The Effects of Progesterone on Glial Cell Line-derived Neurotrophic Factor Secretion from C6 Glioma Cells

Document Type : Original Article

Authors

Research Centre for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Objective(s)
Progesterone is a steroid hormone whose biology has been greatly studied within the confines of reproductive function. In recent years, the neuroprotective effects of progesterone have attracted growing interest. Glial cell line-derived neurotrophic factor (GDNF), is a neurotrophic factor which plays a crucial role in the development and maintenance of distinct sets of central and peripheral neurons. In the present study, we investigated the potential implication of GDNF in the neuroprotective action of progesterone.
Materials and Methods
Cultured rat C6 glioma cells were treated with progesterone (100 nm, 1 μM, and 10 μM) or its vehicle. After 24, 36, 48 and 72 hr, GDNF protein levels were measured in the cell-conditioned media and cell lysates using a GDNF ELISA kit. Cell numbers were determined by a cell-counting assay kit.
Results
Forty-eight hr treatment with progesterone (10 μM) resulted in a significant elevation of GDNF secretion from C6 glioma cells that remained elevated up to 72 hr. The intracellular content of GDNF and cell numbers were not affected by progesterone treatment.
Conclusion
Stimulation of GDNF release from glial cells appears as a potential mechanism through which progesterone exerts its neuroprotective effects.

