Article Type: Original Articles
Changes in CREB Activity and BDNF Plasma Levels in Patients with Post-Traumatic Stress Disorder (PTSD)
Naci Olam, Aslihan Okan Ibiloglu


Objective: A number of studies were conducted to determine whether brain-derived neurotrophic factor (BDNF) and cAMP-responsive element-binding protein (CREB) play a critical role in synaptic plasticity and memory in neuronal survival and post-traumatic stress disorder (PTSD) pathophysiology. Biological mechanisms and relationships for PTSD diagnosis or etiology are lacking. Therefore, further examination of the underlying biological mechanisms of PTSD is required. In the present study, we aimed to determine the relationship between plasma CREB and BDNF levels and PTSD.

Methods: This study was designed to determine the association of CREB activity and BDNF concentration in peripheral blood of patients with or without PTSD. 50 drug-free patients with PTSD and 40 psychiatrically healthy control included in this study. All participants completed a form that included sociodemographic form, the Beck Depression Inventory (BDE), and the Dissociative Experience Scale (DES). In order to assess the severity of PTSD, the Clinician-Administered PTSD Scale (CAPS) was administered to patients by researchers. Blood was drawn from the patients under appropriate conditions and CREB and BDNF were studied.

Results: The average age of the participants was 31.94±8.86. 37 (41.1%) of the participants were female. There was a statistically significant difference in terms of BNDF, CREB, BDI and DES values between the two groups (p-values were 0.001, 0.023, <0.001, and <0.001, respectively). There was no statistically significant difference between the trauma types in terms of BDNF and CREB (p-values were 0.569 and 0.312, respectively).

Conclusions: We found that serum levels of BDNF and CREB were lower in PTSD patients as compared to control psychiatrically healthy subjects. BDNF and CREB levels did not change with trauma types in PTSD patients. Therefore, these results suggest that CREB and BDNF might be involved in the pathophysiology of PTSD.

REFERENCES

1.Keane TM, Marshall AD, Taft CT. Posttraumatic stress disorder: etiology, epidemiology, and treatment outcome. Annu Rev Clin Psychol 2006;2:161-97.

2.Association AP. Diagnostic and statistical manual of mental disorders (DSM-5®): American Psychiatric Pub, 2013.

3.Demir S, Bulut M, Atli A, Kaplan İ, Kaya MC, Bez Y, et al. Decreased prolidase activity in patients with posttraumatic stress disorder. Psychiatry Investig 2016;13(4):420-6.

4.Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Psychoneuroimmunology and psychosomatic medicine: back to the future. Psychosom Med 2002;64(1):15-28.

5.Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H. BDNF function and intracellular signaling in neurons. Histol Histopathol 2010;25(2):237-58.

6.Park Y-M, Lee B-H. Alterations in Serum BDNF and GDNF Levels after 12 Weeks of Antidepressant Treatment in Female Outpatients with Major Depressive Disorder. Psychiatry Investig. 2018;15(8):818-23.

7.Kim E-J, Kim Y-K. 196G/A of the Brain-Derived Neurotrophic Factor Gene Polymorphisms Predicts Suicidal Behavior in Schizophrenia Patients. Psychiatry Investig 2018;15(7):733-8.

8.Guo JC, Yang YJ, Guo M, Wang XD, Juan Y, Gao YS, et al. Correlations of four genetic single nucleotide polymorphisms in brain-derived neurotrophic factor with posttraumatic stress disorder. Psychiatry Investig 2018;15(4):407-12.

9.Su S, Xiao Z, Lin Z, Qiu Y, Jin Y, Wang Z. Plasma brain-derived neurotrophic factor levels in patients suffering from the post-traumatic stress disorder. Psychiatry Res 2015;229(1-2):365-9.

10.Angelucci F, Ricci V, Gelfo F, Martinotti G, Brunetti M, Sepede G, et al. BDNF serum levels in subjects developing or not post-traumatic stress disorder after trauma exposure. Brain Cogn 2014;84(1):118-22.

11.Dell'Osso L, Carmassi C, Del Debbio A, Dell'Osso MC, Bianchi C, da Pozzo E, et al. Brain-derived neurotrophic factor plasma levels in patients suffering from post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(5):899-902.

12.Jin MJ, Jeon H, Hyun MH, Lee SH. Influence of childhood trauma and brain-derived neurotrophic factor Val66Met polymorphism on posttraumatic stress symptoms and cortical thickness. Sci Rep 2019;9(1):6028.

13.Voisey J, Lawford B, Bruenig D, Harvey W, Morris CP, Young RM, et al. Differential BDNF methylation in combat exposed veterans and the association with exercise. Gene 2019;698:107-12.

14.Lu Y, Christian K, Lu B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008;89(3):312-23.

15.Marie H, Morishita W, Yu X, Calakos N, Malenka RC. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 2005;45(5):741-52.

16.Saura CA, Valero J. The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 2011;22(2):153-69.

17.Schmidt HD, Duman RS. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 2010;35(12):2378-91.

