Role of melatonin receptors in the effect of estrogen on brain edema, intracranial pressure and expression of aquaporin 4 after traumatic brain injury

Document Type: Original Article


1 Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran

2 Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran

3 Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran

4 Medical Student, Kerman University of Medical Sciences, Kerman, Iran


Objective(s): Traumatic brain injury (TBI) is one of the most common causes of death and disability in modern societies. The role of steroids and melatonin is recognized as a neuroprotective factor in traumatic injuries. This study examined the role of melatonin receptors in the neuroprotective effects of estrogen.
Materials and Methods: Seventy female ovariectomized Wistar rats were divided into five groups and two subgroups. All animals underwent brain trauma. The groups were as follow: 1) trauma, 2) melatonin receptor antagonist vehicle + estrogen, 3) MT1 melatonin receptor antagonist + estrogen, 4) MT2 melatonin receptor antagonist+ estrogen, 5) MT3 melatonin receptor antagonist+ estrogen. Brain edema (24 hr), intracranial pressure (ICP) (-1, 0, 1, 4 and 24 hr) and blood–brain barrier (BBB) permeability (5 hr) and aquaporin (AQP4) expression (24 hr) were evaluated after TBI.
Results: MT1, MT2 and MT3 melatonin receptors had anti-edema effects while MT1 and MT2 have a role in protecting BBB by estrogen. Furthermore, the activity of MT3 and MT2 melatonin receptors weakened the effect of estrogen on ICP. However, melatonin receptors had no role in the effect of estrogen on AQP4 protein.
Conclusion: Based on the above results, it seems that melatonin receptors appear to influence the effect of estrogen in TBI without altering AQP4 expression. The role of the receptors is different in this interaction.


Main Subjects

1.Vink R, Van Den Heuvel C. Recent advances in the development of multifactorial therapies for the treatment of traumatic brain injury. Expert opinion on investigational drugs 2004; 13:1263-1274.

2.Fazel MR, Fakharian E, Mahdian M, Mohammadzadeh M, Salehfard L, Ramezani M. Demographic Profiles of Adult Trauma During a 5 Year Period (2007-2011) in Kashan, IR Iran. Archives of trauma research 2012; 1:63.

3.Stahel PF, Shohami E, Younis FM, Kariya K, Otto VI, Lenzlinger PM, et al. Experimental closed head injury: analysis of neurological outcome, blood–brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines. Journal of Cerebral Blood Flow & Metabolism 2000; 20:369-380.

4.Meffre D, Pianos A, Liere P, Eychenne B, Cambourg A, Schumacher M, et al. Steroid profiling in brain and plasma of male and pseudopregnant female rats after traumatic brain injury: analysis by gas chromatography/mass spectrometry. Endocrinology 2007; 148:2505-2517.

5.Badaut J, Brunet J-F, Regli L. Aquaporins in the brain: from aqueduct to “multi-duct”. Metabolic brain disease 2007; 22:251-263.

6.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. Experimental neurology 2006; 198:469-478.

7.Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. The Lancet Neurology 2008; 7:728-741.

8.Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Archives of physical medicine and rehabilitation 2014; 95:986-995. e981.

9.Saatman KE, Duhaime A-C, Bullock R, Maas AI, Valadka A, Manley GT. Classification of traumatic brain injury for targeted therapies. Journal of neurotrauma 2008; 25:719-738.

10.Ding Z, Zhang J, Xu J, Sheng G, Huang G. Propofol administration modulates AQP-4 expression and brain edema after traumatic brain injury. Cell biochemistry and biophysics 2013; 67:615-622.

11.Sarkaki AR, Khaksari Haddad M, Soltani Z, Shahrokhi N, Mahmoodi M. Time-and dose-dependent neuroprotective effects of sex steroid hormones on inflammatory cytokines after a traumatic brain injury. Journal of neurotrauma 2013; 30:47-54.

12.Shahrokhi N, Khaksari M, Soltani Z, Mahmoodi M, Nakhaee N. Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury. Canadian journal of physiology and pharmacology 2010; 88:414-421.

