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Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke

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A Correction to this article was published on 18 May 2023

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Abstract

Studies have shown that progesterone enhances functional recovery after ischemic stroke, but the underlying mechanisms are not completely understood. Therefore, we investigated the effect of progesterone on vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and neurogenesis in a rodent stroke model. Rats underwent permanent middle cerebral artery occlusion (pMCAO) and then received intraperitoneal injections of progesterone (15 mg/kg) or vehicle at 1 h followed by subcutaneous injections at 6, 24, and 48 h. We examined VEGF and BDNF expression by Western blotting and/or immunostaining and microvessel density by lectin immunostaining. Neurogenesis in the subventricular zone was determined by immunostaining of Ki67 and doublecortin, and double BrdU/Nestin immunostaining. We calculated brain water content with the wet-dry weight method on day 3 and assessed neurologic deficits with the modified neurological severity score on days 1, 3, 7, and 14. Progesterone-treated rats showed a significant decrease in VEGF expression, but an increase in BDNF expression, compared with that of vehicle-treated pMCAO rats on day 3 post-occlusion. Progesterone did not alter the microvessel density, but it reduced brain water content compared with that in vehicle-treated rats on day 3 post-occlusion. Progesterone treatment increased the numbers of newly generated neurons in the subventricular zone and doublecortin-positive cells in the peri-infarct region on day 7 post-occlusion. In addition, progesterone improved neurologic function on days 7 and 14 post-occlusion. Our data suggest that the enhancement of endogenous BDNF and subsequent neurogenesis could partially underlie the neuroprotective effects of progesterone.

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References

  1. Moyse E, Bauer S, Charrier C, Coronas V, Krantic S, Jean A (2006) Neurogenesis and neural stem cells in the dorsal vagal complex of adult rat brain: new vistas about autonomic regulations—a review. Auton Neurosci 126–127:50–58

    Article  PubMed  Google Scholar 

  2. Stein DG (2012) A clinical/translational perspective: can a developmental hormone play a role in the treatment of traumatic brain injury? Horm Behav. doi:10.1016/j.yhbeh.2012.1005.1004

    PubMed Central  Google Scholar 

  3. Vandromme M, Melton SM, Kerby JD (2008) Progesterone in traumatic brain injury: time to move on to phase III trials. Crit Care 12(3):153

    Article  PubMed  PubMed Central  Google Scholar 

  4. Li Z, Wang B, Kan Z, Zhang B, Yang Z, Chen J, Wang D, Wei H et al (2012) Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats. J Neurotrauma 29(2):343–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. Gibson CL, Coomber B, Murphy SP (2011) Progesterone is neuroprotective following cerebral ischaemia in reproductively ageing female mice. Brain 134(Pt 7):2125–2133

    Article  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. Labombarda F, Gonzalez S, Lima A, Roig P, Guennoun R, Schumacher M, De Nicola AF (2011) Progesterone attenuates astro- and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury. Exp Neurol 231(1):135–146

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. Jiang C, Cui K, Wang J, He Y (2011) Microglia and cyclooxygenase-2: possible therapeutic targets of progesterone for stroke. Int Immunopharmacol 11(11):1925–1931

    Article  CAS  PubMed  Google Scholar 

  12. Schumacher M, Sitruk-Ware R, De Nicola AF (2008) Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 8(6):740–746

    Article  CAS  PubMed  Google Scholar 

  13. Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438

    Article  CAS  PubMed  Google Scholar 

  14. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255(5052):1707–1710

    Article  CAS  PubMed  Google Scholar 

  15. Zhang RL, Zhang ZG, Chopp M (2008) Ischemic stroke and neurogenesis in the subventricular zone. Neuropharmacology 55(3):345–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, Shen J, Mao Y et al (2006) Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A 103(35):13198–13202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fournier NM, Duman RS (2012) Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav Brain Res 227(2):440–449. doi:10.1016/j.bbr.2011.04.022

    Article  CAS  PubMed  Google Scholar 

  18. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242–248. doi:10.1038/35025215

