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- Copyright: © Iranian Journal of Basic Medical Sciences
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Abstract
Iranian Journal of Basic Medical Sciences ijbms.mums.ac.ir Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury 1 2 3 2 Vida Naderi , Mohammad Khaksari *, Reza Abbasi , Fatemeh Maghool Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran A R T I C L E I N F O A B S T R A C T Article type: Objective(s): Estrogen (E2) has neuroprotective effects on blood-brain-barrier (BBB) after traumatic Original article brain injury (TBI). In order to investigate the roles of estrogen receptors (ERs) in these effects, ER -α antagonist (MPP) and, ER-β antagonist (PHTPP), or non-selective estrogen receptors antagonist (ICI Article history: 182780) were administered. Received: Apr 13, 2014 Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E , oil, Accepted: Aug 3, 2014 MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg) or oil were administered 30 min after TBI. 1 dose (150 µg/Kg) of each of MPP, PHTPP, and (4 mg/kg) ICI182780 was injected Keywords: two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content) and Blood-brain-barrier brain edema (brain water content) evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Brain edema Results: The results showed that E reduced brain edema after TBI compared to vehicle (P<0.01). The ERα antagonist brain edema in the MPP+E2 and PHTPP+E2 groups decreased compared to the vehicle (P<0.001). There ERβ antagonist was no significant difference in MPP+PHTPP+E2 and ICI+E2 compared to TBI. This parameter in MPP ICI182780 was similar to vehicle. Evans blue content in E2 group was lower than vehicle (P<0.05).The inhibitory Traumatic brain injury effect of E2 on Evans blue was not reduced by MPP+E2 and PHTPP+E2 groups, but decreased by treatment with MPP+PHTPP or ICI. MPP had no effect on Evans blue content. Conclusion: A combined administration of MPP and PHTPP or ICI inhibited the E2-induced decrease in brain edema and BBB disruption; this may suggest that these effects were mediated via both receptors. ►Please cite this paper as: 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; 18:138-144. (6). Previous study in our laboratory showed that the Introduction administration of estrogen and progesterone, alone Traumatic brain injury (TBI) is a complex and in combination after TBI decreases brain edema, neurodegenerative disease, involving many cellular blood-brain-barrier permeability, and intracranial and molecular pathways, including inflammation (1). pressure (7). Paradoxically, the inflammatory response can lead to Many of E2 functions are carried via the classic both aggravation and amelioration of the resulting receptors, estrogen receptor alpha and beta. tissue damage, depending on the tissue involved and Estrogen receptors (ERs) are involved in signaling the type of injury evoked (2). After traumatic brain pathways of classical and non-classical pathways (4). injury (TBI), disruption of blood-brain-barrier (BBB) Both receptors express throughout the CNS, will led to the release of neutrophils, lymphocytes including microglia, astrocytes, and neurons, and monocytes from blood to central nervous system and also in many immune system cells such and cause inflammatory responses (3). as macrophages/monocytes, T and B cells and Estrogen (E2) is a cholesterol-derived hormone dendrites are expressed (8). It has been reported that is often known as a reproduction regulator and that ERα expression in ischemic brain after stroke can play a protective role in different kinds of brain greatly increases (9). Beta receptor agonist in animal injuries; it has been revealed that the treatment by models of arthritis and inflammatory bowel disease, estradiol following ischemia, will decrease cortical has anti-inflammatory effects and suppress gene injuries (4). E2 regulates the selective permeability expression of pro-inflammation. Both receptors ERα (5) of the BBB in several models of injury, including and ERβ are involved in cell proliferation induced by systemic inflammation, neurotrauma, and ischemia *Corresponding author: Mohammad Khaksari. Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran. email: [email protected] Naderi et al Anti-edema effect of estrogen receptors α and β estradiol after ischemia (10). After brain ischemia, E (33.3 µg/Kg) or oil were administered (IP) 30 min the expression of ERα in injured cortex increases after TBI (15, 16). rapidly (11). Which of these two receptors alpha MPP(1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2- and beta-estradiol-mediated control inflammation, piperidinylethoxy)phenol]-1H-pyrazole hydrochloride), depends on the inflamed tissue (12). ERα antagonist, and PHTPP(4-[2-Phenyl-5, 7-bis In agreement with previous studies, it was shown (trifluoromethyl) pyrazolo [1,5-a] pyrimidine-3- yl] that estrogen reduces brain edema and BBB phenol), ERβ antagonist, or DMSO were used as permeability after trauma (7, 13), although the roles follows:1 dose (150 µg/Kg) of each of MPP and, PHTPP of estrogen receptors ERα and ERβ in the was injected two times, 24 hr apart, before TBI and neuroprotective actions of estrogen on TBI remain oestrogen treatment (17). Then treated with E (33.3 poorly understood. The goal of the present study was µg/Kg) 30 min after TBI (13). One group received only to use these ER-selective and non-selective an injection of MPP(150 µg/Kg) 30 min after TBI (17). 4 antagonists (MPP, PHTPP and ICI 182780) to mg/kg ICI182780 was injected similar to the other two evaluate the relative necessity of ERα- and ERβ- antagonists (18). activation in mediating the neuroprotective effect of estrogen following diffuse TBI in OVX rats. Induction of diffuse traumatic brain injury (TBI) All animals were intubated before TBI. The TBI Materials and Methods was induced by the Marmarou method (16), using a Animals TBI induction device made by the Department of This study was conducted in accordance with the Physiology, Kerman University of Medical Sciences. guidelines for the animal experimental protocols of The protocol was as follows: a weight of 300 g was Kerman University of Medical Sciences. The protocol dropped from a 2 m height onto the head of the was approved by the ethics committee (no. KNRC/90– anesthetized rat while a metal disc (stainless steel, 40) of this University, in accordance with the 10 mm in diameter, 3 mm thick) was attached to the internationally accepted principles for laboratory animal’s skull. After induction of the trauma, the rats animal use and care, as found in the European were immediately connected to a respiratory pump Community guidelines (EEC Directive of 1986; untill spontaneous breathing had been restored. 86/609/EEC) or US guidelines (NIH publication #85– 23, revised in 1985). Adult female Albino N Mary rats Determination of brain edema (weighing 200–250 g) were housed in an air- The brain edema of each animal was assessed by conditioned room at 22–25°C, with a 12 hr light: 12 hr measuring brain water content 24 hr after TBI. dark cycle and free access to food and water. Anesthetized animals were sacrificed by cervical dislocation; the brain was removed, and brain samples Ovariectomy surgury were placed in pre-weighed glass vials and weighed In the first step, animals were anesthetized by (wet weight). The lids were removed and the vials injection of 60 mg/kg thiopental (IP), sub abdominal placed in an incubator (Memmert, Germany) at 60 C for area was shaved and an incision of 1 cm was made. 72 hr, and then reweighed (dry weight). The Afterwards, skin, fascia, and abdominal muscles were percentage of water in each sample was then calculated opened. Both fallopian tubes and vascular base of the using a formula published previously (16, 19): (100 * ovaries were legated in the proximal parts and then [(wet weight–dry weight)/ wet weight]). cut from the distal parts. Abdominal cavity was irrigated by 2 ml of normal saline. The incision was Determination of blood–brain barrier (BBB) closed with a 2–0 silk surgical suture. To avoid disruption interference due to the estrus cycle, all experimental The degree of BBB disruption was assessed by animals were ovariectomized (OVX) 2 weeks before measuring Evans blue dye leakage (16). Briefly, the experiments (14). Evans blue dye was dissolved in 0.01 mol/l PBS at a concentration of 2%, then the dye (2 ml/kg IV) was Experimental protocols injected into the tail vein 4 hr after TBI, as a BBB Before induction of TBI, ovariectomized rats were permeability tracer. The rats were then deeply randomly divided into 10 groups, as follows: sham anesthetized and transcardiac perfused with 200 ml (animals that underwent ovariectomy 