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Effect of estrogen and/or progesterone administration on traumatic brain injury-caused brain edema: the changes of aquaporin-4 and interleukin-6

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Abstract

The role of aquaporin-4 (AQP4) and interleukin-6 (IL-6) in the development of brain edema post-traumatic brain injury (TBI) has been indicated. The present study was designed to investigate the effect(s) of administration of progesterone (P) and/or estrogen (E) on brain water content, AQP4 expression, and IL-6 levels post-TBI. The ovariectomized rats were divided into 11 groups: sham, one vehicle, two vehicles, E1, E2, P1, P2, E1 + P1, E1 + P2, E2 + P1, and E2 + P2. The brain AQP4 expression, IL-6 levels, and water content were evaluated 24 h after TBI induced by Marmarou’s method. The low (E1 and P1) and high (E2 and P2) doses of estrogen and progesterone were administered 30 min post-TBI. The results showed that brain water content and AQP4 expression decreased in the E1, E2, P1, and P2-treated groups. The administration of E1 decreased IL-6 levels. Addition of progesterone decreased the inhibitory effect of E1 and E2 on the accumulation of water in the brain. Administration of E1 + P1 and E1 + P2 decreased the inhibitory effect of E1 on the IL-6 levels and AQP4 protein expression. Our findings suggest that estrogen or progesterone by itself has more effective roles in decrease of brain edema than combination of both. Possible mechanism may be mediated by the alteration of AQP4 and IL-6 expression. However, further studies are required to verify the exact mechanism.

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Abbreviations

AQP4:

Aquaporin-4

IL-6:

Interleukin-6

TBI:

Traumatic brain injury

E1:

Low dose of estrogen

P1:

Low dose of progesterone

E2:

High dose of estrogen

P2:

High dose of progesterone

AQPs:

Aquaporins

IL-1β:

Interleukin-1β

NFκB:

Nuclear factor kappa b

OVX:

Ovariectomized

T-PER:

Tissue protein extraction reagent

ELISA:

Enzyme-linked immunosorbent assay

RT-PCR:

Reverse transcription-polymerase chain reaction

β-actin:

Beta-actin

ANOVA:

Analysis of variance

BBB:

Blood-brain barrier

mRNA:

Messenger RNA

HIF-1α:

Hypoxia-inducible factor 1-alpha

MMP-9:

Matrix metallopeptidase 9

RT:

Room temperature

References

  1. Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, Engel A, Nielsen S (2002) Aquaporin water channels—from atomic structure to clinical medicine. J Physiol 542:3–16

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Alexander JJ, Jacob A, Cunningham P, Hensley L, Quigg RJ (2008) TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. Neurochem Int 52:447–456

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Bloch O, Manley GT (2007) The role of aquaporin-4 in cerebral water transport and edema. Neurosurg Focus 22:E3

    Article  PubMed  Google Scholar 

  4. Ding Z, Zhang J, Xu J, Sheng G, Huang G (2013) Propofol administration modulates AQP-4 expression and brain edema after traumatic brain injury. Cell Biochem Biophys 67:615–622

    Article  CAS  PubMed  Google Scholar 

  5. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG (2005) The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 22:106–118

    Article  PubMed  Google Scholar 

  6. 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 U S A 98:1952–1957

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Gibson CL, Murphy SP (2004) Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. J Cereb Blood Flow Metab 24:805–813

    Article  CAS  PubMed  Google Scholar 

  8. Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG (2006) Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol 198:469–478

    Article  CAS  PubMed  Google Scholar 

  9. Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P, Ding JY, Dornbos D 3rd, Li X, Guthikonda M, Rossi NF, Ding Y (2011) The role of hypoxia-inducible factor-1alpha, aquaporin-4, and matrix metalloproteinase-9 in blood–brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg 114:92–101

    Article  CAS  PubMed  Google Scholar 

  10. Hillman J, Aneman O, Persson M, Andersson C, Dabrosin C, Mellergard P (2007) Variations in the response of interleukins in neurosurgical intensive care patients monitored using intracerebral microdialysis. J Neurosurg 106:820–825