    Article  CAS  PubMed  Google Scholar 

  19. Khaibullina AA, Rosenstein JM, Krum JM (2004) Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures. Brain Res Dev Brain Res 148(1):59–68

    Article  CAS  PubMed  Google Scholar 

  20. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21(17):6706–6717

    CAS  PubMed  Google Scholar 

  21. Suh H, Deng W, Gage FH (2009) Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 25:253–275

    Article  CAS  PubMed  Google Scholar 

  22. Cekic M, Johnson SJ, Bhatt VH, Stein DG (2012) Progesterone treatment alters neurotrophin/proneurotrophin balance and receptor expression in rats with traumatic brain injury. Restor Neurol Neurosci 30(2):115–126

    CAS  PubMed  Google Scholar 

  23. González SL, Labombarda F, Gonzalez Deniselle MC, Guennoun R, Schumacher M, De Nicola AF (2004) Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord. Neuroscience 125(3):605–614

    Article  PubMed  Google Scholar 

  24. Jones NC, Constantin D, Prior MJ, Morris PG, Marsden CA, Murphy S (2005) The neuroprotective effect of progesterone after traumatic brain injury in male mice is independent of both the inflammatory response and growth factor expression. Eur J Neurosci 21(6):1547–1554

    Article  PubMed  Google Scholar 

  25. Kaur P, Jodhka PK, Underwood WA, Bowles CA, de Fiebre NC, de Fiebre CM, Singh M (2007) Progesterone increases brain-derived neuroptrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants. J Neurosci Res 85(11):2441–2449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Minnerup J, Sutherland BA, Buchan AM, Kleinschnitz C (2012) Neuroprotection for stroke: current status and future perspectives. Int J Mol Sci 13(9):11753–11772. doi:10.3390/ijms130911753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH (2009) Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40(6):2244–2250

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jiang C, Wang J, Yu L, Ou C, Liu X, Zhao X, Wang J (2013) Comparison of the therapeutic effects of bone marrow mononuclear cells and microglia for permanent cerebral ischemia. Behav Brain Res 250:222–229. doi:10.1016/j.bbr.2013.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zan L, Wu H, Jiang J, Zhao S, Song Y, Teng G, Li H, Jia Y et al (2011) Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema. Neurochem Int 58(8):872–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q et al (2015) CXCR4(+)CD45(−) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice. Brain Behav Immun 45:98–108. doi:10.1016/j.bbi.2014.12.015

    Article  CAS  PubMed  Google Scholar 

  31. 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

    CAS  PubMed  Google Scholar 

  32. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. Wu H, Wu T, Hua W, Dong X, Gao Y, Zhao X, Chen W, Cao W et al (2015) PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice. Neurobiol Aging 36(3):1439–1450. doi:10.1016/j.neurobiolaging.2014.12.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zan L, Zhang X, Xi Y, Wu H, Song Y, Teng G, Li H, Qi J et al (2014) Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion. Neuroscience 262:118–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang RL, Zhang ZG, Zhang L, Chopp M (2001) Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105(1):33–41

    Article  CAS  PubMed  Google Scholar 

  38. Wu T, Wu H, Wang J, Wang J (2011) Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain. J Neuroinflammation 8:22

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhao X, Wu T, Chang CF, Wu H, Han X, Li Q, Gao Y, Li Q et al (2015) Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. Brain Behav Immun 46:293–310. doi:10.1016/j.bbi.2015.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang ZG, Chopp M (2009) Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol 8(5):491–500. doi:10.1016/S1474-4422(09)70061-4

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yao RQ, Zhang L, Wang W, Li L (2009) Cornel iridoid glycoside promotes neurogenesis and angiogenesis and improves neurological function after focal cerebral ischemia in rats. Brain Res Bull 79(1):69–76

    Article  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  PubMed  Google Scholar 

  43. Murphy SJ, Littleton-Kearney MT, Hurn PD (2002) Progesterone administration during reperfusion, but not preischemia alone, reduces injury in ovariectomized rats. J Cereb Blood Flow Metab 22(10):1181–1188