13.O'Connor CA, Cernak I, Vink R. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain research 2005; 1062:171-174.

14.Dehghan F, Hadad MK, Asadikram G, Najafipour H, Shahrokhi N. Effect of melatonin on intracranial pressure and brain edema following traumatic brain injury: role of oxidative stresses. Archives of medical research 2013; 44:251-258.

15.Shekleton J, Parcell DL, Redman JR, Phipps-Nelson J, Ponsford J, Rajaratnam S. Sleep disturbance and melatonin levels following traumatic brain injury. Neurology 2010; 74:1732-1738.

16.Beni SM, Kohen R, Reiter RJ, Tan DX, Shohami E. Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-κB and AP-1. The FASEB journal 2004; 18:149-151.

17.Borlongan CV, Yamamoto M, Takei N, Kumazaki M, Ungsuparkorn C, Hida H, et al. Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia. The FASEB Journal 2000; 14:1307-1317.

18.Kondoh T, Uneyama H, Nishino H, Torii K. Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life sciences 2002; 72:583-590.

19.Boutin JA, Audinot V, Ferry G, Delagrange P. Molecular tools to study melatonin pathways and actions. Trends in pharmacological sciences 2005; 26:412-419.

20.Doolen S, Krause DN, Dubocovich ML, Duckles SP. Melatonin mediates two distinct responses in vascular smooth muscle. European journal of pharmacology 1998; 345:67-69.

21.Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabó C. Melatonin is a scavenger of peroxynitrite. Life sciences 1997; 60:PL169-PL174.

22.Dubocovich M, Rivera-Bermudez M, Gerdin M, Masana M. Molecular pharmacology, regulation and function of mammalian melatonin receptors. Frontiers in bioscience: a journal and virtual library 2003; 8:d1093-1108.

23.Haldar C, Fukada Y, Araki M. Effects of gonadal steroids on pineal morphogenesis and cell differentiation of the embryonic quail studied under cell culture conditions. Developmental brain research 2003; 145:71-79.

24.Luboshitzky R, Dharan M, Goldman D, Hiss Y, Herer P, Lavie P. Immunohistochemical localization of gonadotropin and gonadal steroid receptors in human pineal glands. The Journal of Clinical Endocrinology & Metabolism 1997; 82:977-981.

25.Harrod CG, Bendok BR, Batjer HH. Interactions between melatonin and estrogen may regulate cerebrovascular function in women: clinical implications for the effective use of HRT during menopause and aging. Medical hypotheses 2005; 64:725-735.

26.Chuffa LGA, Seiva FR, Fávaro WJ, Teixeira GR, Amorim JP, Mendes LO, et al. Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation. Reproductive Biology and Endocrinology 2011; 9:108.

27.Rato AG, Pedrero JG, MartÍnez MA, Del Rio B, Lazo PS, Ramos S. Melatonin blocks the activation of estrogen receptor for DNA binding. The FASEB journal 1999; 13:857-868.

28.Sánchez‐Barceló EJ, Cos S, Mediavilla D, Martínez‐Campa C, González A, Alonso‐González C. Melatonin–estrogen interactions in breast cancer. Journal of pineal research 2005; 38:217-222.

29.Mazurais D, Porter M, Lethimonier C, Le Dréan G, Le Goff P, Randall C, et al. Effects of melatonin on liver estrogen receptor and vitellogenin expression in rainbow trout: an in vitro and in vivo study. General and comparative Endocrinology 2000; 118:344-353.

30.Izzo G, d'Istria M, Serino I, Minucci S. Inhibition of the increased 17β-estradiol-induced mast cell number by melatonin in the testis of the frog Rana esculenta, in vivo and in vitro. Journal of experimental biology 2004; 207:437-441.

31.Shahrokhi N, Haddad MK, Joukar S, Shabani M, Keshavarzi Z, Shahozehi B. Neuroprotective antioxidant effect of sex steroid hormones in traumatic brain injury. Pak J Pharm Sci 2012; 25:219-225.

