Abstract
Both sex and steroid hormones are important to consider in human ischemic stroke and its experimental models. Stroke initiates a cascade of changes that lead to neural cell death, but also activates endogenous protective processes that counter the deleterious consequences of ischemia. Steroids may be part of these cerebroprotective processes. One option to provide cerebroprotection is to reinforce these intrinsic protective mechanisms. In the current review, we first summarize studies describing sex differences and the influence of steroid hormones in stroke. We then present and discuss our recent results concerning differential changes in endogenous steroid levels in the brains of male and female mice and the importance of progesterone receptors (PR) during the early phase after stroke. In the third part, we give an overview of experimental studies, including ours, that provide evidence for the pleiotropic beneficial effects of progesterone and its promising cerebroprotective potential in stroke. We also highlight the key role of PR signaling as well as potential additional mechanisms by which progesterone may provide cerebroprotection.
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References
Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27(5):1129–1138. https://doi.org/10.1523/JNEUROSCI.4468-06.2007
Aggarwal R, Medhi B, Pathak A, Dhawan V, Chakrabarti A (2008) Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischaemia in mice. J Pharm Pharmacol 60(6):731–737. https://doi.org/10.1211/jpp.60.6.0008
Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA (2010) NAD + depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci 30(8):2967–2978. https://doi.org/10.1523/JNEUROSCI.5552-09.2010
Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD (1998) Gender-linked brain injury in experimental stroke. Stroke 29(1):159–165 (discussion 166)
Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD, Miller VM (2000) Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 31(1):161–168
Allen RS, Sayeed I, Oumarbaeva Y, Morrison KC, Choi PH, Pardue MT, Stein DG (2016) Progesterone treatment shows greater protection in brain vs. retina in a rat model of middle cerebral artery occlusion: progesterone receptor levels may play an important role. Restor Neurol Neurosci 34(6):947–963. https://doi.org/10.3233/RNN-160672
Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG (2009) Classification of stroke subtypes. Cerebrovasc Dis 27(5):493–501. https://doi.org/10.1159/000210432
Anderson MF, Sims NR (2002) The effects of focal ischemia and reperfusion on the glutathione content of mitochondria from rat brain subregions. J Neurochem 81(3):541–549
Andersson AM, Jensen TK, Juul A, Petersen JH, Jorgensen T, Skakkebaek NE (2007) Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys. J Clin Endocrinol Metab 92(12):4696–4705. https://doi.org/10.1210/jc.2006-2633
Andrabi SS, Parvez S, Tabassum H (2017) Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats. Dis Model Mech 10(6):787–796. https://doi.org/10.1242/dmm.025692
Ankolekar S, Rewell S, Howells DW, Bath PM (2012) The influence of stroke risk factors and comorbidities on assessment of stroke therapies in humans and animals. Int J Stroke 7(5):386–397. https://doi.org/10.1111/j.1747-4949.2012.00802.x
Appelros P, Stegmayr B, Terent A (2010) A review on sex differences in stroke treatment and outcome. Acta Neurol Scand 121(6):359–369. https://doi.org/10.1111/j.1600-0404.2009.01258.x
Arevalo MA, Azcoitia I, Garcia-Segura LM (2015) The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci 16(1):17–29. https://doi.org/10.1038/nrn3856
Auchus RJ, Sampath Kumar A, Andrew Boswell C, Gupta MK, Bruce K, Rath NP, Covey DF (2003) The enantiomer of progesterone (ent-progesterone) is a competitive inhibitor of human cytochromes P450c17 and P450c21. Arch Biochem Biophys 409(1):134–144
Belelli D, Lambert JJ, Peters JA, Gee KW, Lan NC (1996) Modulation of human recombinant GABAA receptors by pregnanediols. Neuropharmacology 35(9–10):1223–1231
Brazil DP, Yang ZZ, Hemmings BA (2004) Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 29(5):233–242. https://doi.org/10.1016/j.tibs.2004.03.006
Cai W, Zhu Y, Furuya K, Li Z, Sokabe M, Chen L (2008) Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage. Neuropharmacology 55(2):127–138. https://doi.org/10.1016/j.neuropharm.2008.04.023
Calabrese EJ (2008) Drug therapies for stroke and traumatic brain injury often display U-shaped dose responses: occurrence, mechanisms, and clinical implications. Crit Rev Toxicol 38(6):557–577. https://doi.org/10.1080/10408440802014287
Carpenter RS, Iwuchukwu I, Hinkson CL, Reitz S, Lee W, Kukino A, Zhang A, Pike MM, Ardelt AA (2016) High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke. Brain Res 1639:200–213. https://doi.org/10.1016/j.brainres.2016.01.058
