The Effect of Progesterone Therapy in Severe Traumatic Brain Injury Patients on Serum Levels of s-100β, Interleukin 6, and Aquaporin-4

  • Mahyudanil Mahyudanil Department of Neurosurgery, Faculty of Medicine Universitas Sumatera Utara – Central General Hospital Haji Adam Malik Medan, Indonesia
  • A. H. Bajamal Department of Neurosurgery, Faculty of Medicine Airlangga University – Central General Hospital Dr. Soetomo Surabaya, Indonesia
  • R. J. Sembiring Department of Neurosurgery, Faculty of Medicine Universitas Sumatera Utara – Central General Hospital Haji Adam Malik Medan, Indonesia
  • R. Dharmajaya Department of Neurosurgery, Faculty of Medicine Universitas Sumatera Utara – Central General Hospital Haji Adam Malik Medan, Indonesia
Keywords: Traumatic Brain Injur, S-100β, IL-6, AQ-4, Glasgow outcome scale

Abstract

BACKGROUND: Severe TBI is leading in death and disability worldwide. The initial stage resulted from direct tissue damage and impaired autoregulation of cerebral blood flow. The level of S-100β, IL-6 and AQ4 in CSF increased in neuronal injury and BBB damage. PROG effect is assessed on biomarkers of S-100β, IL-6, and AQP4.

AIM: The study examined the 1st to 4th day of progesterone administration.

METHODS: The sample consisted of 23 participants in the control group and 16 participants in the treated group. Patients with GCS 4–8, not surgical, aged 15-50 years, coming in the first 24 h and patient’s family agreed to this research are included. The sample was taken from the serum, and the biomarker processed using ELISA. GOS 3 months used as prognostic.

RESULTS: The result showed the mean value serum level of S100β, AQP4, and IL-6 increased on 24 h and 96 h after given PROG. Change of mean value of S100β day to day was 44.75 (96 h)–40.57 (24 h) – 4.18. In control group, change of S100β decrease to 42.51 (96 h)–46.11 (24 h) = −3.60, showing effect still unclearly proven in repairing neuronal injury, BBB disruption or another consideration on concentration of S100β, AQP4, and IL-6 in serum.

CONCLUSION: S-100β serum levels is significant to predict outcome of severe TBI. Progesterone still unclearly proven in repairing neuronal injury and/or BBB disruption. Another consideration is temporal trajectory of S100β, AQP4, and IL-6. In future study, natural endogenous PROG should be sought. S-100β in future pharmaceutical trials may be possible as pharmacological target.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Engel DC. Secondary Damage After Traumatic Brain Injury: Epidemiology, Pathophysiology and Therapy. Rotterdam: Erasmus Universiteit; 2008.

RISKESDAS. Indonesia Ministry of Health, Health Research and Development. Jakarta, Indonesia: Indonesia Ministry of Health; 2018.

Reilly PR, Selladurai BE. Pathophysiology of acute non missile head injury. In: Initial Management of Head Injury, a Comprehensive Guide. Australia: McGraw-Hill Australia Pty Limited.; 2007. p. 10-32.

Rothermundt M, Ponath G, Glaser T, Hetzel G, Arolt V. S-100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology. 2004;29(5):1004-11. https://doi.org/10.1038/sj.npp.1300403 PMid:14997170

Kleindienst A, Ross Bullock M. A critical analysis of the role of the neurotrophic protein S-100B in acute brain injury. J Neurotrauma. 2006;23(8):1185-200. https://doi.org/10.1089/ neu.2006.23.1185 PMid:16928177

Tala MI, Darmadipura S. Hubungan Perubahan Kadar Protein S-100β Dalam Cairan Serebrospinalis Dengan Tingkat Kesadaran Pasien Cedera Otak Berat. Karya Akhir S2 Skripsi. Surabaya, Indonesia: Airlangga University-School of Medicine; 2008.

Ndraha E, Bajamal AH. Hubungan Antara Perubahan Kadar S-100β Pada Pasien Cedera Kepala Berat Pada Fase Akut Dengan Outcome. Karya Akhir S2 Skripsi. Surabaya, Indonesia: Airlangga University-School of Medicine; 2010.

