Int J Clin Exp Med 2018;11(8): /ISSN: /IJCEM Jun Luo, Peng Hao, Xuesong Gao, Yuchuan Wang, Ruiqiang Sun
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1 Int J Clin Exp Med 2018;11(8): /ISSN: /IJCEM Originl Article Dexmedetomidine pretretment llevites cerebrl ischemi-reperfusion injury in rts through resisting oxidtive dmge nd regulting TGF-β1/Smd2/3 signling pthwy Jun Luo, Peng Ho, Xuesong Go, Yuchun Wng, Ruiqing Sun Tinjin Eye Hospitl, Tinjin Key Lbortory of Ophthlmology nd Vision Science, Tinjin Eye Institute, Clinicl College of Ophthlmology, Tinjin Medicl University, Tinjin , Chin Received November 2, 2017; Accepted July 2, 2018; Epub August 15, 2018; Published August 30, 2018 Abstrct: Bckground: Cerebrl ischemi-reperfusion (I/R) injury is clinicl frequently-occurring nd common disese. Dexmedetomidine (DEX), novel highly selective α2a-drenergic receptor gonist, hs been widely used in vrious fields of clinic. The oxidtive dmge nd trnsforming growth fctor-β1 (TGF-β1)/Smd2/3 signling pthwy re involved in I/R injury. This study imed to investigte the protective effects of DEX on cerebrl I/R injury in rts through resisting oxidtive stress nd regulting TGF-β1/Smd2/3 signling pthwy. Methods: Fifty SD rts were rndomly divided into shm-opertion, I/R, nd low-, middle- nd high-dose DEX group, 10 rts in ech group. In lter four groups, the cerebrl I/R model ws estblished. In ddition, t 30 min before estblishment of I/R model, the low-, middle- nd high-dose DEX group were intrperitonelly injected with DEX with dose of 10, 20 nd 40 mg/kg, respectively. After 24 h from ischemi, the neurologicl deficit scores, serum tumor necrosis fctor-α (TNF-α) nd interleukin-1β (IL-β) levels, brin wter content (BWC), percentge of brin infrction re (BIA), brin tissue superoxide dismutse (SOD) nd glutthione peroxidse (GSH-Px) ctivity, mlondildehyde (MDA), cyclooxygense (COX-2) nd 5 lipoxygense (5-LOX) level nd TGF-β1 nd phosphorylted Smd2/3 (p-smd2/3) protein expression were determined. Results: After tretment, compred with I/R group, the neurologicl deficit score, BWC, percentges of BIA, serum TNF-α nd IL-1β level, nd brin tissue MDA, COX-2 nd 5-LOX level in highdose DEX group were significntly decresed, respectively (P < 0.05), nd the brin tissue SOD nd GSH-Px ctivity nd TGF-β1 nd p-smd2/3 expression level in high-dose DEX group were significntly incresed, respectively (P < 0.05). Person correltion nlysis showed tht, the brin tissue SOD nd GSH-Px ctivity were positively correlted with brin tissue TGF-β1 nd p-smd2/3 level, respectively (P < 0.05 or P < 0.01) Conclusion: DEX pretretment cn llevite the cerebrl I/R injury in rts. The mechnism my be relted to its resistnce of oxidtive dmge nd up-regultion of TGF-β1/Smd2/3 signling pthwy in brin tissue. Keywords: Dexmedetomidine, ischemi/reperfusion, rts, oxidtive stress, TGF-β1, Smd2/3 Introduction Cerebrovsculr diseses re the min diseses ffecting humn helth nd cusing deth nd disbility, mong which the ischemic cerebrovsculr disese is the most common. In the high-risk surgery in nervous system, hert nd lrge vessels, elderly nd criticl illness, the risk of cerebrl ischemi in periopertive period is very high [1]. The timely reperfusion in ischemic brin tissues is n effective mesure for treting cerebrl ischemi. It cn mke the ischemic brin tissues to obtin oxygen gin for providing nutrients necessry for norml metbolism of brin nd removing metbolic wstes [2]. However, the recent studies hve found tht, the further tissue dmge or dysfunction often occur fter the blood flow is restored in brin tissues. This is clled cerebrl ischemi-reperfusion (I/R) injury. In clinic, vriety of tretment modlities cn llevite this disese, but most of the ptients suffer from disbility or even deth due to the lck of effective tretment [3]. Dexmedetomidine (DEX) is novel highly selective α2a-drenergic receptor gonist. DEX hs the nlgesic, sedtive nd nxiolytic effects.
