-c-Jun kinases induced by corticosterone. These results indicate that the protective effect of UA against the cytotoxicity induced by corticosterone in HT22 cells may involve PKA, PKC, CaMKII, and ERK1/2 activation. The cytoprotective potential of UA against corticosterone-induced cytotoxicity and its ability to modulate intracellular signaling pathways involved in cell proliferation and survival suggest that UA may be a relevant strategy to manage stress-related disorders such as MDD.


Corticosterone Cytotoxicity HT22 cells Neuroprotection Protein kinase Ursolic acid 



The technical support of “Laboratório Multiusuário de Estudos em Biologia (LAMEB)” from Universidade Federal de Santa Catarina and technicians of the “Unidad de Citometría” from Universidad Autónoma de Madrid are acknowledged. This study was supported by the Financiadora de Estudos e Projetos (FINEP) research grant “Rede Instituto Brasileiro de Neurociência (IBN-Net/CNPq)”, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), “Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC)” Project/PRONEX Program CNPq/FAPESC (Brazil). ALSR, MPK, and RBL are recipients of Research Scholarship from CNPq. The experiments conducted in the Instituto Teófilo Hernando by ABRH were supported by the Grant “Proyecto de Cooperación Interuniversitaria UAM-Santander con América Latina” (CEAL-AL/2015-05). MGL is the recipient of a scholarship from the Spanish Ministry of Economy and Competence Ref. SAF2015-63935R.

Compliance with Ethical Standards

Conflicts of interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  1. 1.Department of Biochemistry, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Department of Pharmacology, Faculty of Medicine, Instituto Teófilo HernandoUniversidad Autónoma de MadridMadridSpain
  3. 3.Instituto de Biología y Medicina Experimental (IBYME)-CONICETBuenos AiresArgentina

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