Effects of sex steroid hormones on neuromedin S and neuromedin U2 receptor expression following experimental traumatic brain injury

Document Type: Original Article

Authors

1 Endocrinology and Metabolism Research, and Physiology Research Centers, Kerman University of Medical Sciences, Kerman, Iran

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

Abstract

Objective(s): Neuroprotective effects of female gonadal steroids are mediated through several pathways involving multiple peptides and receptors after traumatic brain injury (TBI). Two of these peptides are including the regulatory peptides neuromedin U (NMU) and neuromedin S (NMS), and their common receptor neuromedin U2 receptor (NMUR2). This study investigates the effects of physiological doses of estradiol and progesterone on brain edema, NMS and NMU as well as NMUR2 expression following TBI.
Materials and Methods: Ovariectomized female rats were given high-and low-dose of female sex steroid hormones through implantation of capsules for a week before trauma. The brain NMUR2 expression, prepro-NMS expression, NMU content, and water content (brain edema) were evaluated 24 hr after TBI induced by Marmarou’s method.
Results: Percentage of brain water content in high- and low-dose estradiol, and in high- and low- dose progesterone was less than vehicle (P<0.01).  Results show high expression of prepro-NMS in high dose progesterone (TBI-HP) rats compared to the high dose estrogen (TBI-HE), as well as vehicle (P<0.01). NMU content in low-dose progesterone (TBI-LP) group was more than that of vehicle group (P<0.001). Furthermore a difference in NMU content observed between TBI-HP compared to TBI-HE, and vehicle (P<0.05). The NMUR2 mRNA expression revealed an upregulation in TBI-HP rats compared to the TBI-HE group (P<0.001).
Conclusion: Findings indicate that progesterone attenuates brain edema and induces an increase in NMS and its receptor which may mediate the anti-edematous effect of progesterone after TBI.

Keywords


1. Roof RL, Duvdevani R, Stein DG. Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res 1993; 607:333-336.

2. Carswell HVO, Dominiczak AF, Macrae IM. Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2000; 278:H290.

3. Roof RL, Hall ED. Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats. J Neurotrauma 2000; 17:1155-1169.

4. 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.

5. Attella MJ, Nattinville A, Stein DG. Hormonal state affects recovery from frontal cortex lesions in adult female rats. Behav Neural Biol 1987; 48:352-367.

6. Stein DG. The case for progesterone. Ann N Y Acad Sci 2005; 1052:152-169.

7. 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.

8. Guan XM, Yu H, Jiang Q, Van der Ploeg LH, Liu Q. Distribution of neuromedin U receptor subtype 2 mRNA in the rat brain. Gene Exp Patterns 2001; 1:1-4.

9. Brighton PJ, Szekeres PG, Willars GB. Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev 2004; 56:231.

10. Cao CQ, Yu XH, Dray A, Filosa A, Perkins MN. A pro-nociceptive role of neuromedin U in adult mice. Pain 2003; 104:609-616.

11. Fukue Y, Sato T, Teranishi H, Hanada R, Takahashi T, Nakashima Y, et al. Regulation of gonadotropin secretion and puberty onset by neuromedin U. FEBS Lett 2006; 580:3485-3488.

12. Hanada R, Nakazato M, Murakami N, Sakihara S, Yoshimatsu H, Toshinai K, et al. A role for neuromedin U in stress response. Biochem Biophys Res Commun 2001; 289:225-228.

13. Moriyama M, Matsukawa A, Kudoh S, Takahashi T, Sato T, Kano T, et al. The neuropeptide neuromedin U promotes IL-6 production from macrophages and endotoxin shock. Biochem Biophys Res Commun 2006; 341:1149-1154.

14. Okamura N, Reinscheid RK, Ohgake S, Iyo M, Hashimoto K. Neuropeptide S attenuates neuropatho-logical, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801. Neuropharmacology 2010; 58:166-172.

15. Iwai T, Iinuma Y, Kodani R, Oka J-I. Neuromedin U inhibits inflammation-mediated memory impairment and neuronal cell-death in rodents. Neurosci Res 2008; 61:113-119.

16. Castro AA, Moretti M, Casagrande TS, Martinello C, Petronilho F, Steckert AV, et al. Neuropeptide S produces hyperlocomotion and prevents oxidative stress damage in the mouse brain: a comparative study with amphetamine and diazepam. Pharmacol Biochem Behav 2009; 91:636-642.

17. 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 Res 2004; 1008:147-154.

18. Strom JO, Theodorsson E, Holm L, Theodorsson A. Different methods for administering 17 -estradiol to ovariectomized rats result in opposite effects on ischemic brain damage. BMC Neurosci 2010; 11:39.

19. Smith MS, Freeman ME, Neill JD. The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy 1 2. Endocrinology 1975; 96:219-226.

20. DePaolo LV, Barraclough CA. Dose dependent effects of progesterone on the facilitation and inhibition of spontaneous gonadotropin surges in estrogen treated ovariectomized rats. Biol Reprod 1979; 21:1015.

21. DePaolo LV, Rowlands KL. Deceleration of age-associated changes in the preovulatory but not secondary follicle-stimulating hormone surge by progesterone. Biol Reprod 1986; 35:320.

22. Butcher RL, Collins WE, Fugo NW. Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17β throughout the 4-day estrous cycle of the rat. Endocrinology 1974; 94:1704-1708.

23. Mandl AM. The phases of the oestrous cycle in the adult white rat. J Exp Biol 1951; 28:576-584.

24. Marmarou A, Foda MA, van den Brink W , Campbell J, Kita H, Demetriadou K. A new model of diffuse brain injury in rats: Part I: Pathophysiology and biomechanics. J Neurosurg 1994; 80:291-300.

