Downregulation of G‑protein‑coupled receptor 30 in the hippocampus attenuates the neuroprotection of estrogen in the critical period hypothesis

Wu,Yingxi; Feng,Dayun; Lin,Jiaji; Qu,Yan; He,Shiming; Wang,Yuan; Gao,Guodong; Zhao,Tianzhi

doi:10.3892/mmr.2018.8618

Downregulation of G‑protein‑coupled receptor 30 in the hippocampus attenuates the neuroprotection of estrogen in the critical period hypothesis

Authors:
- Yingxi Wu
- Dayun Feng
- Jiaji Lin
- Yan Qu
- Shiming He
- Yuan Wang
- Guodong Gao
- Tianzhi Zhao
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Affiliations: Department of Neurosurgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: February 16, 2018 https://doi.org/10.3892/mmr.2018.8618
Pages: 5716-5725
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the role of G‑protein‑coupled receptor 30 (GPR30) in long‑term 17β‑estradiol (E2) deprivation (LTED) in a rat model with global cerebral ischemia (GCI), and its therapeutic target for ischemic stroke in the clinical setting. Following bilateral ovariectomy, GCI was induced in rats 1 or 10 weeks post‑surgery. To determine the protein and mRNA expression levels of GPR30 in the hippocampal CA1 region of LTED rats, short‑term E2 deprivation (STED) rats and naturally aging rats, western blot analysis and reverse transcription-quantitative polymerase chain reaction were performed. The results of the present study demonstrated that E2 treatment revealed significant neuroprotection post‑GCI in STED rats, but not in LTED rats, as well as a decrease in the expression levels of GPR30 in the hippocampal CA1 region. In LTED rats,. Notably, no effects were observed on the ubiquitination of GPR30 following investigation in STED or LTED rats. While the protein and mRNA expression levels of GPR30 were also decreased in the hippocampal CA1 region of female 24‑month‑old rats compared with 3‑month‑old rats. E2 treatment initiated for the entire ovariectomy period elevated GPR30 mRNA and protein expression levels, and attenuated the loss of hippocampal neurons in the GCI‑induced CA1 region, indicating that E2 treatment exerted robust neuroprotection within LTED rats. However, the neuroprotective effect of E2 may be blocked by G15. The results of the present study revealed that downregulation of GPR30 expression may attenuate the neuroprotection of E2 within LTED conditions in rats post‑ovariectomy by leading to neuronal insensitivity to E2 neuroprotection following cerebral ischemia. These results provide evidence that GPR30 may have potential as a novel therapeutic target for the treatment of clinical ischemic stroke.