Carswell HV, Anderson NH, Clark JS, Graham D, Jeffs B, Dominiczak AF, Macrae IM (1999) Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension 33(2):681–685
Carswell HV, Dominiczak AF, Macrae IM (2000) Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 278(1):H290–H294. https://doi.org/10.1152/ajpheart.2000.278.1.H290
Carswell HV, Dominiczak AF, Garcia-Segura LM, Harada N, Hutchison JB, Macrae IM (2005) Brain aromatase expression after experimental stroke: topography and time course. J Steroid Biochem Mol Biol 96(1):89–91. https://doi.org/10.1016/j.jsbmb.2005.02.016
Chen M, Penning TM (2014) 5beta-reduced steroids and human delta(4)-3-ketosteroid 5beta-reductase (AKR1D1). Steroids 83:17–26. https://doi.org/10.1016/j.steroids.2014.01.013
Chen J, Chopp M, Li Y (1999) Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat. J Neurol Sci 171(1):24–30
Chen RL, Balami JS, Esiri MM, Chen LK, Buchan AM (2010) Ischemic stroke in the elderly: an overview of evidence. Nat Rev Neurol 6(5):256–265. https://doi.org/10.1038/nrneurol.2010.36
Chen A, Xiong LJ, Tong Y, Mao M (2013) The neuroprotective roles of BDNF in hypoxic ischemic brain injury. Biomed Rep 1(2):167–176. https://doi.org/10.3892/br.2012.48
Chen Y, Garcia GE, Huang W, Constantini S (2014) The involvement of secondary neuronal damage in the development of neuropsychiatric disorders following brain insults. Front Neurol 5:22. https://doi.org/10.3389/fneur.2014.00022
Cheng J, Hurn PD (2010) Sex shapes experimental ischemic brain injury. Steroids 75(11):754–759. https://doi.org/10.1016/j.steroids.2009.10.014
Cheng J, Alkayed NJ, Hurn PD (2007) Deleterious effects of dihydrotestosterone on cerebral ischemic injury. J Cereb Blood Flow Metab 27(9):1553–1562. https://doi.org/10.1038/sj.jcbfm.9600457
Choleris E, Galea LAM, Sohrabji F, Frick KM (2018) Sex differences in the brain: implications for behavioral and biomedical research. Neurosci Biobehav Rev 85:126–145. https://doi.org/10.1016/j.neubiorev.2017.07.005
Coughlan T, Gibson C, Murphy S (2005) Modulatory effects of progesterone on inducible nitric oxide synthase expression in vivo and in vitro. J Neurochem 93(4):932–942. https://doi.org/10.1111/j.1471-4159.2005.03068.x
Dang J, Mitkari B, Kipp M, Beyer C (2011) Gonadal steroids prevent cell damage and stimulate behavioral recovery after transient middle cerebral artery occlusion in male and female rats. Brain Behav Immun 25(4):715–726. https://doi.org/10.1016/j.bbi.2011.01.013
Della Torre S, Benedusi V, Fontana R, Maggi A (2014) Energy metabolism and fertility: a balance preserved for female health. Nat Rev Endocrinol 10(1):13–23. https://doi.org/10.1038/nrendo.2013.203
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397
Downs JL, Wise PM (2009) The role of the brain in female reproductive aging. Mol Cell Endocrinol 299(1):32–38. https://doi.org/10.1016/j.mce.2008.11.012
Dubal DB, Wise PM (2001) Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology 142(1):43–48. https://doi.org/10.1210/endo.142.1.7911
Dubal DB, Kashon ML, Pettigrew LC, Ren JM, Finklestein SP, Rau SW, Wise PM (1998) Estradiol protects against ischemic injury. J Cereb Blood Flow Metab 18(11):1253–1258. https://doi.org/10.1097/00004647-199811000-00012
Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM (2001) Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci USA 98(4):1952–1957. https://doi.org/10.1073/pnas.041483198
Dubal DB, Rau SW, Shughrue PJ, Zhu H, Yu J, Cashion AB, Suzuki S, Gerhold LM, Bottner MB, Dubal SB, Merchanthaler I, Kindy MS, Wise PM (2006) Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERalpha in estradiol-mediated protection against delayed cell death. Endocrinology 147(6):3076–3084. https://doi.org/10.1210/en.2005-1177
Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3(10):1089–1095
Espinosa-Garcia C, Sayeed I, Yousuf S, Atif F, Sergeeva EG, Neigh GN, Stein DG (2017) Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone. Brain Behav Immun 66:177–192. https://doi.org/10.1016/j.bbi.2017.06.012
Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8(4):355–369. https://doi.org/10.1016/S1474-4422(09)70025-0
Ford ES, Maynard LM, Li C (2014) Trends in mean waist circumference and abdominal obesity among US adults, 1999–2012. JAMA 312(11):1151–1153. https://doi.org/10.1001/jama.2014.8362
Frechou M, Zhang S, Liere P, Delespierre B, Soyed N, Pianos A, Schumacher M, Mattern C, Guennoun R (2015) Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection. Neuropharmacology 97:394–403. https://doi.org/10.1016/j.neuropharm.2015.06.002
Gaignard P, Savouroux S, Liere P, Pianos A, Therond P, Schumacher M, Slama A, Guennoun R (2015) Effect of sex differences on brain mitochondrial function and its suppression by ovariectomy and in aged mice. Endocrinology 156(8):2893–2904. https://doi.org/10.1210/en.2014-1913
