Antidepressant effect of geranylgeranylacetone in a chronic mild stress model of depression and its possible mechanism

Zhong,Jing-Mei; Wu,Shao-Yuan; Bai,Jie; Guo,Qiang; Tao,Jian; Chen,Hui; Zhao,Nai-Wei; Zhao,Zhong; Fu,Hao

doi:10.3892/etm.2012.669

Antidepressant effect of geranylgeranylacetone in a chronic mild stress model of depression and its possible mechanism

Authors:
- Jing-Mei Zhong
- Shao-Yuan Wu
- Jie Bai
- Qiang Guo
- Jian Tao
- Hui Chen
- Nai-Wei Zhao
- Zhong Zhao
- Hao Fu
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Affiliations: Department of Neurology, The First People's Hospital of Yunnan, Kunhua Affiliated Hospital of Kunming Medical University, Kunming 650032, P.R. China, Medical Faculty, Kunming University of Science and Technology, Kunming 650500, P.R. China
Published online on: August 16, 2012 https://doi.org/10.3892/etm.2012.669
Pages: 627-632

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Abstract

Depression is a highly debilitating and widely distributed illness in the general population. Geranylgeranylacetone (GGA), a non-toxic anti-ulcer drug, has been reported to have protective effects in the central nervous system. The aim of this study was to determine the antidepressant effect of GGA in a chronic mild stress (CMS) model of depression. We confirmed that CMS in rats caused a reduction in locomotor activity and an increase in the levels of monoamine oxidase-A (MAO-A) and caspase-3 in the hippocampus. GGA treatment reversed stress-induced alterations in locomotor activity and target levels of MAO-A and caspase-3. In addition, GGA treatment induced heat shock protein 70 (Hsp70) expression in the hippocampus. These findings suggest that GGA possesses an antidepressant activity in a CMS model of depression. The activity of GGA in the relief of depression may be mediated via the induction of Hsp70 expression to suppress MAO-A expression and the apoptosis cascade.

