Changes in neuromedin S and its receptor after traumatic brain injury in cycling rats

Animal studies indicate that gonadal steroids have prominent neuroprotective effects in several models of experimental traumatic brain injury (TBI). Neuromedin U (NMU) and neuromedin S (NMS) are regulatory peptides involved in inflammatory and stress responses, and modulation of the gonadotropic axis. Since steroid hormone levels change during the estrous cycle, we sought to determine whether variations in ovarian hormones would affect blood-brain barrier (BBB) permeability and brain levels of NMS, NMU, and neuromedin S receptor 2 in experimental TBI. Two groups (proestrus and nonproestrus) of female rats underwent diffuse TBI. At 24 hrs after TBI, results showed a significantly decrease in BBB permeability in traumatic-proestrus animals (TBI-P) in comparison to traumatic nonproestrus (TBI-NP) rats. Western blot analyzes demonstrated an enhanced expression of prepro-NMS in TBI-P compared with that in the TBI-NP group. Likewise, TBI-P rats exhibited significantly higher NMUR2 gene expression compared with those of TBI-NP, whereas no significant difference in brain NMU content was seen between sham and traumatic animals. Our findings indicate that diffuse TBI induces an increase in prepro-NMS and neuromedin S receptor 2 expression in traumatic-proestrus rats which may mediate the anti-edematous effects of gonadal hormones in proestrus rats following trauma. Neurology Asia 2015; 20(4) : 375 – 384 Address correspondence to: Fatemeh Maghool, Neuroscience Research Center, School of Medicine, Kerman University of medical Science, Kerman, 7614715977 Iran. Tel: +98 913 207 4423, Fax: +98 31195016799. Email: [email protected], [email protected] INTRODUCTION It is well documented that female sex steroid hormones provide neuroprotection in various models of central nervous system (CNS) injury such as diffuse traumatic brain injury (TBI). However, the underlying mechanisms have not been totally clarified. There are evidences that circulating estradiol and progesterone at the time of injury are important for neuroprotection. High circulating estradiol levels in cycling female rats are associated with less brain damage after cerebral ischemia. A converse correlation between serum levels of progesterone and the extent of edema after TBI has been reported. Administration of estradiol and progesterone, exclusively or in combination, results in a rising concentration of sex steroid hormones and the decline of brain edema after TBI. It has shown that rodent estrous cycle influences the outcome of brain injury. The normal estrous cycle in a female rat contains two main phases: the proestrus phase and the non-proestrus phases including estrus, diestrus and metestrus. Since plasma levels of female sex hormones are significantly elevated throughout the proestrus stage of the estrous cycle, it appears that differences in gonadal hormone concentrations between proestrus and non-proestrus phases affect TBI outcomes. Recent study in our laboratory showed that the brain edema and intracranial pressure in injured proestrus rats is less than that in the non-proestrus animals. It has demonstrated that vulnerability in the proestrus stage is lower than the other phases of the reproductive cycle; however, the underlying mechanisms are not well understood. The regulatory peptides, neuromedin U (NMU) and structurally related neuropeptide neuromedin S (NMS), are implicated in the regulation of numerous biological processes such as autonomic, endocrine and behavioral functions. They share the same C-terminal amino-acid sequence and bind to the same G protein-coupled receptors (GPCRs), neuromedin u receptor 1 (NMUR1) and neuromedin u receptor 2 (NMUR2), also have identified as FM-3/GPR66 and FM-4/ TGR-1 respectively. NMU is implicated in a wide variety of physiological functions, including nociception, pituitary hormone secretion, stress responses, HPA (hypothalamic-pituitary-adrenal) Neurology Asia December 2015 376 axis activation and immunomodulation. NMS is involved in modulation of the reproductive system, regulation of circadian rhythms, stimulating the HPA axis and stress related behavior. The NMU-NMS-NMUR2 system plays a role in the dynamic control of the gonadotropic axis. The dispersed distribution of NMUR2 in the brain suggests additional functions of NMU and NMS in the CNS. It is present in the ependymal cells lining the third ventricle. These ependymal cells work as a protecting barrier between brain and cerebrospinal fluid. Therefore, this could suggest neuroendocrine and transport functions of NMUR2. In addition, NMUR2 is expressed in the subfornical organ and the vascular organ of the lamina terminalis that are the communication sites between the brain and blood – borne substances. Some studies have recently demonstrated the regulatory role of female sex steroid hormones on NMUR2 expression. They have revealed that variation of brain NMS and NMU is due to the phases of the female rat estrous cycle, however their brain expression after TBI remains unexplored. The purpose of this study was to determine whether changes of estradiol and progesterone during the estrous cycle are associated with difference in blood–brain barrier (BBB) permeability as well as brain levels of NMU, NMS and their receptor expression in experimental TBI.