Gaignard P, Frechou M, Schumacher M, Therond P, Mattern C, Slama A, Guennoun R (2016) Progesterone reduces brain mitochondrial dysfunction after transient focal ischemia in male and female mice. J Cereb Blood Flow Metab 36(3):562–568. https://doi.org/10.1177/0271678X15610338
Gaignard P, Frechou M, Liere P, Therond P, Schumacher M, Slama A, Guennoun R (2018) Sex differences in brain mitochondrial metabolism: influence of endogenous steroids and stroke. J Neuroendocrinol. https://doi.org/10.1111/jne.12497
Garcia-Segura LM, Wozniak A, Azcoitia I, Rodriguez JR, Hutchison RE, Hutchison JB (1999) Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair. Neuroscience 89(2):567–578
Garcia-Segura LM, Veiga S, Sierra A, Melcangi RC, Azcoitia I (2003) Aromatase: a neuroprotective enzyme. Prog Neurobiol 71(1):31–41
Gibson CL (2013) Cerebral ischemic stroke: is gender important? J Cereb Blood Flow Metab 33(9):1355–1361. https://doi.org/10.1038/jcbfm.2013.102
Gibson CL, Murphy SP (2004) Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. J Cereb Blood Flow Metab 24(7):805–813. https://doi.org/10.1097/01.WCB.0000125365.83980.00
Gibson CL, Constantin D, Prior MJ, Bath PM, Murphy SP (2005) Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Exp Neurol 193(2):522–530. https://doi.org/10.1016/j.expneurol.2005.01.009
Gibson CL, Gray LJ, Murphy SP, Bath PM (2006) Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 26(9):1103–1113. https://doi.org/10.1038/sj.jcbfm.9600270
Gibson CL, Gray LJ, Bath PM, Murphy SP (2008) Progesterone for the treatment of experimental brain injury; a systematic review. Brain 131(Pt 2):318–328. https://doi.org/10.1093/brain/awm183
Gibson CL, Coomber B, Rathbone J (2009) Is progesterone a candidate neuroprotective factor for treatment following ischemic stroke? Neuroscientist 15(4):324–332. https://doi.org/10.1177/1073858409333069
Gibson CL, Coomber B, Murphy SP (2011) Progesterone is neuroprotective following cerebral ischaemia in reproductively ageing female mice. Brain 134(Pt 7):2125–2133. https://doi.org/10.1093/brain/awr132
Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289(2):H558–H568. https://doi.org/10.1152/ajpheart.01275.2004
Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29(41):12764–12767. https://doi.org/10.1523/JNEUROSCI.3566-09.2009
Grossman KJ, Goss CW, Stein DG (2004) Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res 1008(1):29–39. https://doi.org/10.1016/j.brainres.2004.02.022
Guennoun R, Labombarda F, Gonzalez Deniselle MC, Liere P, De Nicola AF, Schumacher M (2015) Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection. J Steroid Biochem Mol Biol 146:48–61. https://doi.org/10.1016/j.jsbmb.2014.09.001
Guennoun R, Frechou M, Gaignard P, Liere P, Slama A, Schumacher M, Denier C, Mattern C (2018) Intranasal administration of progesterone: a potential efficient route of delivery for cerebroprotection after acute brain injuries. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2018.06.006
Gunn BG, Cunningham L, Mitchell SG, Swinny JD, Lambert JJ, Belelli D (2015) GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response. Front Neuroendocrinol 36:28–48. https://doi.org/10.1016/j.yfrne.2014.06.001
Haast RA, Gustafson DR, Kiliaan AJ (2012) Sex differences in stroke. J Cereb Blood Flow Metab 32(12):2100–2107. https://doi.org/10.1038/jcbfm.2012.141
Habib P, Beyer C (2015) Regulation of brain microglia by female gonadal steroids. J Steroid Biochem Mol Biol 146:3–14. https://doi.org/10.1016/j.jsbmb.2014.02.018
Habib P, Dang J, Slowik A, Victor M, Beyer C (2014a) Hypoxia-induced gene expression of aquaporin-4, cyclooxygenase-2 and hypoxia-inducible factor 1alpha in rat cortical astroglia is inhibited by 17beta-estradiol and progesterone. Neuroendocrinology 99(3–4):156–167. https://doi.org/10.1159/000362279
Habib P, Slowik A, Zendedel A, Johann S, Dang J, Beyer C (2014b) Regulation of hypoxia-induced inflammatory responses and M1–M2 phenotype switch of primary rat microglia by sex steroids. J Mol Neurosci 52(2):277–285. https://doi.org/10.1007/s12031-013-0137-y
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging. J Clin Endocrinol Metab 86(2):724–731. https://doi.org/10.1210/jcem.86.2.7219
Hawk T, Zhang YQ, Rajakumar G, Day AL, Simpkins JW (1998) Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats. Brain Res 796(1–2):296–298
Herson PS, Hurn PD (2010) Gender and the injured brain. Prog Brain Res 186:177–187. https://doi.org/10.1016/B978-0-444-53630-3.00012-9
Herson PS, Koerner IP, Hurn PD (2009) Sex, sex steroids, and brain injury. Semin Reprod Med 27(3):229–239. https://doi.org/10.1055/s-0029-1216276
Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 11(1):56–64. https://doi.org/10.1038/nrneurol.2014.207