Hergenroeder GW, Moore AN, McCoy JP, Samsel L, Ward NH, Clifton GL, et al. Serum Il-6: a candidate biomarker for intracranial presure elevation following isolated traumatic brain injury. J Neuroinflammation. 2010;7:19. https://doi. org/10.1186/1742-2094-7-19 PMid:20222971

Verkman AS. Aquaporins: Translating bench research to human disease. J Exp Biol. 2008;212(Pt 11):1707-15. https://doi. org/10.1242/jeb.024125 PMid:19448080

Oliviera CO, Ikuta N, Regner A. Outcome biomarker following severe traumatic injury. Rev Bras Ter Intensiva. 2008;20(4):411-21. PMid:25307248

Raheja A, Sinha S, Samson N, Bhoi S, Subramanian, A, Sharma P, et al. Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: Analysis from a randomized placebo-controlled Phase II clinical trial. J Neurosurg. 2016;125(3):631-41. https://doi.org/10.3171/2015.6.jns15674 PMid:26722854

Van Landingham JW, Cutler SM, Cekik M, Wright D, Stein DG. Serum biomarker profiling for progesterone treatment of traumatic brain injury: A comparative study human and rat. FASEB J. 2006;20:1314-25.

Thelin EP, Zeiler FA, Ercole A, Mondello S, Büki A, Bellander B, et al. Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics: A systematic review. Front Neurol. 2017;8:300. https://doi.org/10.3389/ fneur.2017.00300 PMid:28717351

Thelin EP, Nimer FA, Frostell A, Zetterberg H, Blennow K, Nystrom H, et al. A serum protein biomarker panel improves outcome prediction in human traumatic brain injury. J Neurotrauma. 2019;36(20):2850-62. https://doi.org/10.1089/ neu.2019.6375 PMid:31072225

Miao X, Wei S, Qiu-Ping X. Aquaporin-4 and traumatic brain edema. Chin J Traumatol. 2010;13(2):103-10. PMid:20356447

Zanotto C, Abib RT, Batassini C, Tortorelli LS, Biasibetti R, Nardin LR, et al. Non-specific inhibitors of aquaporin-4 stimulate S-100B secretion in acute hippocampal slices of rats. Brain Res. 2013;1491:14-22. https://doi.org/10.1016/j. brainres.2012.10.065 PMid:23142267

Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S-100B protein levels in the assessment of traumatic brain injury. Acta Neurochir. 2017;159:209-25. https:// doi.org/10.1007/s00701-016-3046-3 PMid:27957604

Cutler SM. The Effect of Progesterone Withdrawal on Behavioral and Molecular Indices after Traumatic Brain Injury, PhD Thesis. Georgia: Georgia Institute of Technology; 2005.

Cutler SM, Milos C, Miller DM, Wali B, Vanlandingham JW, Stein DG. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma. 2007;24:1475-86. https://doi.org/10.1089/neu.2007.0294 PMid:17892409

Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F. Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev. 2007;28(4):387-439. https://doi. org/10.1210/er.2006-0050 PMid:17431228

Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev. 2008;57:386-97. https://doi. org/10.1016/j.brainresrev.2007.06.012 PMid:17826842

Stein DG, Wright DW, Kellermann AL. Does progesterone have neuroprotective properties? Ann Emerg Med. 2008;51(2):164- 72. https://doi.org/10.1016/j.annemergmed.2007.05.001 PMid:17588708

Farace E, Alves WM. Do women fare worse? A metaanalysis of gender differences in outcome after traumatic brain injury. J Neurosurg. 2000;93(4):539-45. https://doi.org/10.3171/ jns.2000.93.4.0539 PMid:11014529

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(9):901-9. https://doi. org/10.1089/089771501750451820 PMid:11565602

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(1):106-18. https://doi. org/10.1089/neu.2005.22.106 PMid:15665606

Yao XL, Liu J, Lee E, Ling GS, Mccabe JT. Progesterone differentially regulates pro and anti-apoptotic gene expression in cerebral cortex following traumatic brain injury in rats. J Neurotrauma. 2005;22(6):656-68. https://doi.org/10.1089/neu.2005.22.656 PMid:15941375

Chen G, Shi J, Ding Y, Yin H, Hang C. Progesterone prevents traumatic brain injury-induced intestinal nuclear factor kappa b activation and proinflammatory cytokines expression in male rats. Mediators Inflamm. 2007;2007:93431. https://doi. org/10.1155/2007/93431 PMid:18274644

Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M. proTECT: A randomized clinical trial of Progesterone for acute traumatic brain injury. Ann Emerg Med. 2006;20(10):1-13.

