Effects of β-Estradiol on the level of Bcl2/BAX Expression in the Rat Hippocampus, after Induction of Post-Traumatic Stress Disorder (PTSD)
DOI:
https://doi.org/10.22100/jkh.v10i1.513Keywords:
Post-traumatic stress disorder, β-estradiol, BDNF, Apoptosis.Abstract
Introduction: Post-traumatic stress disorder (PTSD) is an anxiety disorder, that can occur in people who have experienced or witnessed a natural disaster, serious accident or other life-threatening events. It's most important characteristics are memory disorders and hippocampus is one of the essential structure in this relation. Traumatic events cause apoptosis and alter the expression of neurotrophic factors in hippocampus. Therefore, the aim of this study was the examination of the fear memory and evaluation the effects of multiple β-Estradiol injections on behavioral responses in the rat hippocampus, after induction of PTSD. Moreover, we evaluated, the biochemical and histological mechanisms of β-Estradiol on hippocampus.
Methods: We used single prolonged stress (SPS), for PTSD induction. One day after SPS, rats received electrical foot shock within shock chamber. To test the conditioned fear responses one week later, rats were placed back in the chamber without any shock, and freezing behavior was defined. Another fear test was done 4 days after the first test. Animals received multiple subcutaneous injections of β-estradiol (45µg/kg) or sesame oil, immediately after shock and in these 7 days, between shock and test. Bcl-2 and BAX were detected by immunohistochemistry.
Results: Main findings of the present study are: Exaggerated fear response was seen in PTSD group as compared with control group. Moreover, Β-estradiol administration reduced behavioral responses, caused by PTSD induction. SPS decreased the Bcl2/BAX ratio and apoptosis induced by SPS in hippocampus. This effects reversed by β-estradiol injections.
Conclusion: β-estradiol could be useful for treating the memory disorders in PTSD.
References
Jovanovic T, Ressler KJ. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am J Psychiatry 2010; 167:648-62.
Lebron-Milad K, Milad MR. Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders.Biol Mood Anxiety Disord 2012;2:3.
McClure RE, Barha CK, Galea LA. 17beta-Estradiol, but not estrone, increases the survival and activation of new neurons in the hippocampus in response to spatial memory in adult female rats. Horm Behav 2013;63:144-57.
Ormerod BK, Galea LA. Reproductive status influences cell proliferation and cell survival in the dentate gyrus of adult female meadow voles: a possible regulatory role for estradiol. Neuroscience 2001;102:369-79.
Veiga S, Azcoitia I, Garcia-Segura LM. Extragonadal synthesis of estradiol is protective against kainic acid excitotoxic damage to the hippocampus. Neuroreport 2005;16:1599-603.
Cavus I, Duman RS. Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol Psychiatry2003;54:59-69.
Murphy DD, Cole NB, Greenberger V, Segal M. Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons. J Neurosci 1998;18:2550-9.
Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 1997;22:443-53.
Golub Y, Maucha CP, Dahlhoffc M, Wotjaka CT. Consequences of extinction training on associative and non-associative fear in a mouse model of posttraumatic stress disorder PTSD. Behav Brain Res 2009;205:544-9.
Maren S, Chang CH. Recent fearis resistant to extinction.Proc Natl Acad Sci U S A 2006;103:18020-5.
Pitman RK. Overview of biological themes in PTSD.Ann N Y Acad Sci 1997;821:1-9.
Kramar EA, Babayan AH, Gall CM, Lynch G. Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton. Neurosci 2013;239:3-16.
Douma SL, Husband C, O’Donnell ME, Barwin BN, Woodend AK. Estrogen-related mood disorders: reproductive life cycle factors. ANS Adv Nurs Sci 2005;28:364-75.
Solomon MB, Herman JP. Sex differences in psychopathology: of gonads, adrenals and mental illness.Physiol Behav2009;97:250-8.
Mitra SW, Hoskin E, Yudkovitz J, Pear L, Wilkinson HA, Hayashi S, et al. Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha. Endocrinology 2003;144:2055-67.
McEwen B, Akama K, Alves S, Brake WG, Bulloch K, Lee S, et al.Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation. Proc Natl Acad Sci U S A 2001;98:7093-100.
Milad MR, Zeidan MA, Contero A, Pitman RK, Klibanski A, Rauch SL, et al. The influence of gonadal hormones on conditioned fear extinction in healthy humans. Neuroscience 2010;168:652-8.
Bi R, Broutman G, Foy MR, Thompson RF, Baudry M. The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci U.S.A2000;97:3602-7.
Jovanovic T, Norrholm SD. Neural mechanisms of impaired fear inhibition in posttraumatic stress disorder. Front Behav Neurosci 2011;5:44.
Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, et al. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol Psychiatry 2011;70:920-7.
Li XH, Liu NB, Zhang MH, Zhou YL, Liao JW, Liu XQ. Effects of chronic multiple stress on learning andmemory and the expression of Fyn, BDNF, TrkB in the hippocampus of rats. Chinese Medical Journal 2007;120:669-74.