Huhtaniemi IT, Tajar A, Lee DM, O’Neill TW, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Han TS, Kula K, Labrie F, Lean ME, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Forti G, Wu FC (2012) Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur J Endocrinol 166(6):983–991. https://doi.org/10.1530/eje-11-1051
Hun Lee J, Won S, Stein DG (2015) Progesterone attenuates thrombin-induced endothelial barrier disruption in the brain endothelial cell line bEnd.3: the role of tight junction proteins and the endothelial protein C receptor. Brain Res 1613:73–80. https://doi.org/10.1016/j.brainres.2015.04.002
Hurn PD, Macrae IM (2000) Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab 20(4):631–652. https://doi.org/10.1097/00004647-200004000-00001
Iadecola C, Anrather J (2011) Stroke research at a crossroad: asking the brain for directions. Nat Neurosci 14(11):1363–1368. https://doi.org/10.1038/nn.2953
Inagaki T, Etgen AM (2013) Neuroprotective action of acute estrogens: animal models of brain ischemia and clinical implications. Steroids 78(6):597–606. https://doi.org/10.1016/j.steroids.2012.12.015
Ishrat T, Sayeed I, Atif F, Hua F, Stein DG (2010) Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol 226(1):183–190. https://doi.org/10.1016/j.expneurol.2010.08.023
Ishrat T, Sayeed I, Atif F, Hua F, Stein DG (2012) Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway. Neuroscience 210:442–450. https://doi.org/10.1016/j.neuroscience.2012.03.008
Ismail PM, Li J, DeMayo FJ, O’Malley BW, Lydon JP (2002) A novel LacZ reporter mouse reveals complex regulation of the progesterone receptor promoter during mammary gland development. Mol Endocrinol 16(11):2475–2489. https://doi.org/10.1210/me.2002-0169
Jiang C, Wang J, Li X, Liu C, Chen N, Hao Y (2009) Progesterone exerts neuroprotective effects by inhibiting inflammatory response after stroke. Inflamm Res 58(9):619–624. https://doi.org/10.1007/s00011-009-0032-8
Jiang C, Zuo F, Wang Y, Lu H, Yang Q, Wang J (2016) Progesterone changes VEGF and BDNF expression and promotes neurogenesis after ischemic stroke. Mol Neurobiol 54:571–581
Jiang X, Andjelkovic AV, Zhu L, Yang T, Bennett MVL, Chen J, Keep RF, Shi Y (2018) Blood–brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol 163–164:144–171. https://doi.org/10.1016/j.pneurobio.2017.10.001
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99(18):11946–11950. https://doi.org/10.1073/pnas.182296499
Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789. https://doi.org/10.1189/jlb.1109766
Jin Z, Wu J, Yan LJ (2016) Chemical conditioning as an Approach to ischemic stroke tolerance: mitochondria as the target. Int J Mol Sci 17(3):351. https://doi.org/10.3390/ijms17030351
Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702–714. https://doi.org/10.1016/j.redox.2014.05.006
Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med 13(10):1173–1175. https://doi.org/10.1038/nm1651
Kostic T, Andric S, Maric D, Kovacevic R (1998) The effect of acute stress and opioid antagonist on the activity of NADPH-P450 reductase in rat Leydig cells. J Steroid Biochem Mol Biol 66(1–2):51–54
Kumar N, Koide SS, Tsong Y, Sundaram K (2000) Nestorone: a progestin with a unique pharmacological profile. Steroids 65(10–11):629–636
Kumar N, Fagart J, Liere P, Mitchell SJ, Knibb AR, Petit-Topin I, Rame M, El-Etr M, Schumacher M, Lambert JJ, Rafestin-Oblin ME, Sitruk-Ware R (2017) Nestorone(R) as a novel progestin for nonoral contraception: structure-activity relationships and brain metabolism studies. Endocrinology 158(1):170–182. https://doi.org/10.1210/en.2016-1426
Kumon Y, Kim SC, Tompkins P, Stevens A, Sakaki S, Loftus CM (2000) Neuroprotective effect of postischemic administration of progesterone in spontaneously hypertensive rats with focal cerebral ischemia. J Neurosurg 92(5):848–852. https://doi.org/10.3171/jns.2000.92.5.0848
Labrie F (2010) DHEA, important source of sex steroids in men and even more in women. Prog Brain Res 182:97–148. https://doi.org/10.1016/s0079-6123(10)82004-7
Labrie F (2015) All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. J Steroid Biochem Mol Biol 145:133–138. https://doi.org/10.1016/j.jsbmb.2014.06.001
Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A (2016) Poststroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology 103(5):460–475. https://doi.org/10.1159/000439435
Lebesgue D, Chevaleyre V, Zukin RS, Etgen AM (2009) Estradiol rescues neurons from global ischemia-induced cell death: multiple cellular pathways of neuroprotection. Steroids 74(7):555–561. https://doi.org/10.1016/j.steroids.2009.01.003
Lee RJ, Kim JK, Chao D, Kuo L, Mally A, McClean ME, Pemberton HE, Wilmington AR, Wong J, Murphy SP (2015) Progesterone and allopregnanolone improves stroke outcome in male mice via distinct mechanisms but neither promotes neurogenesis. J Neurochem 132(1):32–37. https://doi.org/10.1111/jnc.12990
Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD, McCullough LD (2004) Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol 187(1):94–104. https://doi.org/10.1016/j.expneurol.2004.01.004
Li J, Siegel M, Yuan M, Zeng Z, Finnucan L, Persky R, Hurn PD, McCullough LD (2011) Estrogen enhances neurogenesis and behavioral recovery after stroke. J Cereb Blood Flow Metab 31(2):413–425. https://doi.org/10.1038/jcbfm.2010.181
Liao S, Chen W, Kuo J, Chen C (2001) Association of serum estrogen level and ischemic neuroprotection in female rats. Neurosci Lett 297(3):159–162
Liberale L, Carbone F, Montecucco F, Gebhard C, Luscher TF, Wegener S, Camici GG (2018) Ischemic stroke across sexes: what is the status quo? Front Neuroendocrinol. https://doi.org/10.1016/j.yfrne.2018.05.001
Lisabeth L, Bushnell C (2012) Stroke risk in women: the role of menopause and hormone therapy. Lancet Neurol 11(1):82–91. https://doi.org/10.1016/S1474-4422(11)70269-1
Liu M, Kelley MH, Herson PS, Hurn PD (2010) Neuroprotection of sex steroids. Minerva Endocrinol 35(2):127–143
Liu F, Lang J, Li J, Benashski SE, Siegel M, Xu Y, McCullough LD (2011) Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke. Stroke 42(4):1090–1096. https://doi.org/10.1161/STROKEAHA.110.594861
Liu A, Margaill I, Zhang S, Labombarda F, Coqueran B, Delespierre B, Liere P, Marchand-Leroux C, O’Malley BW, Lydon JP, De Nicola AF, Sitruk-Ware R, Mattern C, Plotkine M, Schumacher M, Guennoun R (2012) Progesterone receptors: a key for neuroprotection in experimental stroke. Endocrinology 153(8):3747–3757. https://doi.org/10.1210/en.2012-1138
Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4(5):399–415. https://doi.org/10.1038/nrn1106
Ma Y, Wang J, Wang Y, Yang GY (2017) The biphasic function of microglia in ischemic stroke. Prog Neurobiol 157:247–272. https://doi.org/10.1016/j.pneurobio.2016.01.005
Madinier A, Wieloch T, Olsson R, Ruscher K (2014) Impact of estrogen receptor beta activation on functional recovery after experimental stroke. Behav Brain Res 261:282–288. https://doi.org/10.1016/j.bbr.2013.12.046
Manzanero S, Santro T, Arumugam TV (2013) Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochem Int 62(5):712–718. https://doi.org/10.1016/j.neuint.2012.11.009
Maric D, Kostic T, Kovacevic R (1996) Effects of acute and chronic immobilization stress on rat Leydig cell steroidogenesis. J Steroid Biochem Mol Biol 58(3):351–355
Martel C, Labrie F, Archer DF, Ke Y, Gonthier R, Simard JN, Lavoie L, Vaillancourt M, Montesino M, Balser J, Moyneur E (2016) Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5 mg intravaginal prasterone for 12 weeks. J Steroid Biochem Mol Biol 159:142–153. https://doi.org/10.1016/j.jsbmb.2016.03.016
McCarthy MM, Arnold AP, Ball GF, Blaustein JD, De Vries GJ (2012) Sex differences in the brain: the not so inconvenient truth. J Neurosci 32(7):2241–2247. https://doi.org/10.1523/JNEUROSCI.5372-11.2012
McColl BW, Allan SM, Rothwell NJ (2007) Systemic inflammation and stroke: aetiology, pathology and targets for therapy. Biochem Soc Trans 35(Pt 5):1163–1165. https://doi.org/10.1042/BST0351163
McCullough LD, Hurn PD (2003) Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab 14(5):228–235
McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 25(4):502–512. https://doi.org/10.1038/sj.jcbfm.9600059
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB (2016) Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 133(4):447–454. https://doi.org/10.1161/cir.0000000000000366
Murphy SJ, Traystman RJ, Hurn PD, Duckles SP (2000) Progesterone exacerbates striatal stroke injury in progesterone-deficient female animals. Stroke 31(5):1173–1178
Ogden CL, Carroll MD, Fryar CD, Flegal KM (2015) Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS Data Brief 219:1–8
Orr TE, Taylor MF, Bhattacharyya AK, Collins DC, Mann DR (1994) Acute immobilization stress disrupts testicular steroidogenesis in adult male rats by inhibiting the activities of 17 alpha-hydroxylase and 17,20-lyase without affecting the binding of LH/hCG receptors. J Androl 15(4):302–308
Ozacmak VH, Sayan H (2009) The effects of 17beta estradiol, 17alpha estradiol and progesterone on oxidative stress biomarkers in ovariectomized female rat brain subjected to global cerebral ischemia. Physiol Res 58(6):909–912
Palmer BF, Clegg DJ (2015) The sexual dimorphism of obesity. Mol Cell Endocrinol 402:113–119. https://doi.org/10.1016/j.mce.2014.11.029
Perez-Alvarez MJ, Maza Mdel C, Anton M, Ordonez L, Wandosell F (2012) Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia. J Neuroinflammation 9:157. https://doi.org/10.1186/1742-2094-9-157
Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA (2009) Gender differences in stroke incidence and poststroke disability in the Framingham heart study. Stroke 40(4):1032–1037. https://doi.org/10.1161/STROKEAHA.108.542894
Petrone AB, Simpkins JW, Barr TL (2014) 17beta-estradiol and inflammation: implications for ischemic stroke. Aging Dis 5(5):340–345. https://doi.org/10.14336/AD.2014.0500340
Quillinan N, Deng G, Grewal H, Herson PS (2014) Androgens and stroke: good, bad or indifferent? Exp Neurol 259:10–15. https://doi.org/10.1016/j.expneurol.2014.02.004
Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8):987–991. https://doi.org/10.1038/nn.4338
Reckelhoff JF (2001) Gender differences in the regulation of blood pressure. Hypertension 37(5):1199–1208
Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L (2008) Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 7(10):915–926. https://doi.org/10.1016/S1474-4422(08)70193-5
Rivest S, Rivier C (1991) Influence of the paraventricular nucleus of the hypothalamus in the alteration of neuroendocrine functions induced by intermittent footshock or interleukin. Endocrinology 129(4):2049–2057. https://doi.org/10.1210/endo-129-4-2049
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J, American Heart Association Statistics C, Stroke Statistics S (2011) Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123(4):e18–e209. https://doi.org/10.1161/CIR.0b013e3182009701
Rothman MS, Carlson NE, Xu M, Wang C, Swerdloff R, Lee P, Goh VH, Ridgway EC, Wierman ME (2011) Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry. Steroids 76(1–2):177–182. https://doi.org/10.1016/j.steroids.2010.10.010
Roy-O’Reilly M, McCullough LD (2018) Age and sex are critical factors in ischemic stroke pathology. Endocrinology. https://doi.org/10.1210/en.2018-00465
Ruan L, Wang B, ZhuGe Q, Jin K (2015) Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res 1623:166–173. https://doi.org/10.1016/j.brainres.2015.02.042
Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgansberger W, Holsboer F (1993) Progesterone receptor-mediated effects of neuroactive steroids. Neuron 11(3):523–530
Rusa R, Alkayed NJ, Crain BJ, Traystman RJ, Kimes AS, London ED, Klaus JA, Hurn PD (1999) 17beta-estradiol reduces stroke injury in estrogen-deficient female animals. Stroke 30(8):1665–1670
Saleh TM, Connell BJ, Legge C, Cribb AE (2004) Stroke-induced changes in estrogen release and neuronal activity in the parabrachial nucleus of the male rat. J Stroke Cerebrovasc Dis 13(1):24–34. https://doi.org/10.1016/j.jstrokecerebrovasdis.2004.01.003
Saleh TM, Connell BJ, Legge C, Cribb AE (2005) Estrogen synthesis in the central nucleus of the amygdala following middle cerebral artery occlusion: role in modulating neurotransmission. Neuroscience 135(4):1141–1153. https://doi.org/10.1016/j.neuroscience.2005.06.061
Sapolsky RM, Pulsinelli WA (1985) Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 229(4720):1397–1400
Sawada M, Alkayed NJ, Goto S, Crain BJ, Traystman RJ, Shaivitz A, Nelson RJ, Hurn PD (2000) Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse. J Cereb Blood Flow Metab 20(1):112–118. https://doi.org/10.1097/00004647-200001000-00015
Sayeed I, Guo Q, Hoffman SW, Stein DG (2006) Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion. Ann Emerg Med 47(4):381–389. https://doi.org/10.1016/j.annemergmed.2005.12.011
Sayeed I, Wali B, Stein DG (2007) Progesterone inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion. Restor Neurol Neurosci 25(2):151–159
Sayeed I, Parvez S, Wali B, Siemen D, Stein DG (2009) Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone. Brain Res 1263:165–173. https://doi.org/10.1016/j.brainres.2009.01.045
Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, El-Etr M, Akwa Y, Rajkowski K, Baulieu EE (2007) Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev 28(4):387–439. https://doi.org/10.1210/er.2006-0050
Selvamani A, Sohrabji F (2010) Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiol Aging 31(9):1618–1628. https://doi.org/10.1016/j.neurobiolaging.2008.08.014
Selvamani A, Williams MH, Miranda RC, Sohrabji F (2014) Circulating miRNA profiles provide a biomarker for severity of stroke outcomes associated with age and sex in a rat model. Clin Sci 127(2):77–89. https://doi.org/10.1042/CS20130565
Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, Sharma R, Parashara D, Savin VJ, Ambrose JA, Barua RS (2015) Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 36(40):2706–2715. https://doi.org/10.1093/eurheartj/ehv346
Sharma N, Lee J, Youssef I, Salifu MO, McFarlane SI (2017) Obesity, cardiovascular disease and sleep disorders: insights into the rising epidemic. J Sleep Disord Ther. https://doi.org/10.4172/2167-0277.1000260