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1	Brann DW, Dhandapani K, Wakade C, Mahesh VB and Khan MM: Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications. Steroids. 72:381–405. 2007. View Article : Google Scholar : PubMed/NCBI
2	Rocca WA, Grossardt BR and Shuster LT: Oophorectomy, menopause, estrogen treatment, and cognitive aging: Clinical evidence for a window of opportunity. Brain Res. 1379:188–198. 2011. View Article : Google Scholar : PubMed/NCBI
3	Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR and Rocca WA: Premature menopause or early menopause: Long-term health consequences. Maturitas. 65:161–166. 2010. View Article : Google Scholar : PubMed/NCBI
4	Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, et al: Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative: A randomized trial. JAMA. 289:2673–2684. 2003. View Article : Google Scholar : PubMed/NCBI
5	Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, et al: Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 291:2959–2968. 2004. View Article : Google Scholar : PubMed/NCBI
6	Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, et al: Postmenopausal hormone therapy: An Endocrine Society scientific statement. J Clin Endocrinol Metab. 95 7 Suppl 1:S1–S66. 2010. View Article : Google Scholar : PubMed/NCBI
7	Sherwin BB: The critical period hypothesis: Can it explain discrepancies in the oestrogen-cognition literature? J Neuroendocrinol. 19:77–81. 2007. View Article : Google Scholar : PubMed/NCBI
8	Sherwin BB: Estrogen therapy: Is time of initiation critical for neuroprotection? Nat Rev Endocrinol. 5:620–627. 2009. View Article : Google Scholar : PubMed/NCBI
9	Craig MC and Murphy DG: Estrogen therapy and Alzheimer's dementia. Ann N Y Acad Sci. 1205:245–253. 2010. View Article : Google Scholar : PubMed/NCBI
10	Gibbs RB: Estrogen therapy and cognition: A review of the cholinergic hypothesis. Endocr Rev. 31:224–253. 2010. View Article : Google Scholar : PubMed/NCBI
11	Moura PJ and Petersen SL: Estradiol acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: Implications for hormone replacement therapy. Rev Neurosci. 21:363–380. 2010. View Article : Google Scholar : PubMed/NCBI
12	Boulware MI, Kent BA and Frick KM: The impact of age-related ovarian hormone loss on cognitive and neural function. Curr Top Behav Neurosci. 10:165–184. 2012. View Article : Google Scholar : PubMed/NCBI
13	Daniel JM and Bohacek J: The critical period hypothesis of estrogen effects on cognition: Insights from basic research. Biochim Biophys Acta. 1800:1068–1076. 2010. View Article : Google Scholar : PubMed/NCBI
14	Prossnitz ER and Barton M: The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol. 7:715–726. 2011. View Article : Google Scholar : PubMed/NCBI
15	Gingerich S, Kim GL, Chalmers JA, Koletar MM, Wang X, Wang Y and Belsham DD: Estrogen receptor alpha and G-protein coupled receptor 30 mediate the neuroprotective effects of 17β-estradiol in novel murine hippocampal cell models. Neuroscience. 170:54–66. 2010. View Article : Google Scholar : PubMed/NCBI
16	Liu SB, Han J, Zhang N, Tian Z, Li XB and Zhao MG: Neuroprotective effects of oestrogen against oxidative toxicity through activation of G-protein-coupled receptor 30 receptor. Clin Exp Pharmacol Physiol. 38:577–585. 2011. View Article : Google Scholar : PubMed/NCBI
17	Zhang B, Subramanian S, Dziennis S, Jia J, Uchida M, Akiyoshi K, Migliati E, Lewis AD, Vandenbark AA, Offner H and Hurn PD: Estradiol and G1 reduce infarct size and improve immunosuppression after experimental stroke. J Immunol. 184:4087–4094. 2010. View Article : Google Scholar : PubMed/NCBI
18	Kosaka Y, Quillinan N, Bond C, Traystman R, Hurn P and Herson P: GPER1/GPR30 activation improves neuronal survival following global cerebral ischemia induced by cardiac arrest in mice. Transl Stroke Res. 3:500–507. 2012. View Article : Google Scholar : PubMed/NCBI
19	Tang H, Zhang Q, Yang L, Dong Y, Khan M, Yang F, Brann DW and Wang R: GPR30 mediates estrogen rapid signaling and neuroprotection. Mol Cell Endocrinol. 387:52–58. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zhang QG, Han D, Wang RM, Dong Y, Yang F, Vadlamudi RK and Brann DW: C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci USA. 108:pp. E617–E624. 2011; View Article : Google Scholar : PubMed/NCBI
21	Stephenson W: Deficiencies in the National Institute of Health's guidelines for the care and protection of laboratory animals. J Med Philos. 18:375–388. 1993. View Article : Google Scholar : PubMed/NCBI
22	Zhang QG, Wang R, Khan M, Mahesh V and Brann DW: Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci. 28:8430–8441. 2008. View Article : Google Scholar : PubMed/NCBI
23	Zhang QG, Raz L, Wang R, Han D, De Sevilla L, Yang F, Vadlamudi RK and Brann DW: Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. J Neurosci. 29:13823–13836. 2009. View Article : Google Scholar : PubMed/NCBI
24	Wang R, Tu J, Zhang Q, Zhang X, Zhu Y, Ma W, Cheng C, Brann DW and Yang F: Genistein attenuates ischemic oxidative damage and behavioral deficits via eNOS/Nrf2/HO-1 signaling. Hippocampus. 23:634–647. 2013. View Article : Google Scholar : PubMed/NCBI
25	Shen Y, He P, Fan YY, Zhang JX, Yan HJ, Hu WW, Ohtsu H and Chen Z: Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity. Free Radic Biol Med. 48:727–735. 2010. View Article : Google Scholar : PubMed/NCBI
26	Wang R, Zhang X, Zhang J, Fan Y, Shen Y, Hu W and Chen Z: Oxygen-glucose deprivation induced glial scar-like change in astrocytes. PLoS One. 7:e375742012. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
28	Lebesgue D, Chevaleyre V, Zukin RS and Etgen AM: Estradiol rescues neurons from global ischemia-induced cell death: Multiple cellular pathways of neuroprotection. Steroids. 74:555–561. 2009. View Article : Google Scholar : PubMed/NCBI
29	Scott E, Zhang QG, Wang R, Vadlamudi R and Brann D: Estrogen neuroprotection and the critical period hypothesis. Front Neuroendocrinol. 33:85–104. 2012. View Article : Google Scholar : PubMed/NCBI
30	Yao J, Hamilton RT, Cadenas E and Brinton RD: Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. Biochim. Biophys. Acta. 1800:1121–1126. 2010.
31	Bohacek J, Bearl AM and Daniel JM: Long-term ovarian hormone deprivation alters the ability of subsequent oestradiol replacement to regulate choline acetyltransferase protein levels in the hippocampus and prefrontal cortex of middle-aged rats. J Neuroendocrinol. 20:1023–1027. 2008. View Article : Google Scholar : PubMed/NCBI
32	Gibbs RB, Nelson D and Hammond R: Role of GPR30 in mediating estradiol effects on acetylcholine release in the hippocampus. Horm Behav. 66:339–345. 2014. View Article : Google Scholar : PubMed/NCBI
33	Liu SB, Zhang N, Guo YY, Zhao R, Shi TY, Feng SF, Wang SQ, Yang Q, Li XQ, Wu YM, et al: G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors. J Neurosci. 32:4887–4900. 2012. View Article : Google Scholar : PubMed/NCBI
34	Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, Parker MA, Tkachenko SE, Savchuck NP, Sklar LA, et al: Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol. 2:207–212. 2006. View Article : Google Scholar : PubMed/NCBI
35	Notas G, Kampa M, Pelekanou V and Castanas E: Interplay of estrogen receptors and GPR30 for the regulation of early membrane initiated transcriptional effects: A pharmacological approach. Steroids. 77:943–950. 2012. View Article : Google Scholar : PubMed/NCBI