Sherwin JE, Nemeroff CB. Post-traumatic stress disorder: the neurobiological impact of psychological trauma.DialoguesClinical Neuroscience2011;13:263-78.
Schuff N, Neylan TC, Lenoci MA, Du AT, Weiss DS, Marmar CR, et al. Stress disorder. Biol Psychiatry 2001;50:952-9.
Glover EM, Jovanovic T, Mercer KB, Kerley K, Bradley B, Ressler KJ, et al.Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder. Biol Psychiatry 2012;72:19-24.
Lebron-Milad K, Graham BM, Milad MR.Low estradiol levels: a vulnerability factor for the development of posttraumatic stress disorder. Biol Psychiatry 2012;72:6-7.
Bremner JD. Hypotheses and controversies related to effects of stress on the hippocampus: an argument for stress-induced damage to the hippocampus in patients with posttraumatic stress disorder. Hippocampus 2001;11:75-81.
Nilsen J, Diaz Brinton R. Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Proc Natl Acad Sci U S A 2003;100:2842-7.
Bremner D, Elzinga B, Schmahl C, Vermetten E. Structural and functional plasticity of the human brain in posttraumatic stress disorder. Prog Brain Res 2008;167:171-86.
Shin LM, Rauch SL,Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci 2006;1071:67-79.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM). American Psychiatric Press: The inststute;1994.
Samuelson KW. Post-traumatic stress disorder and declarative memory functioning: a review. Dialogues Clin Neurosci 2011;13:346-51.
Rao RP, Suvrathan A, editors. Post-traumatic stress disorder. 1th ed. New York: Humana Press;2009.p.151-184.
Bisson JI. Pharmacological treatment of post-traumatic stress disorder. Advances in Psychiatric Treatment 2007;13:119-26.
Wang H, Daiying Z, Bin H, Foxiao Q, Mingqi Zh, Yingliang W. Conditioned fear stress combined with single-prolonged stress: a new PTSD mouse model. Neurosci Res 2012;73:142-52.
Wang W, Liu Y, Zhenga H, Wang HN, Jin X, Chen YC, et al. A modified single-prolonged stress model for post-traumatic stress disorder. Neurosci Lett 2008;441:237-41.
Yamamoto Sh, Morinobu Sh, Takei Sh, Fuchikami M, Matsuki A, Yamawaki Sh,et al. Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depress Anxiety 2009;26:1110-7.
Yehuda R, Golier JA, Halligan SL, Harvey PD. Learning and memory in Holocaust survivors with posttraumatic stress disorder. Biol Psychiatry 2004;55:291-5.
Ding J, Han F, Shi Y. Single-prolonged stress induces apoptosis in the amygdala in a rat model of post-traumatic stress disorder. J Psychiatr Res 2010;44:48-55.
Li XM, Han F, Liu DJ, Shi YX. Single-prolonged stress induced mitochondrial-dependent apoptosis in hippocampus in the rat model of post-traumatic stress disorder. J Chem Neuroanat 2010;40:248-55.
De Nicola AF, Brocca ME, Pietranera L, Garcia-Segura LM. Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy. Mini Rev Med Chem 2012;12:1081-9.
Green PS, Simpkins JW. Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 2000;18:347-58.
Hernández-Fonseca K, Massieu L, García de la Cadena S, Guzmán C, Camacho-Arroyo. Neuroprotective role of estradiol against neuronal death induced by glucose deprivation in cultured rat hippocampal neurons. Neuroendocrinology 2012;96:41-50.
Watson RE, Craven NM, Kang S, Jones CJ, Kielty CM, Griffiths CE. A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents. J Invest Dermatol2001;116:672-678.
Nasiraei-Moghadam S, Kazeminezhad B, Dargahi L, Ahmadiani A. Maternal oral consumption of morphine increases Bax/Bcl-2ratio and caspase 3 activity during early neuralsystem development in rat. EmbryosJ Mol Neurosci 2010;41:156-164.
Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 1999;19:6385-93.
Haraguchi Sh, Sasahara K, Shikimi H, Honda Sh, Harada N, Tsutsui K. Estradiol promotes purkinje dendritic growth, spinogenesis, and synaptogenesis during neonatal life by inducing the expression of BDNF. Cerebellum 2012;11:416-7.
Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science 2010;328:1288-90.
Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, et al. 17 beta-estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats. Neuroscience 2007;1469:60-8.
Inagaki T, Kaneko N, Zukin RS, Castillo PE, Etgen AM. Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats. PLoS One2012;7:e38018.
Jakovljevic M, Brajkovic L, Jaksic N, Loncar M, Aukst-Margetić B, Lasić D. Posttraumatic stress disorders (PTSD) from different perspectives: a transdisciplinary integrative approach. Psychiatr Danub 2012;24:246-55.
Downloads
Published
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.