Peritoneal endometriosis induces time-related depressive- and anxiety-like alterations in female rats: involvement of hippocampal pro-oxidative and BDNF alterations
- 157 Downloads
Endometriosis is a gynecological condition affecting 10% of women in reproductive age. High rates of depression and anxiety are observed in these patients. The mechanisms underlying endometriosis-induced behavioral alterations are still elusive. Animal models provide a useful tool to study the temporal sequence and biological pathways involved in this disease and comorbid states. Here, we sought to characterize time-related behavioral alterations in rats submitted to endometriosis model (EM) induced by peritoneal auto-transplantation of uterine tissues weekly for three weeks. Corticosterone stress reactivity, oxidative stress markers – reduced glutathione (GSH), lipid peroxidation, activity of superoxide dismutase (SOD) and myeloperoxidase (MPO) - and brain-derived-neurotrophic factor (BDNF) levels in the hippocampus were also evaluated. We observed a progressive increase in anxiety-like behavior from 14th to 21st days post-EM. Despair-like behavior was observed from the 14th day post-EM on, while anhedonia and apathetic-like behaviors accompanied by increased corticosterone stress response were detected on 21 days post-EM. Increased pain sensitivity was observed from the 7th day post-EM and was accompanied by increased endometrioma weight. The pro-oxidative alterations, decreased GSH and increased SOD activity were observed on 21 days post-EM, except for lipid peroxidation that was altered from the 14th day. Decreased BDNF also occurred on the 21st day. Therefore, this study demonstrates that EM is related to several features of clinical depression and proposes the contribution of hippocampal oxidative state and neurotrophic support for the emergence of these changes. Our results support the use of this model as a useful tool to test new strategies for endometriosis-related neuropsychiatric symptoms.
KeywordsEndometriosis Depression Animal models Hippocampus Oxidative stress Brain-derived-neurotrophic factor
The authors thank Ms. Maria Vilani for technical support.
Role of funding source
This work was partially supported by CNPq and CAPES.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest for the present investigation.
- Baj G, D’Alessandro V, Musazzi L et al (2012) Physical exercise and antidepressants enhance BDNF targeting in hippocampal CA3 dendrites: further evidence of a spatial code for BDNF splice variants. Neuropsychopharmacology 37:1600–1611. https://doi.org/10.1038/npp.2012.5 CrossRefPubMedPubMedCentralGoogle Scholar
- Bannon AW, Malmberg AB (2007) Models of nociception: hot-plate, tail-Flick, and formalin tests in rodents. In: current protocols in neuroscience. John Wiley & Sons, Inc, Hoboken, pp 8.9.1–8.9.16Google Scholar
- Gur A, Cevik R, Sarac AJ et al (2004) Hypothalamic-pituitary-gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism. Ann Rheum Dis 63:1504–1506. https://doi.org/10.1136/ard.2003.014969 CrossRefPubMedPubMedCentralGoogle Scholar
- Isingrini E, Camus V, Le Guisquet A-M et al (2010) Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice. PLoS One 5:e10404. https://doi.org/10.1371/journal.pone.0010404 CrossRefPubMedPubMedCentralGoogle Scholar
- Koster R, Anderson M and De Beer EJ (1959) Acetic Acid for Analgesic Screening. Federation Proceedings 18:412–417Google Scholar
- Laganà AS, Lucia V, Rosa L, et al (2017a) Anxiety and depression in patients with endometriosis : impact and management challenges. Int J Womens Health 9:323–330. https://doi.org/10.2147/IJWH.S119729
- Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 35:676–692. https://doi.org/10.1016/j.pnpbp.2010.05.004 CrossRefGoogle Scholar
- Mello BSF, Chaves Filho AJM, Custódio CS et al (2018) Sex influences in behavior and brain inflammatory and oxidative alterations in mice submitted to lipopolysaccharide-induced inflammatory model of depression. J Neuroimmunol 320:133–142. https://doi.org/10.1016/j.jneuroim.2018.04.009 CrossRefPubMedGoogle Scholar
- NIH (2011) Guide for the care and use of laboratory animals. National Academies Press, Washington, D.CGoogle Scholar
- Pelch KE, Sharpe-Timms KL, Nagel SC (2012) Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue. J Vis Exp:1–8. https://doi.org/10.3791/3396
- Scutiero G, Iannone P, Bernardi G, et al (2017) Oxidative stress and endometriosis : A systematic review of the literature. Oxid Med Cell Longev 2017:7265238. https://doi.org/10.1155/2017/7265238
- Simsek Y, Gul M, Yilmaz E et al (2014) Atorvastatin exerts anti-nociceptive activity and decreases serum levels of high-sensitivity C-reactive protein and tumor necrosis factor-α in a rat endometriosis model. Arch Gynecol Obstet 290:999–1006. https://doi.org/10.1007/s00404-014-3295-4 CrossRefPubMedGoogle Scholar
- Tariverdian N, Rücke M, Szekeres-Bartho J et al (2010) Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro. J Mol Med 88:267–278. https://doi.org/10.1007/s00109-009-0559-8 CrossRefPubMedGoogle Scholar
- Tomaz VS, Cordeiro RC, Costa AMN et al (2014) Antidepressant-like effect of nitric oxide synthase inhibitors and sildenafil against lipopolysaccharide-induced depressive-like behavior in mice. Neuroscience 268:236–246. https://doi.org/10.1016/j.neuroscience.2014.03.025 CrossRefPubMedGoogle Scholar