32.Yu C-X, Zhu C-B, Xu S-F, Cao X-D, Wu G-C. Selective MT 2 melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neuroscience letters 2000; 282:161-164.

33.Wang LM, Suthana NA, Chaudhury D, Weaver DR, Colwell CS. Melatonin inhibits hippocampal long‐term potentiation. European Journal of Neuroscience 2005; 22:2231-2237.

34.Kabbaj M, Morley‐Fletcher S, Le Moal M, Maccari S. Individual differences in the effects of chronic prazosin hydrochloride treatment on hippocampal mineralocorticoid and glucocorticoid receptors. European Journal of Neuroscience 2007; 25:3312-3318.

35.Wen Y, Yang S, Liu R, Perez E, Yi KD, Koulen P, et al. Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia. Brain research 2004; 1008:147-154.

36.Marmarou A, Foda MAA-E, Brink Wvd, Campbell J, Kita H, Demetriadou K. A new model of diffuse brain injury in rats: Part I: Pathophysiology and biomechanics. Journal of neurosurgery 1994; 80:291-300.

37.Koyama Y, Matsui S, Itoh S, Osakada M, Baba A, Matsuda T. The selective Na+–Ca 2+ exchange inhibitor attenuates brain edema after radiofrequency lesion in rats. European journal of pharmacology 2004; 489:193-196.

38.Lotocki G, Vaccari JP, Perez ER, Sanchez-Molano J, Furones-Alonso O, Bramlett HM, et al. Alterations in blood-brain barrier permeability to large and small molecules and leukocyte accumulation after traumatic brain injury: effects of post-traumatic hypothermia. J Neurotrauma 2009; 26:1123-1134.

39.Kusaka G, Calvert JW, Smelley C, Nanda A, Zhang JH. New lumbar method for monitoring cerebrospinal fluid pressure in rats. J Neurosci Methods 2004; 135:121-127.

40.Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance. Biomedicine & pharmacotherapy 2006; 60:97-108.

41.Turgut M, Erdogan S, Ergin K, Serter M. Melatonin ameliorates blood–brain barrier permeability, glutathione, and nitric oxide levels in the choroid plexus of the infantile rats with kaolin-induced hydrocephalus. Brain research 2007; 1175:117-125.

42.Herrera F, Sainz RM, Mayo JC, Martín V, Antolín I, Rodriguez C. Glutamate induces oxidative stress not mediated by glutamate receptors or cystine transporters: protective effect of melatonin and other antioxidants. Journal of pineal research 2001; 31:356-362.

43.Benitez-King G, Anton-Tay F. Calmodulin mediates melatonin cytoskeletal effects. Cellular and Molecular Life Sciences 1993; 49:635-641.

44.Tai SH, Hung YC, Lee E-j, Lee AC, Chen TY, Shen CC, et al. Melatonin protects against transient focal cerebral ischemia in both reproductively active and estrogen‐deficient female rats: the impact of circulating estrogen on its hormetic dose–response. Journal of pineal research 2011; 50:292-303.

45.Cos S, Sánchez-Barceló EJ. Melatonin and mammary pathological growth. Frontiers in neuroendocrinology 2000; 21:133-170.

46.Sanchez-Barcelo E, Cos S, Mediavilla M. Influence of pineal gland function on the initiation and growth of hormone-dependent breast tumors. Possible mechanisms. The pineal gland and cancer 1988:221-232.

47.Cagnacci A, Arangino S, Angiolucci M, Melis GB, Tarquini R, Renzi A, et al. Different circulatory response to melatonin in postmenopausal women without and with hormone replacement therapy. Journal of pineal research 2000; 29:152-158.

48.Saw MM, Chamberlain J, Barr M, Morgan M, Burnett JR, Ho KM. Differential disruption of blood-brain barrier in severe traumatic brain injury. Neurocritical care 2014; 20:209-216.

49.Laredo SA, Orr VN, McMackin MZ, Trainor BC. The effects of exogenous melatonin and melatonin receptor blockade on aggression and estrogen-dependent gene expression in male California mice (Peromyscus californicus). Physiology & behavior 2014; 128:86-91.