Effects of doxepin on brain-derived neurotrophic factor, tumor necrosis factor alpha, mitogen-activated protein kinase 14, and AKT1 genes expression in rat hippocampus

Eidelkhani, Nastaran; Radahmadi, Maryam; Kazemi, Mohammad; Rafiee, Laleh; Alaei, Hojjatallah; Reisi, Parham

Effects of doxepin on brain-derived neurotrophic factor, tumor necrosis factor alpha, mitogen-activated protein kinase 14, and AKT1 genes expression in rat hippocampus

Authors

¹ Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

² Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

³ Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

⁴ Department of Physiology; Genetics and Molecular Biology, School of Medicine; Biosensor Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: It has been suggested that doxepin in addition to enhancement of noradrenaline and serotonin levels may have neuroprotective effects. Therefore, this study investigated the effect of doxepin on gene expression of brain-derived neurotrophic factor (BDNF), tumor necrosis factor alpha (TNF-α), mitogen-activated protein kinase 14 (MAPK14), and serine-threonine protein kinase AKT1 in rat hippocampus.
Materials and Methods: Male rats were divided randomly into three groups: Control, doxepin 1 mg/kg, and doxepin 5 mg/kg. Rats received an i.p injection of doxepin for 21 days. Then the hippocampi were dissected for the measurement of the expression of BDNF, TNF-α, MAPK14, and AKT1 genes.
Results: Our results showed no significant effects of doxepin on gene expression of BDNF, TNF-α, MAPK14, and AKT1 genes in the hippocampus.
Conclusions: These results did not show significant effects of doxepin on the genes that affect the neuronal survival in intact animals. However, more studies need to be done, especially in models associated with neuronal damage.