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1	Kessler RC, Berglund P, Demler O, et al: The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 289:3095–3105. 2003. View Article : Google Scholar : PubMed/NCBI
2	Nemeroff CB: The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res. 41:189–206. 2007. View Article : Google Scholar : PubMed/NCBI
3	Rosen RC and Marin H: Prevalence of antidepressant-associated erectile dysfunction. J Clin Psychiatry. 64(Suppl 10): 5–10. 2003.
4	Evans CG, Chang L and Gestwicki JE: Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem. 53:4585–4602. 2010. View Article : Google Scholar : PubMed/NCBI
5	Parsell DA and Lindquist S: The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet. 27:437–496. 1993. View Article : Google Scholar : PubMed/NCBI
6	Sharp FR, Massa SM and Swanson RA: Heat-shock protein protection. Trends Neurosci. 22:97–99. 1999. View Article : Google Scholar : PubMed/NCBI
7	Ooie T, Takahashi N, Saikawa T, et al: Single oral dose of geranylgeranylacetone induces heat-shock protein 72 and renders protection against ischemia/reperfusion injury in rat heart. Circulation. 104:1837–1843. 2001. View Article : Google Scholar
8	Guo S, Wharton W, Moseley P and Shi H: Heat shock protein 70 regulates cellular redox status by modulating glutathione-related enzyme activities. Cell Stress Chaperones. 12:245–254. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kimmins S and MacRae TH: Maturation of steroid receptors: an example of functional cooperation among molecular chaperones and their associated proteins. Cell Stress Chaperones. 5:76–86. 2000. View Article : Google Scholar
10	Rajapandi T, Greene LE and Eisenberg E: The molecular chaperones Hsp90 and Hsc70 are both necessary and sufficient to activate hormone binding by glucocorticoid receptor. J Biol Chem. 275:22597–22604. 2000. View Article : Google Scholar : PubMed/NCBI
11	Shimizu S, Nomura K, Ujihara M, et al: An allel-specific abnormal transcript of the heat shock protein 70 gene in patients with major depression. Biochem Biophys Res Commun. 219:745–752. 1996. View Article : Google Scholar : PubMed/NCBI
12	Martini F, Fernández C, Segundo LS, Tarazona JV and Pablos MV: Assessment of potential immunotoxic effects caused by cypermethrin, fluoxetine, and thiabendazole using heat shock protein 70 and interleukin-1beta mRNA expression in the anuran Xenopus laevis. Environ Toxicol Chem. 29:2536–2543. 2010. View Article : Google Scholar
13	Yu J, Roh S, Lee JS, et al: The effects of venlafaxine and dexamethasone on the expression of HSP70 in rat C6 glioma cells. Psychiatry Investig. 7:43–48. 2010. View Article : Google Scholar : PubMed/NCBI
14	Allagui MS, Nciri R, Rouhaud MF, et al: Long-term exposure to low lithium concentrations stimulates proliferation, modifies stress protein expression pattern and enhances resistance to oxidative stress in SH-SY5Y cells. Neurochem Res. 34:453–462. 2009. View Article : Google Scholar
15	Hirakawa T, Rokutan K, Nikawa T and Kishi K: Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology. 111:345–357. 1996. View Article : Google Scholar : PubMed/NCBI
16	Ishii Y, Kwong JM and Caprioli J: Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model. Invest Ophthalmol Vis Sci. 44:1982–1992. 2003. View Article : Google Scholar
17	Latchman DS: Heat shock proteins and cardiac protection. Cardiovasc Res. 51:637–646. 2001. View Article : Google Scholar : PubMed/NCBI
18	Yamagami K, Yamamoto Y, Ishikawa Y, Yonezawa K, Toyokuni S and Yamaoka Y: Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers. J Lab Clin Med. 135:465–475. 2000. View Article : Google Scholar
19	Katsuno M, Sang C, Adachi H, et al: Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci USA. 102:16801–16806. 2005. View Article : Google Scholar
20	Tanito M, Kwon YW, Kondo N, et al: Cytoprotective effects of geranylgeranylacetone against retinal photooxidative damage. J Neurosci. 25:2396–2404. 2005. View Article : Google Scholar : PubMed/NCBI
21	Yasuda H, Shichinohe H, Kuroda S, Ishikawa T and Iwasaki Y: Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischemia. Brain Res. 1032:176–182. 2005. View Article : Google Scholar : PubMed/NCBI
22	Luo FC, Qi L, Lv T, et al: Geranylgeranylacetone protects mice against morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Free Radic Biol Med. 52:1218–1227. 2012. View Article : Google Scholar
23	Meyer JH, Ginovart N, Boovariwala A, et al: Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 63:1209–1216. 2006. View Article : Google Scholar : PubMed/NCBI
24	Duman RS: Depression: a case of neuronal life and death? Biol Psychiatry. 56:140–145. 2004. View Article : Google Scholar : PubMed/NCBI
25	Manji HK, Drevets WC and Charney DS: The cellular neurobiology of depression. Nat Med. 7:541–547. 2001. View Article : Google Scholar : PubMed/NCBI
26	Mathew SJ, Manji HK and Charney DS: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 33:2080–2092. 2008. View Article : Google Scholar : PubMed/NCBI