2 In ddition, it hs functions in resisting sympthy, inhibiting stress response, stbilizing hemodynmics nd reducing the dosge of nesthetics [4]. DEX hs been widely used in vrious fields of clinic. Recent studies hve found tht DEX hs brin protective effects. The possible mechnisms include its decresing the ctecholmine level, reducing the relese of excittory neurotrnsmitters nd regulting the pthwy of cell poptosis [5, 6]. However, the exct protective mechnisms remin uncler, nd the optiml dosge, time nd mnner of clinicl mediction re not cler. At present, the reserches on the mechnism of cerebrl I/R injury re minly focused on the spects including excittory neurotoxicity, oxidtive dmge, inflmmtory response, etc. [7]. In ddition, it is found tht, the exogenous trnsforming growth fctor-β1 (TGF-β1) cn reduce the cerebrl infrction volume nd degenertion of neurl cells fter cerebrl ischemi in rts. Newborn mice lcking TGF-β1 gene expression my exhibit extensive neuronl degenertion nd significntly shorten survivl time [8]. Therefore, TGF-β1 hs the neuroprotective effects. Smd2/3 is the receptor of TGF-β1 pthwy [9]. In cerebrl I/R injury, TGF-β1 cn prevent the oxidtion dmge nd cell poptosis through phosphoryltion of downstrem fctor Smd2/3. Therefore, we hypothesize tht, the brin protective effects of DEX re relted to its ction on oxidtive dmge nd TGF-β1 pthwy. In this study, the protective effects of DEX on cerebrl I/R injury in rts were investigted, nd the mechnisms bsed on resistnce of oxidtive dmge nd regultion of TGF-β1 pthwy were explored. The objective ws to provide bsis for further clrifying the mechnism of DEX in prevention nd tretment of I/R injury. Mterils nd methods Animl grouping nd tretment Fifty SD rts (260±30 g) were rndomly divided into 5 groups: shm-opertion group, I/R group, nd low-, middle- nd high-dose DEX group, 10 rts in ech group. The shm opertion group only underwent surgicl exposure of the externl crotid rtery without cusing ischemi. In model group, nd low-, middle- nd high-dose DEX group, the cerebrl I/R model ws estblished. In ddition, t 30 min before estblishment of I/R model, the low-, middle- nd highdose DEX group were intrperitonelly injected with DEX with dose of 10, 20 nd 40 mg/kg, respectively, nd the shm opertion nd I/R group were intrperitonelly injected with 1 ml of sterile sline, respectively. Estblishment of cerebrl I/R model Rts were fsted for 12 h before surgery. Then the cerebrl I/R model ws estblished by middle cerebrl rtery occlusion [10]. After nesthesi by intrperitonel injection of 10% chlorl hydrte with dose of 0.35 g/kg, the right common crotid rtery, externl crotid rtery nd internl crotid rtery were exposed. The right middle cerebrl rtery ws embolized with nylon thred, with suture depth of mm. After blocking for 2 h, the nylon thred ws removed, nd the middle crotid rtery blood flow ws restored, thus the cerebrl I/R model ws successfully estblished. Neurologicl deficit scoring After 24 h from ischemi, the neurologicl deficit scoring ws performed ccording to the scoring stndrd estblished by Long et l [8] s follows: 0 point: symptomtic; 1 point: the rts could not fully extend the forepw or the Horner s syndrome ppered; 2 points: the rts turned round to the opposite side; 3 points: the rts dumped to the opposite side; 4 points: the rts could not wlk spontneously, with loss of consciousness. Determintion of serum tumor necrosis fctor-α nd interleukin-1β level Three milliliter of blood ws tken from the tight ventricle of rts. After centrifuging t 3000 r/ min for 15 min, the superntnt ws immeditely obtined nd ws kept in 20 C refrigertor. The serum tumor necrosis fctor-α (TNF-α) nd interleukin-1β (IL-β) level were determined using ELISA. The opertions were ccording to the instructions of kits. Determintion of brin wter content Five rts were scrificed by decpittion, nd the left side of brin ws immeditely tken. After ccurtely weighing by electronic blnce, 8480 Int J Clin Exp Med 2018;11(8):
3 Rt brin tissue ws homogenized on the ice, followed by centrifuging t 4 C nd 3500 r/min for 15 min. The superntnt ws obtined. The superoxide dismutse (SOD) ctivity ws determined using xnthine oxidse method. The glutthione peroxidse (GSH-Px) ctivity ws determined using glutthione oxidtion method. The mlondildehyde (MDA) level ws determined using thiobrbituric cid method. The opertions were ccording to the instructions of kits. Determintion of cyclooxygense-2 nd 5-lipoxygense level in brin tissue Figure 1. Neurologicl deficit scores of rts in different groups. P < 0.01 compred with shm-opertion group; b P < 0.05 compred with I/R group; c P < 0.05 compred with low-dose DEX group. I/R, ischemireperfusion; DEX, dexmedetomidine. the brin tissue ws plced in 110 C constnttemperture