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GPER1/GPR30 Activation Improves Neuronal Survival Following Global Cerebral Ischemia Induced by Cardiac Arrest in Mice

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Abstract

Female sex steroids, particularly estrogens, contribute to the sexually dimorphic response observed in cerebral ischemic outcome, with females being relatively protected compared to males. Using a mouse model of cardiac arrest and cardiopulmonary resuscitation, we previously demonstrated that estrogen neuroprotection is mediated in part by the estrogen receptor β, with no involvement of estrogen receptor α. In this study, we examined the neuroprotective effect of the novel estrogen receptor, G protein-coupled estrogen receptor 1 (GPER1/GPR30). Male mice administered with the GPR30 agonist G1 exhibited significantly reduced neuronal injury in the hippocampal CA1 region and striatum. The magnitude of neuroprotection observed in G1-treated mice was indistinguishable from estrogen-treated mice, implicating GPR30 in estrogen neuroprotection. Real-time quantitative RT-PCR indicates that G1 treatment increases expression of the neuroprotective ion channel, small-conductance calcium-activated potassium channel 2. We conclude that GPR30 agonists show promise in reducing brain injury following global cerebral ischemia.

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References

  1. Roger VL, et al. Heart disease and stroke statistics—2012 update: A report from the American Heart Association. Circulation. 2012;125(1):e2–220.

    Article  PubMed  Google Scholar 

  2. McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: An integrated view. Trends Endocrinol Metab. 2003;14(5):228–35.

    Article  PubMed  CAS  Google Scholar 

  3. Reeves MJ, et al. Sex differences in stroke: Epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7(10):915–26.

    Article  PubMed  Google Scholar 

  4. Appelros P, Stegmayr B, Terent A. A review on sex differences in stroke treatment and outcome. Acta Neurol Scand. 2010;121:359–69.

    Article  PubMed  CAS  Google Scholar 

  5. Alkayed NJ, et al. Gender-linked brain injury in experimental stroke. Stroke. 1998;29(1):159–65.

    Article  PubMed  CAS  Google Scholar 

  6. Renoux C, Suissa S. Hormone therapy administration in postmenopausal women and risk of stroke. Womens Health (Lond Engl). 2011;7(3):355–61.

    Article  CAS  Google Scholar 

  7. Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–12.

    Article  PubMed  CAS  Google Scholar 

  8. Billeci AM, et al. Hormone replacement therapy and stroke. Curr Vasc Pharmacol. 2008;6(2):112–23.

    Article  PubMed  CAS  Google Scholar 

  9. Hoffman GE, et al. Ovarian steroid modulation of seizure severity and hippocampal cell death after kainic acid treatment. Exp Neurol. 2003;182(1):124–34.

    Article  PubMed  CAS  Google Scholar 

  10. Abdelhamid R, et al. Benzothiophene selective estrogen receptor modulators provide neuroprotection by a novel GPR30-dependent mechanism. ACS Chem Neurosci. 2011;2(5):256–68.

    Article  PubMed  CAS  Google Scholar 

  11. Prossnitz ER, Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol. 2011;7(12):715–26.

    Article  PubMed  CAS  Google Scholar 

  12. Bologa CG, et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol. 2006;2(4):207–12.

    Article  PubMed  CAS  Google Scholar 

  13. Liu SB, et al. Neuroprotective effects of oestrogen against oxidative toxicity through activation of G-protein-coupled receptor 30 receptor. Clin Exp Pharmacol Physiol. 2011;38(9):577–85.

    Article  PubMed  CAS  Google Scholar 

  14. Hutchens MP, et al. Estrogen Is renoprotective via a nonreceptor-dependent mechanism after cardiac arrest in vivo. Anesthesiology. 2010.

  15. Wu WW, Adelman JP, Maylie J. Ovarian hormone deficiency reduces intrinsic excitability and abolishes acute estrogen sensitivity in hippocampal CA1 pyramidal neurons. J Neurosci. 2011;31(7):2638–48.

    Article  PubMed  CAS  Google Scholar 

  16. Zhang C, Kelly MJ, Ronnekleiv OK. 17Beta-estradiol rapidly increases K(ATP) activity in GnRH via a protein kinase signaling pathway. Endocrinology. 2010;151(9):4477–84.

    Article  PubMed  CAS  Google Scholar 

  17. Zadran S, et al. 17-Beta-estradiol increases neuronal excitability through MAP kinase-induced calpain activation. Proc Natl Acad Sci U S A. 2009;106(51):21936–41.

    Article  PubMed  Google Scholar 

  18. Allen D, et al. SK2 channels are neuroprotective for ischemia-induced neuronal cell death. Journal of Cerebral Blood Flow & Metabolism. 2011.

  19. Zhang B, et al. Estradiol and G1 reduce infarct size and improve immunosuppression after experimental stroke. J Immunol. 2010;184(8):4087–94.

    Article  PubMed  CAS  Google Scholar 

  20. Kofler J, et al. Histopathological and behavioral characterization of a novel model of cardiac arrest and cardiopulmonary resuscitation in mice. J Neurosci Methods. 2004;136(1):33–44.

    Article  PubMed  Google Scholar 

  21. Kelley MH, et al. Ischemic insult to cerebellar Purkinje cells causes diminished GABAA receptor function and allopregnanolone neuroprotection is associated with GABAA receptor stabilization. J Neurochem. 2008;107(3):668–78.

    Article  PubMed  CAS  Google Scholar 

  22. Nakano T, et al. Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. Brain Res. 2010;1357:124–30.

    Article  PubMed  CAS  Google Scholar 

  23. Bond CT, et al. Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J Neurosci. 2004;24(23):5301–6.

    Article  PubMed  CAS  Google Scholar 

  24. Miller NR, et al. Estrogen can act via estrogen receptor alpha and beta to protect hippocampal neurons against global ischemia-induced cell death. Endocrinology. 2005;146(7):3070–9.

    Article  PubMed  CAS  Google Scholar 

  25. Noppens RR, et al. Dose-dependent neuroprotection by 17beta-estradiol after cardiac arrest and cardiopulmonary resuscitation. Crit Care Med. 2005;33(7):1595–602.

    Article  PubMed  CAS  Google Scholar 

  26. Noppens RR, et al. Estradiol after cardiac arrest and cardiopulmonary resuscitation is neuroprotective and mediated through estrogen receptor-beta. J Cereb Blood Flow Metab. 2009;29(2):277–86.

    Article  PubMed  CAS  Google Scholar 

  27. Lebesgue D, et al. Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged female rats. PLoS One. 2010;5(1):e8642.

    Article  PubMed  Google Scholar 

  28. Notas G, et al. Interplay of estrogen receptors and GPR30 for the regulation of early membrane initiated transcriptional effects: A pharmacological approach. Steroids. 2011.

  29. Ngo-Anh TJ, et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat Neurosci. 2005;8(5):642–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NIH R01NS058792, RO1NS046072, and RO1NR03521. This work was also supported by a Walter S. and Lucienne Driskill Foundation grant.

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Correspondence to P. S. Herson.

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Kosaka, Y., Quillinan, N., Bond, C.T. et al. GPER1/GPR30 Activation Improves Neuronal Survival Following Global Cerebral Ischemia Induced by Cardiac Arrest in Mice. Transl. Stroke Res. 3, 500–507 (2012). https://doi.org/10.1007/s12975-012-0211-8

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  • DOI: https://doi.org/10.1007/s12975-012-0211-8

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