    Article  CAS  PubMed  Google Scholar 

  11. Holmin S, Hojeberg B (2004) In situ detection of intracerebral cytokine expression after human brain contusion. Neurosci Lett 369:108–114

    Article  CAS  PubMed  Google Scholar 

  12. Hu H, Yao HT, Zhang WP, Zhang L, Ding W, Zhang SH, Chen Z, Wei EQ (2005) Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors. J Zhejiang Univ Sci B 6:33–37

    Article  PubMed Central  PubMed  Google Scholar 

  13. Ito H, Yamamoto N, Arima H, Hirate H, Morishima T, Umenishi F, Tada T, Asai K, Katsuya H, Sobue K (2006) Interleukin-1beta induces the expression of aquaporin-4 through a nuclear factor-kappaB pathway in rat astrocytes. J Neurochem 99:107–118

    Article  CAS  PubMed  Google Scholar 

  14. Jain SK, Kannan K, Prouty L, Jain SK (2004) Progesterone, but not 17beta-estradiol, increases TNF-alpha secretion in U937 monocytes. Cytokine 26:102–105

    Article  CAS  PubMed  Google Scholar 

  15. Khaksari M, Soltani Z, Shahrokhi N, Moshtaghi G, Asadikaram G (2011) The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury. Can J Physiol Pharmacol 89:31–40

    Article  CAS  PubMed  Google Scholar 

  16. Kleindienst A, Dunbar JG, Glisson R, Marmarou A (2013) The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury. Acta Neurochir (Wien) 155:151–164

    Article  Google Scholar 

  17. Laird MD, Vender JR, Dhandapani KM (2008) Opposing roles for reactive astrocytes following traumatic brain injury. Neurosignals 16:154–164

    Article  CAS  PubMed  Google Scholar 

  18. Leonardo CC, Pennypacker KR (2009) Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation 6:13

    Article  PubMed Central  PubMed  Google Scholar 

  19. Lobo RA (1995) Estrogen replacement: the evolving role of alternative delivery systems. Introduction. Am J Obstet Gynecol 173:981

    Article  CAS  PubMed  Google Scholar 

  20. Marmarou A (2007) A review of progress in understanding the pathophysiology and treatment of brain edema. Neurosurg Focus 22:E1

    Google Scholar 

  21. 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 22:1181–1188

    Article  CAS  PubMed  Google Scholar 

  22. O'Connor CA, Cernak I, Vink R (2005) Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res 1062:171–174

    Article  PubMed  Google Scholar 

  23. Papadopoulos MC, Verkman AS (2008) Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res 170:589–601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Roof RL, Hall ED (2000) Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 17:367–388

    Article  CAS  PubMed  Google Scholar 

  25. Sarkaki AR, Khaksari Haddad M, Soltani Z, Shahrokhi N, Mahmoodi M (2013) Time- and dose-dependent neuroprotective effects of sex steroid hormones on inflammatory cytokines after a traumatic brain injury. J Neurotrauma 30:47–54

    Article  PubMed  Google Scholar 

  26. Shahrokhi N, Khaksari M, Soltani Z, Mahmoodi M, Nakhaee N (2010) Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury. Can J Physiol Pharmacol 88:414–421

    Article  CAS  PubMed  Google Scholar 

  27. Shi WZ, Qi LL, Fang SH, Lu YB, Zhang WP, Wei EQ (2012) Aggravated chronic brain injury after focal cerebral ischemia in aquaporin-4-deficient mice. Neurosci Lett 520:121–125

    Article  CAS  PubMed  Google Scholar 

  28. Shi WZ, Zhao CZ, Zhao B, Zheng XL, Fang SH, Lu YB, Zhang WP, Chen Z, Wei EQ (2012) Aquaporin-4 deficiency attenuates acute lesions but aggravates delayed lesions and microgliosis after cryoinjury to mouse brain. Neurosci Bull 28:61–68

    Article  CAS  PubMed  Google Scholar 

  29. Shin JA, Choi JH, Choi YH, Park EM (2011) Conserved aquaporin 4 levels associated with reduction of brain edema are mediated by estrogen in the ischemic brain after experimental stroke. Biochim Biophys Acta 1812:1154–1163

