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

Mahyudanil Mahyudanil; A. H. Bajamal; R. J. Sembiring; R. Dharmajaya

doi:10.3889/oamjms.2020.3974

Authors

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

DOI:

https://doi.org/10.3889/oamjms.2020.3974

Keywords:

Traumatic Brain Injur, S-100Î², 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.

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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