2 weeks before heparinized saline through the left ventricle to the start of the experiment and underwent false brain remove the intravascular dye. The brains were trauma under anesthesia but did not receive hormones removed, then dissected, weighed, and stored at – or vehicle), TBI (brain injury was induced 2 weeks after 80 C for quantitative measurement. Brain samples ovariectomy), E , MPP+E , PHTPP+E , MPP+PHTPP+E2, were homogenized in 1 ml of 0.1 mol/l PBS, and 0.7 2 2 2 MPP, ICI+E2, oil (sesame oil, which was used as ml of 100% (w/v) trichloroacetic acid was added, estrogen solvent) and DMSO (dimethyl sulfoxide, which and centrifuged. After centrifugation for 30 min at was used as antagonists solvent). (n=6 in each group). 1000 g, the absorbance of Evans blue in supernatant Iran J Basic Med Sci, Vol. 18, No. 2, Feb 2015 Anti-edema effect of estrogen receptors α and β Naderi et al Figure 1a *** 79 ## ## ## ### 76 76 sham TBI Oil DMSO E2 TBI E2 MPP+E2 PHTPP+E2 MPP+PHTPP+E2 ICI+E2 Groups Group Figure 1c Figure 1. (a) Comparison of brain water content (%) after traumatic brain injury in ovariectomized (OVX) rats (n =6 in each group). The data are represented as mean±SEM. ***: P< 0.001, TBI vs. sham. ##: P<0.01, E2 vs. TBI and PHTPP+E2vs TBI., Oil and DMSO groups. (b) Comparison of brain water content in OVX rats treated with ERs antagonist. ###: P<0.001 MPP+E2. There were no significant differences in MPP+E2 and PHTPP+E compared to E (c) Brain water content (%) after 2 2 traumatic brain injury in OVX rats treated with MPP and DMSO. MPP (ER-α 74 antagonist), PHTPP(ER-β antagonist), ICI182780 (non selective estrogen receptors DMSO MPP antagonist), DMSO (dimethyl sulfoxide, antagonists solvent), oil (sesame oil, estrogen solvent) Groups was measured at 610 nm using a spectrophotometer Figure 2a shows that the Evans blue content in the (UV/VIS, Spectrometer, UK). The amount of TBI (37.18±0.4 μg/g tissue) group was significantly extravasated Evans blue dye was quantified as µg/g higher than in the sham (33.25±0.05 μg/g tissue, brain tissue. P<0.05) group and the Evans blue content in E2 (33.5±0.65 μg/g tissue) was lower than oil Statistical analysis (37.67±0.44 μg/g tissue), TBI, and DMSO Quantitative data were expressed as mean ± SEM. (37.34±0.22 μg/g tissue) groups. P<0.05. Figure 2b The data were analyzed by parametric analysis of shows the effect of administration of estrogen variance (ANOVA) or independent t test. Fisher’s LSD receptors antagonist. In the presence of MPP and was employed for the post-hoc analysis. The criterion PHTPP, Evans blue content decreased and was for statistical significance was sign at P < 0.05. 30.78±0.31 μg/g tissue in MPP+E2and 31.4±0.38 μg/g tissue in PHTPP+E2 groups (P<0.001). There were no significant differences in MPP+PHTPP+E & Results ICI+E2 compared to TBI. Figure 2c shows that the Brain edema Evans blue content in the groups treated with MPP Changes in the brain water content of the (36.46±0.68) has no significant difference with the ovariectomized rats are shown in Figure 1. Figure 1a Evans blue in the E2 group. shows that the brain water content in the TBI (78.6±0.33%) group was significantly higher than Discussion in sham (75.65±0.001%, P<0.001) group and brain Previous studies have reported, the neuroprotective water content in the group treated with E effects of estrogen on brain edema and blood-brain (76.76±0.17%) was significantly lower than those in barrier permeability (7, 13), In the present study, the the oil (78.32±0.15%) and DMSO (78.4±0.22%) roles of alpha and beta estrogen receptors in the groups, (P<0.01). Figure 1b shows the effects of development of these effects were investigated. The administration of estrogen receptors antagonists. In main findings of this research are as follows: 1-estrogen the presence of MPP and PHTPP, brain water content exerts its anti-edema effects through both receptors, so decreased and was 74.86±0.54% in MPP+E2 group that any differences between the results of combined and 75.41±0.88% in PHTPP+E2 group. There was no use of selective antagonists and a non-selective significant difference in MPP+PHTPP+E and ICI+E2 antagonist do not exist. 2 -BBB protection after TBI by compared to TBI. Figure 1c shows that the brain estrogen is mediated by both receptors, which is similar water content in the group treated with MPP to the results of the anti-edema effect of estrogen. 