18.Zubenko GS, Jones ML, Estevez AO, Hughes HB, Estevez M. Identification of a CREB‐dependent serotonergic pathway and neuronal circuit regulating foraging behavior in Caenorhabditis elegans: a useful model for mental disorders and their treatments? Am J Med Genet B Neuropsychiatr Genet 2009;150(1):12-23.

19.Atli A, Can Z, Cim EFA, Ibiloglu AO. The levels of BDNF and CREB patients with major depressive disorder. Bulletin of Clinical Psychopharmacology 2018;28:23.

20.Martini C, Da Pozzo E, Carmassi C, Cuboni S, Trincavelli ML, Massimetti G, et al. Cyclic adenosine monophosphate responsive element binding protein in post-traumatic stress disorder. World J Biol Psychiatry 2013;14(5):396-402.

21.Hazra S, Kumar S, Saha GK, Mondal AC. Reversion of BDNF, Akt and CREB in hippocampus of chronic unpredictable stress induced rats: effects of phytochemical, Bacopa Monnieri. Psychiatry Investig 2017;14(1):74-80.

22.Aker AT, Ozeren M, Basoglu M, Kaptanoglu C, Erol A, Buran B. Clinician-Administered Post-Traumatic Stress Disorder Scale (CAPS): a validity and reliability study. Turkish Journal of Psychiatry 1999;10(4):286-93.

23.Weathers F, Blake D, Schnurr P, Kaloupek D, Marx B, Keane T. The clinician-administered PTSD scale for DSM-5 (CAPS-5). 2019 November; Available from: https://www.ptsd.va.gov/professional/assessment/adult-int/caps.asp.

24.Hisli N. A reliability and validity study of Beck Depression Inventory in a university student sample. J Psychol 1989;7:3-13.

25.Yargic LI, Tutkun H, Sar V. Reliability and validity of the Turkish version of the Dissociative Experiences Scale. Dissociation: Progress in the Dissociative Disorders, 1995.

26.Laifenfeld D, Karry R, Klein E, Ben-Shachar D. Alterations in cell adhesion molecule L1 and functionally related genes in major depression: a postmortem study. Biol Psychiatry 2005;57:716-25.

27.Hauck S, Kapczinski F, Roesler R, de Moura Silveira Jr É, Magalhães PV, Kruel LRP, et al. Serum brain-derived neurotrophic factor in patients with trauma psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2010;34(3):459-62.

28.Règue M, Poilbout C, Martin V, Franc B, Lanfumey L, Mongeau R. Increased 5-HT2C receptor editing predisposes to PTSD-like behaviors and alters BDNF and cytokines signaling. Translational psychiatry 2019;9(1):100.

29.Lee B, Shim I, Lee H, Hahm D-H. Melatonin ameliorates cognitive memory by regulation of cAMP-response element-binding protein expression and the anti-inflammatory response in a rat model of post-traumatic stress disorder. BMC Neurosci. 2018;19(1):38.

30.Saruta J, Lee T, Shirasu M, Takahashi T, Sato C, Sato S, et al. Chronic stress affects the expression of brain-derived neurotrophic factor in rat salivary glands. Stress 2010;13(1):53-60.

31.Issa G, Wilson C, Terry Jr AV, Pillai A. An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies. Neurobiol. Dis. 2010;39(3):327-33.

32.Bevans K, Cerbone AB, Overstreet S. The interactive effects of elevated mid-afternoon cortisol and trauma history on PTSD symptoms in children: A preliminary study. Psychoneuroendocrinology 2009;34(10):1582-5.

33.Aspesi D, Pinna G. Could a blood test for PTSD and depression be on the horizon? Expert Rev Proteomics 2018;15(12):983-1006.

34.Singh S, Siddiqui SA, Tripathy S, Kumar S, Saha S, Ugale R, et al. Decreased level of histone acetylation in the infralimbic prefrontal cortex following immediate extinction may result in deficit of extinction memory. Brain Res Bull 2018;140:355-64.

35.Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T, et al. Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 2006;30(7):1256-60.

36.Ji LL, Peng JB, Fu CH, Tong L, Wang ZY. Sigma-1 receptor activation ameliorates anxiety-like behavior through NR2A-CREB-BDNF signaling pathway in a rat model submitted to single-prolonged stress. Mol Med Rep 2017;16(4):4987-93.

37.Chen J, Hutchison KE, Calhoun VD, Claus ED, Turner JA, Sui J, et al. CREB‐BDNF pathway influences alcohol cue‐elicited activation in drinkers. Hum Brain Mapp 2015;36(8):3007-19.

38.Pláteník J, Fišar Z, Buchal R, Jirák R, Kitzlerová E, Zvěřová M, et al. GSK3β, CREB, and BDNF in peripheral blood of patients with Alzheimer's disease and depression. Prog Neuropsychopharmacol Biol Psychiatry 2014;50:83-93.



Key words: Brain-derived neurotrophic factor (BDNF), biomarker, cAMP-responsive element-binding protein (CREB), Posttraumatic stress disorder (PTSD)
Psychiatry and Behavioral Sciences 2019;9(4):158-165
Online ISSN: 2636-834X
Creative Commons License This work is licensed under a Creative Commons Attribution 3.0 Unported License