27	Elhwuegi AS: Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 28:435–451. 2004. View Article : Google Scholar : PubMed/NCBI
28	Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D and Hrdina PD: High activity-related allele of MAO-A gene associated with depressed suicide in males. Neuroreport. 13:1195–1198. 2002. View Article : Google Scholar : PubMed/NCBI
29	Wouters J: Structural aspects of monoamine oxidase and its reversible inhibition. Curr Med Chem. 5:137–162. 1998.PubMed/NCBI
30	Riederer P, Lachenmayer L and Laux G: Clinical applications of MAO-inhibitors. Curr Med Chem. 11:2033–2043. 2004. View Article : Google Scholar : PubMed/NCBI
31	Terano A, Shiga J, Hiraishi H, Ota S and Sugimoto T: Protective action of tetraprenylacetone against ethanol-induced damage in rat gastric mucosa. Digestion. 35:182–188. 1986. View Article : Google Scholar : PubMed/NCBI
32	Hirota K, Nakamura H, Arai T, et al: Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes. Biochem Biophys Res Commun. 275:825–830. 2000. View Article : Google Scholar
33	Bremner JD: Does stress damage the brain? Biol Psychiatry. 45:797–805. 1999. View Article : Google Scholar : PubMed/NCBI
34	Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL and Charney DS: Hippocampal volume reduction in major depression. Am J Psychiatry. 157:115–118. 2000.
35	Colla M, Kronenberg G, Deuschle M, et al: Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatr Res. 41:553–560. 2007.PubMed/NCBI
36	Eastwood SL and Harrison PJ: Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a western blot study of synaptophysin, GAP-43 and the complexins. Brain Res Bull. 55:569–578. 2001. View Article : Google Scholar : PubMed/NCBI
37	Lenze E, Cross D, McKeel D, Neuman RJ and Sheline YI: White matter hyperintensities and gray matter lesions in physically healthy depressed subjects. Am J Psychiatry. 156:1602–1607. 1999. View Article : Google Scholar : PubMed/NCBI
38	Nolan CL, Moore GJ, Madden R, et al: Prefrontal cortical volume in childhood-onset major depression: preliminary findings. Arch Gen Psychiatry. 59:173–179. 2002.PubMed/NCBI
39	Ongür D, Drevets WC and Price JL: Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA. 95:13290–13295. 1998.PubMed/NCBI
40	Bachis A, Cruz MI, Nosheny RL and Mocchetti I: Chronic unpredictable stress promotes neuronal apoptosis in the cerebral cortex. Neurosci Lett. 442:104–108. 2008. View Article : Google Scholar : PubMed/NCBI
41	Gould E and Tanapat P: Stress and hippocampal neurogenesis. Biol Psychiatry. 46:1472–1479. 1999. View Article : Google Scholar
42	McEwen BS: Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 87:873–904. 2007. View Article : Google Scholar : PubMed/NCBI
43	Lee AL, Ogle WO and Sapolsky RM: Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. 4:117–128. 2002. View Article : Google Scholar : PubMed/NCBI
44	Woo M, Hakem R, Soengas MS, et al: Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12:806–819. 1998. View Article : Google Scholar : PubMed/NCBI
45	Salvesen GS: Caspases: opening the boxes and interpreting the arrows. Cell Death Differ. 9:3–5. 2002. View Article : Google Scholar : PubMed/NCBI
46	Ghavami S, Hashemi M, Ande SR, et al: Apoptosis and cancer: mutations within caspase genes. J Med Genet. 46:497–510. 2009. View Article : Google Scholar : PubMed/NCBI
47	Ghribi O, Herman MM and Savory J: The endoplasmic reticulum is the main site for caspase-3 activation following aluminum-induced neurotoxicity in rabbit hippocampus. Neurosci Lett. 324:217–221. 2002. View Article : Google Scholar
48	Shiraishi H, Okamoto H, Yoshimura A and Yoshida H: ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci. 119:3958–3966. 2006. View Article : Google Scholar : PubMed/NCBI
49	Kim YH, Song JJ, Kim YC, et al: Geranylgeranylacetone ameliorates acute cochlear damage caused by 3-nitropropionic acid. Neurotoxicology. 31:317–325. 2010. View Article : Google Scholar : PubMed/NCBI
50	Mikuriya T, Sugahara K, Sugimoto K, et al: Attenuation of progressive hearing loss in a model of age-related hearing loss by a heat shock protein inducer, geranylgeranylacetone. Brain Res. 1212:9–17. 2008. View Article : Google Scholar : PubMed/NCBI
51	Fujiki M, Kobayashi H, Abe T and Ishii K: Astroglial activation accompanies heat shock protein upregulation in rat brain following single oral dose of geranylgeranylacetone. Brain Res. 991:254–257. 2003. View Article : Google Scholar : PubMed/NCBI
52	Mosser DD, Caron AW, Bourget L, et al: The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol. 20:7146–7159. 2000. View Article : Google Scholar : PubMed/NCBI
53	Yin HY, Ma XF, Liu F, Xia M and Xu AT: Protective effect of geranylgeranylacetone on cisplatin ototoxicity. Chemotherapy. 55:1–5. 2009. View Article : Google Scholar : PubMed/NCBI
54	Li CY, Lee JS, Ko YG, Kim JI and Seo JS: Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J Biol Chem. 275:25665–25671. 2000. View Article : Google Scholar : PubMed/NCBI