3- (78.06±0.32%) has no significant difference with the The estrogen receptor alpha antagonist (MPP) has no water content in DMSO group. agonistic effect on its receptor. TBI caused an increase in brain water content Extravasation of Evans blue content and BBB permeability, these increases were The effects of estrogen and ERs antagonists on inhibited by estrogen compared to vehicle (oil). BBB disruption after TBI are shown in Figure 2. Iran J Basic Med Sci, Vol. 18, No. 2, Feb 2015 Brain water content (%) Brain water content (%) Brain water content (%) Naderi et al Anti-edema effect of estrogen receptors α and β Figure 2a ** ## ## ### ### 15 15 sham TBI 0il DMSO E2 TBI E2 MPP+E2 PHTPP+E2 MPP+PHTPP+E2 ICI+E2 Group Group Figure 2c Figure 2. (a) Comparison of Evans blue content (μg/g tissue) after traumatic brain injury in ovariectomized (OVX) rats (n =6 in each group). The data are represented as mean±SEM. **: P< 0.01, TBI vs. sham. ##: P< 0.01, E vs. TBI, oil and DMSO groups. (b) Comparison of brain water content in OVX rats treated with ERs antagonist. ###: P< 0.001 MPP+E2 and PHTPP+E2 vs TBI. There were no significant differences in MPP+E2 and PHTPP+E2 compared to E2 (c) Evans blue content (μg/g tissue) after traumatic brain injury in OVX rats treated with MPP and 5 DMSO. MPP(ER-α antagonist), PHTPP(ER-β antagonist), ICI182780 (non selective estrogen receptors antagonist). DMSO ( dimethyl sulfoxide, antagonists solvent), oil (sesame oil, estrogen solvent) DMSO MPP Group There have been a number of reports supporting a development of neuroprotective effects of estrogen, neuroprotective role for estrogen after various We found that more than one receptor is activated by insults to the CNS. Ovariectomy increases ischemic estrogen at the same time, perhaps activation of both brain damage in females, and estradiol exerts receptors at the same time has reciprocal neuroprotective and anti-inflammatory action modulatory effects. Whenever the effect of estrogen against the ischemic brain when administered was observed during receptor inhibition , it was immediately upon ovariectomy (20). E2 regulates caused by activation of the other receptor at the the selective permeability of the BBB in several same time. To the best of our knowledge, the roles of models of injury (5). The BBB permeability neither ERα antagonist nor ERβ antagonist in TBI decreased in E2-treated mice (4). Recently, our have been reported thus far. Because this study is the research showed that estrogen loss facilitates, first to use a selective ERα and ERβ antagonist to whereas administration of a different dose of investigate the effects on TBI. However, the effects of estradiol could prevent edema formation (7) and these receptors or antagonists in other non-TBI destruction of the BBB after TBI (13). A significant studies, and other estrogen-mediated effects have reduction in the brain water content after TBI was been demonstrated, including: The receptors ERα induced by estrogen; there is no difference between and ERβ are essential for E2-mediated regulation of estrogen and solo administration of antagonist BBB permeability, anti-inflammatory properties, and groups. This suggested that neither selective ERα regulation of neutrophil recruitment into the brain antagonist (MPP) nor ERβ antagonist (PHTPP) can (4). Both ER receptors are involved in the control of abolish these effects of estrogen. inflammation by estradiol (21), neuromodulation, On the other hand, administration of the two and neuroprotection processes after brain injury antagonists together (MPP + PHTPP) or the use of (22). The affinity of MPP to ERα is only 11% of that non-selective estrogen receptor antagonist of E2 (23). ER antagonists (MPP and ERβ antagonist (ICI182780) eliminates the inhibitory effect of (R,R)-THC) treatments alone did not significantly estrogen on brain edema and BBB permeability, this change NPY release levels (24). MPP failed to means that, the effects of estrogen were not inhibited attenuate the anorexigenic effects of estradiol and an by the administration of antagonists alone, but when ERα agonist in OVX rats (25). MPP did attenuate the these antagonists were administered in combination, estrous-related decrease in food intake in cycling they have an inhibitory effect. It is suggested that, rats (25). MPP shows no activation of either receptor probably both receptors are involved in the subtype (23). 