Gibson CL, Gray LJ, Bath PM, Murphy SP. Progesterone for the treatment of experimental brain injury; a systematic review. Brain. 2008;31:318-28. https://doi.org/10.1093/brain/awm183 PMid:17715141

Gibson CL, Coomber B, Rathbone J. Is Progesterone a candidate neuroprotective factor for treatment following ischemic stroke? Neuroscientist. 2009;15(4):324-32. https://doi. org/10.1177/1073858409333069 PMid:19359672

Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Crit Care. 2008;12(2):R61. https://doi.org/10.1186/cc6887 PMid:18447940

Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371(26):2467- 76. https://doi.org/10.1056/nejmoa1411090 PMid:25493978

Pan ZY, Zhao YH, Huang WH, Xiao ZZ, Li ZQ. Effect of progesterone administration on the prognosis of patients with severe traumatic brain injury: A meta-analysis of randomized clinical trials. Drug Des Dev Ther. 2019;13:265-73. https://doi. org/10.2147/dddt.s192633 PMid:30666088

Davis DP, Douglas JD, Smith DW, Sisegary M, Troy LV, Kennedy A, et al. Post-menopausal females versus age-matched males. J Neurotrauma. 2006;23(2):140-8. PMid:16503798

Chesnut RM, Ghajar J, Maas AI, Marion DW, Servadei F. Early indicators of prognosis in severe traumatic injury. In: Part II Management and Prognosis of Severe Traumatic Injury. A Joint project of Brain Trauma Foundation. New York: American Association of Neurological Surgeon, Joint section of Neurotrauma and Critical Care, Brain Trauma Foundation; 2003. https://doi.org/10.1089/neu.2000.17.555

Cooper PR. Post traumatic intracranial mass lesion. In: Cooper PR, editor. Head Injury. Baltimore: Williams and Wilkins; 1993. p. 275-330.

Benjamin A, Matthew L, Hitomi, E, Peng W, Liao Y, Lou N, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci. 2015;35(2):518- 26. https://doi.org/10.1523/jneurosci.3742-14.2015 PMid:25589747

Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir. 2017;159(2):209-25. https://doi.org/10.1007/s00701-016-3046-3 PMid:27957604

Pham N, Fazio V, Cucullo L, Teng Q, Biberthaler P, Bazarian JJ, et al. Extracranial Sources of S100B Do Not Affect Serum Levels. PLoS One. 2010;5(9):e12691. https://doi.org/10.1371/ journal.pone.0012691 PMid:20844757

Korfias S, Stranjalis G, Papadimitriou A, Psachoulia C, Daskalakis G, Antsaklis A, et al. Serum S-100B protein as a biochemical marker of brain injury: A review of current concept. Curr Med Chem. 2006;13(30):3719-31. https://doi. org/10.2174/092986706779026129 PMid:17168733

Wei J, Xiao GM. The neuroprotective effects of progesterone on traumatic brain injury: current status and future prospects. Acta Pharmacol Sin. 2013;34(12):1485-90. https://doi.org/10.1038/ aps.2013.160 PMid:24241345

Stein DG. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015;29(11):1259-72. https://doi.org/10.3109/02699052.2015.1 065344 PMid:26274493

Eduardo OD, Luciano MP. Medical theory: Why does progesterone not work after a traumatic brain injury in humans? Am J Biomed Sci Res. 2019;5(4):929.

Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457- 66. https://doi.org/10.1056/nejmoa1404304 PMid:25493974

Zhu X, Frechou M, Liere P, Zhang S, Pianos A, Fernandez N, et al. A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors. J Neurosci. 2017;37(45):10998-1020. https://doi. org/10.1523/jneurosci.3874-16.2017 PMid:28986464

Published
2020-05-01
How to Cite
1.
Mahyudanil M, Bajamal AH, Sembiring RJ, Dharmajaya R. The Effect of Progesterone Therapy in Severe Traumatic Brain Injury Patients on Serum Levels of s-100β, Interleukin 6, and Aquaporin-4. Open Access Maced J Med Sci [Internet]. 2020May1 [cited 2020Oct.31];8(B):236-44. Available from: https://www.id-press.eu/mjms/article/view/3974