Shet MS, Fisher CW, Arlotto MP, Shackleton CH, Holmans PL, Martin-Wixtrom CA, Saeki Y, Estabrook RW (1994) Purification and enzymatic properties of a recombinant fusion protein expressed in Escherichia coli containing the domains of bovine P450 17A and rat NADPH-P450 reductase. Arch Biochem Biophys 311(2):402–417
Sims NR, Muyderman H (2010) Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta 1802(1):80–91. https://doi.org/10.1016/j.bbadis.2009.09.003
Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT (2014) Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8:315. https://doi.org/10.3389/fnins.2014.00315
Slowik A, Beyer C (2015) Inflammasomes are neuroprotective targets for sex steroids. J Steroid Biochem Mol Biol 153:135–143. https://doi.org/10.1016/j.jsbmb.2015.02.013
Sohrabji F, Park MJ, Mahnke AH (2017) Sex differences in stroke therapies. J Neurosci Res 95(1–2):681–691. https://doi.org/10.1002/jnr.23855
Spratt NJ, Tomkins AJ, Pepperall D, McLeod DD, Calford MB (2014) Allopregnanolone and its precursor progesterone do not reduce injury after experimental stroke in hypertensive rats—role of postoperative temperature regulation? PLoS ONE 9(9):e107752. https://doi.org/10.1371/journal.pone.0107752
Stankowski JN, Gupta R (2011) Therapeutic targets for neuroprotection in acute ischemic stroke: lost in translation? Antioxid Redox Signal 14(10):1841–1851. https://doi.org/10.1089/ars.2010.3292
Strom JO, Theodorsson A, Theodorsson E (2009) Dose-related neuroprotective versus neurodamaging effects of estrogens in rat cerebral ischemia: a systematic analysis. J Cereb Blood Flow Metab 29(8):1359–1372. https://doi.org/10.1038/jcbfm.2009.66
Sugo N, Hurn PD, Morahan MB, Hattori K, Traystman RJ, DeVries AC (2002) Social stress exacerbates focal cerebral ischemia in mice. Stroke 33(6):1660–1664
Sutherland BA, Neuhaus AA, Couch Y, Balami JS, DeLuca GC, Hadley G, Harris SL, Grey AN, Buchan AM (2016) The transient intraluminal filament middle cerebral artery occlusion model as a model of endovascular thrombectomy in stroke. J Cereb Blood Flow Metab 36(2):363–369. https://doi.org/10.1177/0271678x15606722
Suzuki S, Gerhold LM, Bottner M, Rau SW, Dela Cruz C, Yang E, Zhu H, Yu J, Cashion AB, Kindy MS, Merchenthaler I, Gage FH, Wise PM (2007) Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. J Comp Neurol 500(6):1064–1075. https://doi.org/10.1002/cne.21240
Suzuki S, Brown CM, Wise PM (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30(2):201–211. https://doi.org/10.1016/j.yfrne.2009.04.007
Tilbrook AJ, Turner AI, Clarke IJ (2000) Effects of stress on reproduction in non-rodent mammals: the role of glucocorticoids and sex differences. Rev Reprod 5(2):105–113
Toung TJ, Traystman RJ, Hurn PD (1998) Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke 29(8):1666–1670
Toung TK, Hurn PD, Traystman RJ, Sieber FE (2000) Estrogen decreases infarct size after temporary focal ischemia in a genetic model of type 1 diabetes mellitus. Stroke 31(11):2701–2706
Toung TJ, Chen TY, Littleton-Kearney MT, Hurn PD, Murphy SJ (2004) Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats. J Cereb Blood Flow Metab 24(10):1160–1166. https://doi.org/10.1097/01.WCB.0000135594.13576.D2
Uchida M, Palmateer JM, Herson PS, DeVries AC, Cheng J, Hurn PD (2009) Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice. J Cereb Blood Flow Metab 29(8):1454–1462. https://doi.org/10.1038/jcbfm.2009.60
Vigen R, O’Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM (2013) Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310(17):1829–1836. https://doi.org/10.1001/jama.2013.280386
Wali B, Ishrat T, Won S, Stein DG, Sayeed I (2014) Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study. Brain 137(Pt 2):486–502. https://doi.org/10.1093/brain/awt319
Wali B, Ishrat T, Stein DG, Sayeed I (2016) Progesterone improves long-term functional and histological outcomes after permanent stroke in older rats. Behav Brain Res 305:46–56. https://doi.org/10.1016/j.bbr.2016.02.024
Wang HY, Wang GL, Yu YH, Wang Y (2009) The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats. Brain Res 1297:177–184. https://doi.org/10.1016/j.brainres.2009.08.054
Wang J, Jiang C, Liu C, Li X, Chen N, Hao Y (2010) Neuroprotective effects of progesterone following stroke in aged rats. Behav Brain Res 209(1):119–122. https://doi.org/10.1016/j.bbr.2010.01.026
Wang J, Zhao Y, Liu C, Jiang C, Zhao C, Zhu Z (2011) Progesterone inhibits inflammatory response pathways after permanent middle cerebral artery occlusion in rats. Mol Med Rep 4(2):319–324. https://doi.org/10.3892/mmr.2011.418
Wang Q, Bottalico L, Mesaros C, Blair IA (2015) Analysis of estrogens and androgens in postmenopausal serum and plasma by liquid chromatography-mass spectrometry. Steroids 99(Pt A):76–83. https://doi.org/10.1016/j.steroids.2014.08.012
Westberry JM, Prewitt AK, Wilson ME (2008) Epigenetic regulation of the estrogen receptor alpha promoter in the cerebral cortex following ischemia in male and female rats. Neuroscience 152(4):982–989. https://doi.org/10.1016/j.neuroscience.2008.01.048