17ßestradiol protects dopamine neurons Iran J Basic Med Sci, Vol. 18, No. 2, Feb 2015 Brain Evans Blue content (μg/g Brain Evans Blue content (μg/g tissue) tissue) Brain Evans Blue content (μg/g tissue) Anti-edema effect of estrogen receptors α and β Naderi et al from injury, an effect that was blocked by ICI 182,780 after TBI, it was observed this compound did not (26). ICI 182,780 after ischemia abolished estrogen reduce brain edema, and BBB permeability. In other protection (27). Estrogen neuroprotection was related words, MPP has no agonist effect on ERα. This to microglial activation of estrogen receptors (ERs), this finding is consistent with other studies that have protective effect was overridden by pretreatment with reported that MPP counteracted the effects of ICI 182,780, the specific ERa, only partially blocked the PPT(estrogen receptor agonist) but had little effect effects of estrogen (6). on its own (44). On the other hand, it has also been An alternate mechanism which could explain the reported that estrogen receptor/(ERα), even in differential effects of ICI and MPP, is an involvement absence of estrogen (E2), plays a critical role in of non-genomic/non-classical signaling mechanisms lactotroph homeostasis (45). In vivo tests of MPP's activated by anti-estrogen-occupied ER. Indeed, e ff ects on food intake revealed estrogenic activity, ICI-mediated Erk1/2(extracellular signal-regulated suggesting that MPP functions as a SERM(Selective kinases) activation appears to be critical for estrogen receptor modulator), rather than as an ERα modulation in immature cerebellar neurons (28). antagonist (46). Some studies suggest that MPP acts as an ERα antagonist following in vitro applications, but exerts Conclusion mixed ERα agonist/antagonist actions following in The present study showed that the vivo applications (29). It is possible that the MPP administration of PPT or PHTPP alone will not lead concentration in this experiment was too low to to reduced brain edema, and prevention of BBB completely compete with E2 for binding to ER α, disruption following TBI, but a combined because it is reported that MPP is needed in high administration of MPP and PHTPP or ICI inhibited excess to fully antagonize E2 (30). There are several the E2-induced decrease in brain edema and BBB probable mechanisms by which ERα and ERβ disruption, this may suggest that estrogen attenuate BBB permeability and brain edema after neuroprotection was mediated via both ERα and TBI that result from the inflammatory response; up ERβ. Both of them can play roles in classic and non- regulation of defense-related genes, IL-6, MMP-9, classic pathways. Further study is needed and and some of phagocytic receptors (31), protection of intracellular mechanism activation in the presence of cortical cells against oxidative glutamate toxicity E2 should be evaluated. These data, makes them (32), neuroprotection of estrogen against activated exciting therapeutic targets for further study, in microglia (33) and inhibition of the cytoplasmic addition, perhaps it is essential that non-genomic transport of NF- B (nuclear factor kappa-light-chain- mechanisms are also investigated. enhancer of activated B cells) (34). There is, however, some controversy. MPP Acknowledgment reduced the E2 effect on protein vitellogenin (35). The present study was financially supported by MPP and PTHPP inhibited DNA synthesis, oxygen the Neuroscience Research Center and Physiology species (ROS) formation induced by estrogens Research Center, Kerman University of Medical according to their receptors affinity (36). Sciences, Kerman, Iran. The results reported in this Experiments with PHTPP, indicated that E2- paper were part of a student thesis. mediated neuroprotection against NMDA toxicity was mediated via ERβ receptor (37). Many studies References have reported a primary role for ERα as a regulator 1. Raghupathi R. Cell death mechanisms following of the anti-inflammatory properties of estradiol, traumatic brain injury. Brain pathology 2004; including the anti-inflammatory and neuroprotective 14:215-222. activity of estradiol (38), neuroprotection after 2. Cederberg D, Siesjö P. 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Journal
Iranian Journal of Basic Medical Sciences – Pubmed Central
Published: Feb 1, 2015