25. Vink R, Young A, Bennett CJ, Hu X, Connor CO, Cernak I, et al. Neuropeptide release influences brain edema formation after diffuse traumatic brain injury. Acta Neurochir Suppl 2003; 86:257.

26. Hagelberg E, Gray IC, Jeffreys AJ. Identification of the skeletal remains of a murder victim by DNA analysis. Nature 1991; 352:427-429.

27. Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 2002; 30:e36-e.

28. Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 1993; 15:532-534,53 6-537.

29. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-254.

30. Rucinski M, Ziolkowska A, Neri G, Trejter M, Zemleduch T, Tyczewska M, et al. Expression of neuromedins S and U and their receptors in the hypothalamus and endocrine glands of the rat. Int J Mol Med 2007; 20:255-259.

31.  Yang G, Su J, Li X, Yao Y, Lei Z, Yang X, et al. Expression of NMS and NMU2R in the pig reproductive axis   during the estrus cycle and the effect of NMS on the reproductive axis in vitro. Peptides 2009; 30:2206-2212.

32. Ida T, Mori K, Miyazato M, Egi Y, Abe S, Nakahara K, et al. Neuromedin S is a novel anorexigenic hormone. Endocrinology 2005; 146:4217-4223.

33. Del Bigio MR. The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia 1995; 14:1-13.

34. Guan XM, Yu H, Jiang Q, Van der Ploeg LHT, Liu Q. Distribution of neuromedin U receptor subtype 2 mRNA in the rat brain. Gene Expr Patterns 2001; 1:1-4.

35. Chan PH, Schmidley JW, Fishman RA, Longar SM. Brain injury, edema, and vascular permeability changes induced by oxygen-derived free radicals. Neurology 1984; 34:315.

36. Nishio S, Yunoki M, Noguchi Y, Kawauchi M, Asari S, Ohmoto T. Detection of lipid peroxidation and hydroxyl radicals in brain contusion of rats.  Brain Edema X: Springer; 1997. p. 84-86.

37. Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol 1997; 31:1-11.

38. Khaksari M, Soltani Z, Shahrokhi N, Moshtaghi G, Asadikaram G. The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury. Can J Physiol Pharmacol 2010; 89:31-40.

39. 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.

40. Naderi V, Khaksari M, Abbasi R, Maghool F. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury. Iran J Basic Med Sci 2015; 18:138.

41. Ida T, Mori K, Miyazato M, Egi Y, Abe S, Nakahara K, et al. Neuromedin S is a novel anorexigenic hormone. Endocrinology 2005; 146:4217.

42. Huang Q, Tatro JB. α-Melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-α and interleukin-1β gene expression following transient cerebral ischemia in mice. Neurosci Lett 2002; 334:186-190.

43. Rajora N, Boccoli G, Burns D, Sharma S, Catania AP, Lipton JM. α-MSH modulates local and circulating tumor necrosis factor-α in experimental brain inflammation.  J Neurosci 1997; 17:2181-2186.

44. Clausen F, Hanell A, Israelsson C, Hedin J, Ebendal T, Mir AK, et al. Neutralization of interleukin -1β reduces cerebral edema and tissue loss and improves late cognitive outcome following traumatic brain injury in mice. Eur J Neurosci 2011; 34:110-123.

45. Stover JF, Schoning B, Beyer TF, Woiciechowsky C, Unterberg AW. Temporal profile of cerebrospinal fluid glutamate, interleukin-6, and tumor necrosis factor-alpha in relation to brain edema and contusion following controlled cortical impact injury in rats. Neurosci Lett 2000; 288:25-28.

46. Bhardwaj RS, Schwarz A, Becher E, Mahnke K, Aragane Y, Schwarz T, et al. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J Immunol 1996; 156:2517-2521.

47. Jaszberényi M, Bagosi Z, Thurzَ B, Fِldesi I, Telegdy G. Endocrine and behavioral effects of neuromedin S. Hormon Behav 2007; 52:631-639.

48. Sakamoto T, Mori K, Nakahara K, Miyazato M, Kangawa K, Sameshima H, et al. Neuromedin S exerts an antidiuretic action in rats. Biochem Biophys Res Commun 2007; 361:457-461.

49. Guennoun R, Meffre D, Labombarda F, Gonzalez SL, Deniselle MC, Stein DG, et al. The membrane-associated progesterone-binding protein 25-Dx: expression, cellular localization and up-regulation after brain and spinal cord injuries. Brain Res Rev 2008; 57:493-505.

50. Niermann H, Amiry-Moghaddam M, Holthoff K, Witte OW, Ottersen OP. A novel role of vasopressin in the brain: modulation of activity-dependent water flux in the neocortex.  J Neurosci 2001; 21:3045-3051.

51. Guennoun R, Meffre D, Labombarda F, Gonzalez S, Deniselle MG, Stein D, et al. The membrane-associated progesterone-binding protein 25-Dx: expression, cellular localization and up-regulation after brain and spinal cord injuries. Brain Res Rev 2008; 57:493-505.

52. Vigo E, Roa J, Pineda R, Castellano JM, Navarro VM, Aguilar E, et al. Novel role of the anorexigenic peptide neuromedin U in the control of LH secretion and its regulation by gonadal hormones and photoperiod. Am J Physiol Endocrinol Metab 2007; 293:E1265.

53. Moriyama M, Sato T, Inoue H, Fukuyama S, Teranishi H, Kangawa K, et al. The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells.  J Exp Med 2005; 202:217.