Keywords

References

1.	Roumestan C, Michel A, Bichon F, Portet K, Detoc M, Henriquet C, et al. Anti-inflammatory properties of desipramine and fluoxetine. Respir Res 2007;8:35.
2.	Jacobson MD, Raff MC. Programmed cell death and Bcl-2 protection in very low oxygen. Nature 1995;374:814-6.
3.	Jin Y, Lim CM, Kim SW, Park JY, Seo JS, Han PL, et al. Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Brain Res 2009;1281:108-16.
4.	Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 1999;46:1181-91.
5.	Xu H, Steven Richardson J, Li XM. Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus. Neuropsychopharmacology 2003;28:53-62.
6.	Watanabe Y, Gould E, Daniels DC, Cameron H, McEwen BS. Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 1992;222:157-62.
7.	Bianchi M, Sacerdote P, Panerai AE. Chlomipramine differently affects inflammatory edema and pain in the rat. Pharmacol Biochem Behav 1994;48:1037-40.
8.	Abdel-Salam OM, Baiuomy AR, Arbid MS. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacol Res 2004;49:119-31.
9.	Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:201-17.
10.	Manderbacka K, Sund R, Koski S, Keskimäki I, Elovainio M. Diabetes and depression? Secular trends in the use of antidepressants among persons with diabetes in Finland in 1997-2007. Pharmacoepidemiol Drug Saf 2011;20:338-43.
11.	Zautra AJ, Yocum DC, Villanueva I, Smith B, Davis MC, Attrep J, et al. Immune activation and depression in women with rheumatoid arthritis. J Rheumatol 2004;31:457-63.
12.	Ali S, Stone MA, Peters JL, Davies MJ, Khunti K. The prevalence of co-morbid depression in adults with Type 2 diabetes: A systematic review and meta-analysis. Diabet Med 2006;23:1165-73.
13.	Castanon N, Leonard BE, Neveu PJ, Yirmiya R. Effects of antidepressants on cytokine production and actions. Brain Behav Immun 2002;16:569-74.
14.	Raison CL, Capuron L, Miller AH. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24-31.
15.	Hajak G, Rodenbeck A, Voderholzer U, Riemann D, Cohrs S, Hohagen F, et al. Doxepin in the treatment of primary insomnia: A placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry 2001;62:453-63.
16.	Drake LA, Fallon JD, Sober A. Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream. The Doxepin Study Group. J Am Acad Dermatol 1994;31:613-6.
17.	Sun XY, Zhang L, Wei CX, Piao HR, Quan ZS. Characterization of the anticonvulsant activity of doxepin in various experimental seizure models in mice. Pharmacol Rep 2009;61:245-51.
18.	Ji BS, Ji H, Liu GQ. Doxepin protects cultured neurons against oxidative stress-induced injury. Acta Pharmacol Sin 2004;25:297-300.
19.	Lee MM, Reif A, Schmitt AG. Major depression: A role for hippocampal neurogenesis? Curr Top Behav Neurosci. 2013;14:153-79.
20.	Gharzi M, Dolatabadi HR, Reisi P, Javanmard SH. Dose related effects of doxepin on passive avoidance learning in rats. Res Pharm Sci 2012;7:S35.
21.	Arabpoor Z, Hamidi G, Rashidi B, Shabrang M, Alaei H, Sharifi MR, et al. Erythropoietin improves neuronal proliferation in dentate gyrus of hippocampal formation in an animal model of Alzheimer's disease. Adv Biomed Res 2012;1:50. [PUBMED]
22.	Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I. regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 2008;1211:37-43.
23.	Wang R, Li YH, Xu Y, Li YB, Wu HL, Guo H, et al. Curcumin produces neuroprotective effects via activating brain-derived neurotrophic factor/TrkB-dependent MAPK and PI-3K cascades in rodent cortical neurons. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:147-53.
24.	Beaulieu JM, Gainetdinov RR, Caron MG. Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 2009;49:327-47.
25.	Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL, et al. TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J 2005;19:362-70.
26.	Chaparro-Huerta V, Rivera-Cervantes MC, Flores-Soto ME, Gómez-Pinedo U, Beas-Zárate C. Proinflammatory cytokines and apoptosis following glutamate-induced excitotoxicity mediated by p38 MAPK in the hippocampus of neonatal rats. J Neuroimmunol 2005;165:53-62.
27.	Ji BS, Ji H, Liu GQ. Protective effects of doxepin on focal cerebral ischemia-reperfusion injured rats. Chin Pharmacol Bull 2003;19:896-8.
28.	Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci 1997;20:245-67.
29.	Drzyzga LR, Marcinowska A, Obuchowicz E. Antiapoptotic and neurotrophic effects of antidepressants: A review of clinical and experimental studies. Brain Res Bull 2009;79:248-57.
30.	McKernan DP, Dinan TG, Cryan JF. "Killing the Blues": A role for cellular suicide (apoptosis) in depression and the antidepressant response? Prog Neurobiol 2009;88:246-63.
31.	Djordjevic A, Djordjevic J, Elakovic I, Adzic M, Matic G, Radojcic MB. Effects of fluoxetine on plasticity and apoptosis evoked by chronic stress in rat prefrontal cortex. Eur J Pharmacol 2012;693:37-44.
32.	Yamada K, Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 2003;91:267-70.
33.	Peng CH, Chiou SH, Chen SJ, Chou YC, Ku HH, Cheng CK, et al. Neuroprotection by Imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway. Eur Neuropsychopharmacol 2008;18:128-40.
34.	Zhang Y, Gu F, Chen J, Dong W. Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat. Brain Res 2010;1366:141-8.
35.	Coppell AL, Pei Q, Zetterström TS. Bi-phasic change in BDNF gene expression following antidepressant drug treatment. Neuropharmacology 2003;44:903-10.
36.	Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr Rev 2001;22:153-83.
37.	Di Benedetto B, Radecke J, Schmidt MV, Rupprecht R. Acute antidepressant treatment differently modulates ERK/MAPK activation in neurons and astrocytes of the adult mouse prefrontal cortex. Neuroscience 2013;232:161-8.
38.	Chou CT, He S, Jan CR. Paroxetine-induced apoptosis in human osteosarcoma cells: Activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation. Toxicol Appl Pharmacol 2007;218:265-73.
39.	Kodama M, Russell DS, Duman RS. Electroconvulsive seizures increase the expression of MAP kinase phosphatases in limbic regions of rat brain. Neuropsychopharmacology 2005;30:360-71.

Advanced Biomedical Research