Keywords


1. Di Cosmo A, Paolucci M, Di Cristo C, Botte V, Ciarcia G. Progesterone receptor in the reproductive system of the female of Octopus vulgaris: characterization and immunolocalization. Mol Reprod Dev 1998; 50:451–460.
2. Inoue T, Akahira J, Suzuki T, Darnel AD, Kaneko C, Takahashi K, et al. Progesterone production and actions in the human central nervous system and neurogenic tumors. J Clin Endocrinol Metab 2002; 87:5325–5331.
3. Meffre D, Delespierre B, Gouezou M, Leclerc P, Vinson GP, Schumacher M, et al. The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury. J Neurochem 2005; 93:1314–1326.
4. Sakamoto H, Shikimi H, Ukena K, Tsutsui K. Neonatal expression of progesterone receptor isoforms in the cerebellar Purkinje cell in rats. Neurosci Lett 2003; 343:163–166.
5. Reddy DS, O'Malley BW, Rogawski MA. Anxiolytic activity of progesterone in progesterone receptor knockout mice. Neuropharmacology 2005; 48:14–24.
6. Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 1995; 7:171–177.
7. Coughlan T, Gibson C, Murphy S. Progesterone, BDNF and neuroprotection in the injured CNS. Int J Neurosci 2009; 119:1718-1740.
8. Gibson CL, Coomber B, Rathbone J. Is progesterone a candidate neuroprotective factor for treatment following ischemic stroke? Neuroscientist 2009; 15:324-332.
9. Singh M. Progesterone-induced neuroprotection. Endocrine 2006; 29:271-274.
10. Stein DG. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci 2001; 24:386–391.
11. Desarnaud F, Do Thi AN, Brown AM, Greg L, Suter U, Baulieu EE, et al. Progesterone stimulates the activity of the promoters of peripheral myelin protein-22 and protein zero genes in Schwann cells. J Neurochem 1998; 71:1765-1768.
12. De Nicola AF, Labombarda F, Gonzalez DMC, Gonzalez SL, Garay L, Meyer M, et al. Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration. Front Neuroendocrinol 2009; 30:173-187.
13. Gonzalez Deniselle MC, López-Costa JJ, Saavedra JP, Pietranera L, Gonzalez SL, Garay L, et al. Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease. Neurobiol Dis 2002; 11:457-468.
14. Gibson CL, Murphy SP. Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. J Cereb Blood Flow Metabol 2004; 24:805–813.
15. Sayeed I, Wali B, Stein DG. Progesterone inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion. Res Neurol Neurosci 2007; 25:151–159.
16. Coughlan T, Gibson C, Murphy S. Progesterone, BDNF and neuroprotection in the injured CNS. Int J Neurosci 2009; 119:1718-1740.
17. Akan P, Kızıldag S, Ormen M, Genc S, Öktem MA, Fadıloglu M. Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not. Chem Biol Interact 2009; 177:65-70.
18. McKay SE, Purcell AL, Carew TJ. Regulation of synaptic function by neurotrophic factors in vertebrates and invertebrates: implications for development and learning. Learn Mem 1999; 6:193-215.
19. Logan A, Ahmed Z, Baird A, Gonzalez AM, Berry M. Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain 2006; 129:490-502.
20. Bemelmans AP, Husson I, Jaquet M, Mallet J, Kosofsky BE, Gressens P. Lentiviral-mediated gene transfer of brain-derived neurotrophic factor is neuroprotective in a mouse model of neonatal excitotoxic challenge. J Neurosci Res 2006; 83:50-60.
21. Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 2005; 136:161–169.
22. Schabitz WR, Steigleder T, Cooper-Kuhn CM, Schwab S, Sommer C, Schneider A, et al. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 2007; 38: 2165–2172.
23. Zhang Y, Pardridge WM. Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Res 2006; 1111:227–229.
24. Obara Y, Nakahata N. The signaling pathway of neurotrophic factor biosynthesis. Drug News Perspect 2002; 15:290-298.
25. Hassanzadeh P, Rahimpour S. The cannabinergic system is implicated in the upregulation of central NGF protein by psychotropic drugs. Psychopharmacology 2011; 215:129–141.
26. Hassanzadeh P, Hassanzadeh A. Involvement of the neurotrophin and cannabinoid systems in the mechanisms of action of neurokinin receptor antagonists. Eur Neuropsychopharmacol 2011; 21:905-917.
27. Hassanzadeh P, Hassanzadeh A. Effects of different psychotropic agents on the central nerve growth factor protein. Iran J Basic Med Sci 2010; 13:202-209.
28. Hassanzadeh P. The endocannabinoid system: critical for the neurotrophic action of psychotropic drugs. Biomed Rev 2010; 21:31-46.
29. Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K, et al. Abnormal expression of brain-derived neurotrophic factor and receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5:293-300.
30. Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM. Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 2002; 954:11-20.
31. Xu H, Qing H, Lu W, Keegan D, Richardson JS, Chlan-Fourney J, et al. Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 2002; 321:65-68.
32. Bai O, Chlan-Fourney J, Bowen R, Keegan D, Li XM. Expression of brain-derived mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 2003; 71:127-131.
33. Sawada H, Ibi M, Kihara T, Urushitani M, Nakanishi M, Akaike A, et al. Neuroprotective mechanism of glial cell line-derived neurotrophic factor in mesencephalic neurons. J Neurochem 2000; 74:1175-1184.
34. Lara J, Kusano K, House S, Gainer H. Interactions of cyclic adenosine monophosphate, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor treatment on the survival and growth of postnatal mesencephalic dopamine neurons in vitro. Exp Neurol 2003; 180:32-45.
35. Hauck SM, Kinkl N, Deeg CA, Swiatek-de Lange M, Scho¨ffmann S, Ueffing M. GDNF family ligands trigger indirect neuroprotective signaling in retinal glial cells. Mol Cell Biol 2006; 26:2746-2757.
36. Chena B, Gaoa XQ, Yanga CX, Tana SK, Suna ZL, Yanb NH, et al. Neuroprotective effect of grafting GDNF gene-modified neural stem cells on cerebral ischemia in rats. Brain Res 2009; 1284:1-11.
37. Trupp M, Ryden M, Jornvall H, Funakoshi H, Timmusk T, Arenas E, et al. Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. J Cell Biol 1995; 130:137-148.
38. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993; 260:1130–1132.
39. Ugarte SD, Lin E, Klann E, Zigmond MJ, Perez RG. Effects of GDNF on 6-OHDA-induced death on a dopaminergic cell line: modulation by inhibitors of PI3 kinase and MEK. J Neurosci Res 2003; 73:105-112.
40. Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 1995; 373:335-339.
41. Oppenheim RW, Houenou LJ, Johnson JE, Lin LH, Linxi LI, Lo AC, et al. Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature 1995; 373: 344-346.
42. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 1996; 380: 252-255.
43. Hisaoka K, Nishida A, Koda T, Miyata M, Zensho H, Morinobu S, et al. Antidepressant drug treatments induce glial cell line-derived neurotrophic factor (GDNF) synthesis and release in rat C6 glioblastoma cells. J Neurochem 2001; 79:25-34.
44. Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol 2006; 198:469–478.
45. He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol 2004; 189:404–412.
46. Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura LM, et al. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 2007; 144: 1293–1304.
47. O'Connor CA, Cernak I, Vink R. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res 2005; 1062:171–174.
48. Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 2005; 1049:112–119.
49. Wright DW, Bauer ME, Hoffman SW, Stein DG. Serum progesterone levels correlate with decreased cerebral edema after traumatic brain injury in male rats. J Neurotrauma 2001; 18: 901–909.
50. Kumon KSC, Tompkins P, Stevens A, Sakaki S, Loftus CM. Neuroprotective effect of postischemic administration of progesterone in spontaneously hypertensive rats with focal cerebral ischemia. J Neurosurg 2000; 92:848–852.
51. Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev 2008; 57:386–397.
52. Gibson CL, Constantin D, Prior MJ, Bath PM, Murphy SP. Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Exp Neurol 2005; 193:522–530.
53. Stein DG, Wright DW, Kellermann AL. Does progesterone have neuroprotective properties? Ann Emerg Med 2008; 51:164-172.
54. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 2005; 22:106–118.
55. Djebaili M, Hoffman SW, Stein DG. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex. Neuroscience 2004; 123:349–359.
56. De Nicola AF, Gonzalez SL, Labombarda F, Deniselle MC, Garay L, Guennoun R, et al. Progesterone treatment of spinal cord injury: effects on receptors, neurotrophins, and myelination. J Mol Neurosci 2006; 28:3–15.
57. Labombarda F, Gonzalez S, Gonzalez Deniselle MC, Garay L, Guennoun R, Schumacher M, et al. Progesterone increases the expression of myelin basic protein and the number of cells showing NG2 immunostaining in the lesioned spinal cord. J Neurotrauma 2006; 23:181–192.
58. Kaur P, Jodhka PK, Underwood WA, Bowles CA, de Fiebre NEC, de Fiebre CM, et al. Progesterone increases BDNF expression and protects against glutamate toxicity in a MAPK- and PI3-K-dependent manner in cerebral cortical explants. J Neurosci Res 2007; 85:2441–2449.
59. Gonzalez SL, Labombarda F, Deniselle MC, Mougel A, Guennoun R, Schumacher M, et al. Progesterone neuroprotection in spinal cord trauma involves up regulation of brain-derived neurotrophic factor in motoneurons. J Steroid Biochem Mol Biol 2005; 94:143–149.
60. Freeman MR. Sculpting the nervous system: glial control of neuronal development. Curr Opin Neurobiol 2006; 16:119–125.
61. Haydon PG. GLIA: Listening and talking to the synapse. Nature Rev Neurosci 2001; 2: 185-193.
62. Slezak M, Pfrieger FW. New roles for astrocytes: Regulation of CNS synaptogenesis. Trend Neurosci 2003; 26:531-535.
63. Slezak M, Pfrieger FW, Soltys Z. Synaptic plasticity, astrocytes and morphological homeostasis. J Physiol 2006; 99:84–91.