Abstract
In an animal model of post-traumatic stress disorder (PTSD), our previous studies showed mitochondrial stress-induced apoptosis in the hippocampus. Metformin, the most commonly prescribed anti-diabetic drug, exerts its effects through 5′-adenosine monophosphate-activated protein kinase (AMPK) activation. It was shown that a neuroprotective role was gradually established against stroke, spinal cord injury and Parkinson’s disease. The aim of this study was to explore the role of the AMPK pathway in neuronal apoptosis in the hippocampus using a rat model of PTSD. The model PTSD rats received acute exposure to prolonged stress (single prolonged stress, SPS), followed by examination of the effects of genes and/or proteins related to the AMPK and oxidative stress pathways in the hippocampus with or without metformin preconditioning. The results indicated that the level of phosphorylated AMPK was markedly increased after SPS. Metformin protected the hippocampus as evidenced by abolishing down-regulation of the AMPK pathway and up-regulating expression of oxidative stress-related genes. These results indicated that metformin attenuated oxidative stress in the hippocampus in rats under SPS. AMPK pathway activation may be a novel therapeutic protocol for PTSD patients.
Similar content being viewed by others
References
Ahn J, Lee H, Kim S et al (2008) The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun 373:545–549. doi:10.1016/j.bbrc.2008.06.077
Al-Hadethe A, Hunt N, Thomas S, Al-Qaysi A (2014) Prevalence of traumatic events and PTSD symptoms among secondary school students in Baghdad. Eur J Psychotraumatol 5:23928. doi:10.3402/ejpt.v5.23928
Ashabi G, Khodagholi F, Khalaj L et al (2014) Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1alpha pathway. Metab Brain Dis 29:47–58. doi:10.1007/s11011-013-9475-2
Cahova M, Palenickova E, Dankova H et al (2015) Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309:G100–G111. doi:10.1152/ajpgi.00329.2014
Cameron AR, Morrison VL, Levin D et al (2016) Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 119:652–665. doi:10.1161/CIRCRESAHA.116.308445
Chen M-B, Zhang Y, Wei M-X et al (2013) Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells. Cell Signal 25:1993–2002. doi:10.1016/j.cellsig.2013.05.026
Chen S, Zhou N, Zhang Z et al (2015) Resveratrol induces cell apoptosis in adipocytes via AMPK activation. Biochem Biophys Res Commun 457:608–613. doi:10.1016/j.bbrc.2015.01.034
Czapski GA, Adamczyk A, Strosznajder RP, Strosznajder JB (2013) Expression and activity of PARP family members in the hippocampus during systemic inflammation: their role in the regulation of prooxidative genes. Neurochem Int 62:664–673. doi:10.1016/j.neuint.2013.01.020
Deng T, Zheng YR, Hou WW et al (2016) Pre-stroke metformin treatment is neuroprotective involving AMPK reduction. Neurochem Res 41:2719–2727. doi:10.1007/s11064-016-1988-8
Dowling RJO, Niraula S, Stambolic V, Goodwin PJ (2012) Metformin in cancer: translational challenges. J Mol Endocrinol 48
Eagle AL, Knox D, Roberts MM et al (2013) Single prolonged stress enhances hippocampal glucocorticoid receptor and phosphorylated protein kinase B levels. Neurosci Res 75:130–137. doi:10.1016/j.neures.2012.11.001
Ekstrand M, Falkenberg M, Rantanen A et al (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet 13:935–944. doi:10.1093/hmg/ddh109
Francati V, Vermetten E, Bremner JD (2007a) Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings. Depress Anxiety 24:202–218
Francati V, Vermetten E, Bremner JD (2007b) Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings. Depress Anxiety 24:202–218. doi:10.1002/da.20208
Han F, Xiao B, Wen LL (2015) Loss of glial cells of the hippocampus in a rat model of post-traumatic stress disorder. Neurochem Res 40:942–951. doi:10.1007/s11064-015-1549-6
Han F, Yan S, Shi Y (2013) Single-prolonged stress induces endoplasmic reticulum-dependent apoptosis in the hippocampus in a rat model of post-traumatic stress disorder. PLoS One 8:e69340. doi:10.1371/journal.pone.0069340
Hughes KC, Shin LM (2011) Functional neuroimaging studies of post-traumatic stress disorder. Expert Rev Neurother 11:275–285. doi:10.1586/ern.10.198
Isoda K, Young JL, Zirlik A et al (2006) Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26:611–617. doi:10.1161/01.ATV.0000201938.78044.75
Jalving M, Gietema JA, Lefrandt JD et al (2010) Metformin: taking away the candy for cancer? Eur J Cancer 46:2369–2380. doi:10.1016/j.ejca.2010.06.012
Kessler RC (2000) Posttraumatic stress disorder: the burden to the individual and to society. Journal of Clinical Psychiatry, In