    Article  CAS  PubMed  Google Scholar 

  44. Goss CW, Hoffman SW, Stein DG (2003) Behavioral effects and anatomic correlates after brain injury: a progesterone dose–response study. Pharmacol Biochem Behav 76(2):231–242

    Article  CAS  PubMed  Google Scholar 

  45. Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J (2007) Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38(1):146–152

    Article  CAS  PubMed  Google Scholar 

  46. Wojtal K, Trojnar MK, Czuczwar SJ (2006) Endogenous neuroprotective factors: neurosteroids. Pharmacol Rep 58(3):335–340

    CAS  PubMed  Google Scholar 

  47. 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 U S A 99(18):11946–11950. doi:10.1073/pnas.182296499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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. doi:10.1038/jcbfm.2013.163

    Article  CAS  PubMed  Google Scholar 

  49. Coughlan T, Gibson C, Murphy S (2009) Progesterone, BDNF and neuroprotection in the injured CNS. Int J Neurosci 119(10):1718–1740

    Article  CAS  PubMed  Google Scholar 

  50. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192(2):348–356

    Article  CAS  PubMed  Google Scholar 

  52. Schabitz WR, Steigleder T, Cooper-Kuhn CM, Schwab S, Sommer C, Schneider A, Kuhn HG (2007) Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38(7):2165–2172

    Article  PubMed  Google Scholar 

  53. Chen K, Henry RA, Hughes SM, Connor B (2007) Creating a neurogenic environment: the role of BDNF and FGF2. Mol Cell Neurosci 36(1):108–120

    Article  CAS  PubMed  Google Scholar 

  54. Klein RL, Muir D, King MA, Peel AL, Zolotukhin S, Moller JC, Kruttgen A, Heymach JV Jr et al (1999) Long-term actions of vector-derived nerve growth factor or brain-derived neurotrophic factor on choline acetyltransferase and Trk receptor levels in the adult rat basal forebrain. Neuroscience 90(3):815–821

    Article  CAS  PubMed  Google Scholar 

  55. Jiang S, Xia R, Jiang Y, Wang L, Gao F (2014) Vascular endothelial growth factors enhance the permeability of the mouse blood–brain barrier. PLoS One 9(2):e86407. doi:10.1371/journal.pone.0086407

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yousuf S, Sayeed I, Atif F, Tang H, Wang J, Stein DG (2014) 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. doi:10.1038/jcbfm.2013.198

    Article  CAS  PubMed  Google Scholar 

  57. Lacroix-Fralish ML, Tawfik VL, Nutile-McMenemy N, Harris BT, Deleo JA (2006) Differential regulation of neuregulin 1 expression by progesterone in astrocytes and neurons. Neuron Glia Biol 2(4):227–234

    Article  PubMed  PubMed Central  Google Scholar 

  58. Morita K, Her S (2008) Progesterone pretreatment enhances serotonin-stimulated BDNF gene expression in rat c6 glioma cells through production of 5alpha-reduced neurosteroids. J Mol Neurosci 34(3):193–200

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81301006), American Heart Association grant 13GRNT15730001, and the National Institutes of Health (R01NS078026, R01AT007317). We thank Claire Levine for assistance with this manuscript.

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Authors and Affiliations

  1. Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, People’s Republic of China

    Chao Jiang, Fangfang Zuo & Yuejuan Wang

  2. Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA

    Chao Jiang & Jian Wang

  3. Department of Neurology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China

    Hong Lu

  4. Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400044, China

    Qingwu Yang

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  1. Chao Jiang
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  2. Fangfang Zuo
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  3. Yuejuan Wang
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  4. Hong Lu
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Correspondence to Chao Jiang or Jian Wang.

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Highlights

• Rats underwent a permanent middle cerebral artery occlusion model of stroke.

• Progesterone increased BDNF but decreased VEGF on day 3 post-occlusion.

• Progesterone reduced brain edema.

• Progesterone increased neurogenesis and improved functional outcome.

• Progesterone treatment provides a therapeutic effect after ischemic stroke.

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Jiang, C., Zuo, F., Wang, Y. et al. Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke. Mol Neurobiol 54, 571–581 (2017). https://doi.org/10.1007/s12035-015-9651-y

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