White UA, Tchoukalova YD (2014) Sex dimorphism and depot differences in adipose tissue function. Biochim Biophys Acta 1842(3):377–392. https://doi.org/10.1016/j.bbadis.2013.05.006
Wilson ME (2013) Stroke: understanding the differences between males and females. Pflugers Arch 465(5):595–600. https://doi.org/10.1007/s00424-013-1260-x
Wise PM, Dubal DB, Wilson ME, Rau SW, Bottner M, Rosewell KL (2001) Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies. Brain Res Rev 37(1–3):313–319
Won S, Lee JH, Wali B, Stein DG, Sayeed I (2014) Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF-MMP pathway. J Cereb Blood Flow Metab 34(1):72–80. https://doi.org/10.1038/jcbfm.2013.163
Won S, Lee JK, Stein DG (2015) Recombinant tissue plasminogen activator promotes, and progesterone attenuates, microglia/macrophage M1 polarization and recruitment of microglia after MCAO stroke in rats. Brain Behav Immun 49:267–279. https://doi.org/10.1016/j.bbi.2015.06.007
Wong R, Bath PM, Kendall D, Gibson CL (2013a) Progesterone and cerebral ischaemia: the relevance of ageing. J Neuroendocrinol 25(11):1088–1094. https://doi.org/10.1111/jne.12042
Wong R, Renton C, Gibson CL, Murphy SJ, Kendall DA, Bath PM, Progesterone Pre-Clinical Stroke Pooling Project C (2013b) Progesterone treatment for experimental stroke: an individual animal meta-analysis. J Cereb Blood Flow Metab 33(9):1362–1372. https://doi.org/10.1038/jcbfm.2013.120
Wong R, Gibson CL, Kendall DA, Bath PM (2014) Evaluating the translational potential of progesterone treatment following transient cerebral ischaemia in male mice. BMC Neurosci 15:131. https://doi.org/10.1186/s12868-014-0131-5
Wullner U, Seyfried J, Groscurth P, Beinroth S, Winter S, Gleichmann M, Heneka M, Loschmann P, Schulz JB, Weller M, Klockgether T (1999) Glutathione depletion and neuronal cell death: the role of reactive oxygen intermediates and mitochondrial function. Brain Res 826(1):53–62
Xu X, Chua CC, Gao J, Chua KW, Wang H, Hamdy RC, Chua BH (2008) Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway. Brain Res 1227:12–18. https://doi.org/10.1016/j.brainres.2008.06.018
Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27(4):697–709. https://doi.org/10.1038/sj.jcbfm.9600375
Yousuf S, Atif F, Sayeed I, Tang H, Stein DG (2014a) Progesterone in transient ischemic stroke: a dose-response study. Psychopharmacology 231(17):3313–3323. https://doi.org/10.1007/s00213-014-3556-8
Yousuf S, Sayeed I, Atif F, Tang H, Wang J, Stein DG (2014b) Delayed progesterone treatment reduces brain infarction and improves functional outcomes after ischemic stroke: a time-window study in middle-aged rats. J Cereb Blood Flow Metab 34(2):297–306. https://doi.org/10.1038/jcbfm.2013.198
Yousuf S, Atif F, Sayeed I, Wang J, Stein DG (2016) Neuroprotection by progesterone after transient cerebral ischemia in stroke-prone spontaneously hypertensive rats. Horm Behav 84:29–40. https://doi.org/10.1016/j.yhbeh.2016.06.002
Yuan M, Siegel C, Zeng Z, Li J, Liu F, McCullough LD (2009) Sex differences in the response to activation of the poly (ADP-ribose) polymerase pathway after experimental stroke. Exp Neurol 217(1):210–218. https://doi.org/10.1016/j.expneurol.2009.02.012
Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106(7):829–838. https://doi.org/10.1172/JCI9369
Zhao H, Sapolsky RM, Steinberg GK (2006) Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 34(3):249–270. https://doi.org/10.1385/MN:34:3:249
Zhu X, Frechou M, Liere P, Zhang S, Pianos A, Fernandez N, Denier C, Mattern C, Schumacher M, Guennoun R (2017) A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors. J Neurosci 37(45):10998–11020. https://doi.org/10.1523/JNEUROSCI.3874-16.2017
Zhu X, Frechou M, Schumacher M, Guennoun R (2018) Cerebroprotection by progesterone following ischemic stroke: Multiple effects and role of the neural progesterone receptors. J Steroid Biochem Mol Biol. https://doi.org/10.1016/j.jsbmb.2018.07.014
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All authors contributed in this work. RG designed, wrote the first draft of the manuscript, revised and edited the manuscript. XZ prepared the figures and revised critically the manuscript. MF revised critically the manuscript. PG revised critically the manuscript. AS revised critically the manuscript. PL revised critically the manuscript. MS revised critically the manuscript.
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Guennoun, R., Zhu, X., Fréchou, M. et al. Steroids in Stroke with Special Reference to Progesterone. Cell Mol Neurobiol 39, 551–568 (2019). https://doi.org/10.1007/s10571-018-0627-0
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DOI: https://doi.org/10.1007/s10571-018-0627-0