Kim J, Kwak HJ, Cha J-Y et al (2014) Metformin suppresses LPS-induced inflammatory response in murine macrophages via ATF-3 induction. J Biol Chem 289:23246–23255. doi:10.1074/jbc.M114.577908
Kim M-S, Park J-Y, Namkoong C et al (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10:727–733. doi:10.1038/nm1061
Knox D, George SA, Fitzpatrick CJ et al (2012) Single prolonged stress disrupts retention of extinguished fear in rats. Learn Mem 19:43–49. doi:10.1101/lm.024356.111
Li XM, Han F, Liu DJ, Shi YX (2010) Single-prolonged stress induced mitochondrial-dependent apoptosis in hippocampus in the rat model of post-traumatic stress disorder. J Chem Neuroanat 40:248–255. doi:10.1016/j.jchemneu.2010.07.001
Liu B, Zhang YH, Jiang Y et al (2015) Gadd45b is a novel mediator of neuronal apoptosis in ischemic stroke. Int J Biol Sci 11:353–360. doi:10.7150/ijbs.9813
Meijer AJ, Codogno P (2007) AMP-activated protein kinase and autophagy. Autophagy 3:238–240
Miranda-Vizuete A, Damdimopoulos AE, Spyrou G (2000) The mitochondrial thioredoxin system. Antioxid Redox Signal 2:801–810. doi:10.1089/ars.2000.2.4-801
Park CE, Yun H, Lee EB et al (2010) The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. J Med Food 13:815–820. doi:10.1089/jmf.2009.1359
Picca A, Lezza AMS (2015) Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: useful insights from aging and calorie restriction studies. Mitochondrion 25:67–75
Ramamurthy S, Ronnett G (2012) AMP-activated protein kinase (AMPK) and energy-sensing in the brain. Exp Neurobiol 21:52. doi:10.5607/en.2012.21.2.52
Rauch SL, Shin LM (1997a) Functional neuroimaging studies in posttraumatic stress disorder. Ann N Y Acad Sci 821:83–98
Rauch SL, Shin LM (1997b) Functional neuroimaging studies in posttraumatic stress disorder. Ann N Y Acad Sci 821:83–98
Rojas LBA, Gomes MB (2013) Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. doi: http://dx.doi.org/10.1186/1758-5996-5-6
Rösen P, Wiernsperger NF (2006) Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress. Diabetes Metab Res Rev 22:323–330. doi:10.1002/dmrr.623
Rutter GA, da Silva Xavier GA, Leclerc I (2003) Roles of 5′ AMP activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J 375:1–16
Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta - Mol Cell Res 1813:1269–1278
Shao J, Zhang A, Qin W et al (2012) AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells. Biochem Biophys Res Commun 423:448–453. doi:10.1016/j.bbrc.2012.05.123
Shin LM, Rauch SL, Pitman RK (2006) Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Annals of the New York Academy of Sciences, In, pp 67–79
Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1α. Cardiovasc Res 79:208–217
Wang C, Liu C, Gao K et al (2016) Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. Biochem Biophys Res Commun 477:534–540. doi:10.1016/j.bbrc.2016.05.148
Yehuda R (2005) Chapter 3.2. Neuroendocrine aspects of PTSD. Tech Behav Neural Sci 15:251–272. doi:10.1016/S0921-0709(05)80058-6
Zhang Y, Ho SMY (2011) Risk factors of posttraumatic stress disorder among survivors after the 512 Wenchuan earthquake in China. PLoS One. doi:10.1371/journal.pone.0022371
Zhao RR, Xu XC, Xu F et al (2014) Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 448:414–417. doi:10.1016/j.bbrc.2014.04.130
Acknowledgements
The authors are grateful to all of the staff members of the China Medical University Experiment Center for their technical support. This study was funded by the National Natural Science Foundation of China (No. 31140060), the Shenyang Science and Technology Project (No. F16-205-1-35) and the Specialized Research Fund for Doctoral Program of Higher Education (No. 20132104110021). We thank the LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest
The authors declare that they have no conflict of interest in this article.
Ethical Statement
This study was carried out in strict accordance with the recommendations of the Guide for the Care and Use of the Laboratory Animals of the National Health and Medical Research Council of China. The experimental protocol was approved by the Department of Psychiatry, China Medical University Animal Ethics Committee, and was endorsed by the Research and Ethics Committee of the Liaoning Key Lab of Biological Psychiatry, China.
Rights and permissions
About this article
Cite this article
Wang, J., Xiao, B., Han, F. et al. Metformin Alleviated the Neuronal Oxidative Stress in Hippocampus of Rats under Single Prolonged Stress. J Mol Neurosci 63, 28–35 (2017). https://doi.org/10.1007/s12031-017-0953-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-017-0953-6