    Article  CAS  PubMed  Google Scholar 

  30. Simpkins JW, Green PS, Gridley KE, Singh M, de Fiebre NC, Rajakumar G (1997) Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease. Am J Med 103:19S–25S

    Article  CAS  PubMed  Google Scholar 

  31. Stein DG (2001) Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci 24:386–391

    Article  CAS  PubMed  Google Scholar 

  32. Sun MC, Honey CR, Berk C, Wong NL, Tsui JK (2003) Regulation of aquaporin-4 in a traumatic brain injury model in rats. J Neurosurg 98:565–569

    Article  CAS  PubMed  Google Scholar 

  33. Suzuki S, Brown CM, Wise PM (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30:201–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Tait MJ, Saadoun S, Bell BA, Papadopoulos MC (2008) Water movements in the brain: role of aquaporins. Trends Neurosci 31:37–43

    Article  CAS  PubMed  Google Scholar 

  35. Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F (1993) Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of pre- and post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. J Neuroimmunol 42:177–185

    Article  CAS  PubMed  Google Scholar 

  36. Teede HJ (2003) The menopause and HRT. Hormone replacement therapy, cardiovascular and cerebrovascular disease. Best Pract Res Clin Endocrinol Metab 17:73–90

    Article  CAS  PubMed  Google Scholar 

  37. Tomas-Camardiel M, Venero JL, Herrera AJ, De Pablos RM, Pintor-Toro JA, Machado A, Cano J (2005) Blood–brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: protective effect by estradiol treatment in ovariectomized animals. J Neurosci Res 80:235–246

    Article  CAS  PubMed  Google Scholar 

  38. Vajda Z, Promeneur D, Doczi T, Sulyok E, Frokiaer J, Ottersen OP, Nielsen S (2000) Increased aquaporin-4 immunoreactivity in rat brain in response to systemic hyponatremia. Biochem Biophys Res Commun 270:495–503

    Article  CAS  PubMed  Google Scholar 

  39. Vajtr D, Benada O, Kukacka J, Prusa R, Houstava L, Toupalik P, Kizek R (2008) Correlation of ultrastructural changes of endothelial cells and astrocytes occuring during blood brain barrier damage after traumatic brain injury with biochemical markers of BBB leakage and inflammatory response. Physiol Res 58:263–268

    PubMed  Google Scholar 

  40. Vizuete ML, Venero JL, Vargas C, Ilundain AA, Echevarria M, Machado A, Cano J (1999) Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema. Neurobiol Dis 6:245–258

    Article  CAS  PubMed  Google Scholar 

  41. Wang X, Zhang J, Yang Y, Dong W, Wang F, Wang L, Li X (2013) Progesterone attenuates cerebral edema in neonatal rats with hypoxic-ischemic brain damage by inhibiting the expression of matrix metalloproteinase-9 and aquaporin-4. Exp Ther Med 6:263–267

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Wise PM, Dubal DB, Wilson ME, Rau SW, Liu Y (2001) Estrogens: trophic and protective factors in the adult brain. Front Neuroendocrinol 22:33–66

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The present study was supported by neuroscience and physiology research centers of Kerman University of Medical Sciences.

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Authors and Affiliations

  1. Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Zahra Soltani & Nader Shahrokhi

  2. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Mohammad Khaksari

  3. Department of Biochemistry, Medical School of Afzalipour, Kerman University of Medical Sciences, Kerman, Iran

    Gholamabbas Mohammadi & Ali Vaziri

  4. Department of Neurosurgery, Shahid Bahonar Hospital of Kerman, Kerman, Iran

    Behshad Mofid

  5. Bam University of Medical Sciences, Kerman, Iran

    Sedigheh Amiresmaili

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  1. Zahra Soltani
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  2. Mohammad Khaksari
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Correspondence to Mohammad Khaksari.

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Soltani, Z., Khaksari, M., Shahrokhi, N. et al. Effect of estrogen and/or progesterone administration on traumatic brain injury-caused brain edema: the changes of aquaporin-4 and interleukin-6. J Physiol Biochem 72, 33–44 (2016). https://doi.org/10.1007/s13105-015-0453-5

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  • DOI: https://doi.org/10.1007/s13105-015-0453-5

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