drying box for 24 h to constnt weight (the difference of mss between two times of weighing ws less thn 0.2 mg). The dry brin tissue ws ccurtely weighed using the sme electronic blnce. The brin wter content (BWC) ws clculted s follows: BWC (%) = [(Wet mss - Dry mss)/wet mss] 100. Determintion of percentge of brin infrction re Brin tissue ws tken from five rts, nd ws plced in the -20 C refrigertor for 20 min. Then the sections of brin tissue were prepred. From the optic chism, 1 slice of brin tissue ws forwrd cut, nd 4 slices of brin tissue were bckwrd cut. The thickness of slice ws 2 mm. These 5 slices were put into 1% TTC solution, strictly voiding light, followed by incubtion t 37 C for 30 min. The slices were turned over every 15 min. The slices were shifted to 10% formldehyde for fixing for 3 h, followed by nlyzing using BI-2000 medicl imge nlysis system. The norml brin tissue fter stining of presented red, nd the infrction re presented white. The percentge of brin infrction re (BIA) ws clculted [11]. Determintion of oxidtive stress indexes in brin tissue Superntnt of brin tissue ws prepred. The protein content in the superntnt ws detected by the biuret method. The cyclooxygense- 2 (COX-2) nd 5-lipoxygense (5-LOX) level in brin tissue of rts were determined using ELISA. The contents of COX-2 nd 5-LOX in per grm of protein were clculted. Determintion of TGF-β1 nd phosphorylted Smd2/3 protein expression in brin tissue Expressions of TGF-β1 nd phosphorylted Smd2/3 (p-smd2/3) protein in brin tissue were determined by Western-blot method. The protein of brin tissue ws extrcted using RIPA lysis buffer (Sigm-Aldrich Corp., MO, USA) ccording to the mnufcturer s instructions. The protein concentrtion ws determined by Coomssie brillint blue method. The protein concentrtion ws djusted to 50 μg/μl. The 10% SDS-PAGE (Sigm-Aldrich Corp., MO, USA) ws performed for 4 h, then the seprted protein ws trnsferred to the PVDF membrne (Sigm-Aldrich Corp., MO, USA). After wshing the membrne with PBS (Sigm-Aldrich Corp., MO, USA) for 2 times, 15 min for ech time, l% BSA (Fuzhou Mixin Biotechnology Development Co., Ltd., Fuzhou, Chin) ws used to block the non-specific ntigen for 3 h. After blocking, the membrnes were incubted with primry ntibody overnight t 4 C, followed by wshing with PBS. The horserdish peroxidse-lbeled second ntibody ws dded, followed by incubtion t room temperture for 3 h. Visuliztion ws ccomplished by the enhnced chemiluminescence (ECL plus Western-blotting detection system, GE Helthcre Life Sciences, MA, USA). The intensity of bnds ws clculted using Imge J nlysis softwre (Europen Moleculr Biology Lbortory Inc., Oxford, UK). The primry ntibodies nd secondry ntibodies for TGF-β1 nd p-smd2/3 were provided by Shnghi Sngon Biologicl Engineering Technology nd Service Co., Ltd. (Shnghi, Chin). β-ctin (Sigm-Aldrich Corp., MO, USA) ws used s the internl reference. The reltive levels of TGF-β1 nd p-smd2/3 protein were 8481 Int J Clin Exp Med 2018;11(8):
4 Tble 1. BWC nd percentge of BIA of rts in different groups Group BWC (%) Percentge of BIA (%) Shm-opertion 77.91± I/R 80.75± ±5.45 Low-dose DEX 79.71± ±4.27 Middle-dose DEX 79.52±1.27 expressed s rtio of the opticl density to β-ctin for ech smple. Sttisticl nlysis All sttisticl nlysis ws crried out using SPSS 20.0 softwre (SPSS Inc., Chicgo, IL, USA). The dt were presented s men ± SD. The difference between two groups ws nlyzed using one-wy nlysis of vrince with SNK-q test. The reltionships between oxidtive dmge nd TGF-β1/Smd2/3 signling pthwy were ws investigted using Person correltion nlysis. P < 0.05 ws considered s sttisticlly significnt. Results Neurologicl deficit scores of rts 22.45±3.72,b,c High-dose DEX 78.62±1.23 b 21.21±3.45,b,c P < 0.01 compred with shm-opertion group; b P < 0.05 compred with I/R group; c P < 0.05 compred with low-dose DEX group. BWC, brin wter content; BIA, brin infrction re; I/R, ischemi-reperfusion; DEX, dexmedetomidine. Tble 2. Serum TNF-α nd IL-1β level of rts in different groups Group TNF-α (pg/ml) IL-1β (pg/ml) Shm-opertion ± ±2.01 I/R ± ±3.21 Low-dose DEX ±13.84,b 26.27±1.37 Middle-dose DEX ±13.22,b 22.39±3.04,b,c High-dose DEX ±15.02,b 20.52±3.28,b,c P < 0.01 compred with shm-opertion group; b P < 0.05 compred with I/R group; c P < 0.05 compred with low-dose DEX group. TNF-α, tumor necrosis fctor-α; IL-1β, interleukin- 1β; I/R, ischemi-reperfusion; DEX, dexmedetomidine. After 24 h from ischemi, compred with the shm-opertion group, the neurologicl deficit scores of rts in I/R, low-, middle- nd highdose DEX group were significntly incresed, respectively (P < 0.01). Compred with the I/R group, the neurologicl deficit scores in middlend high-dose DEX group were significntly decresed, respectively (P < 0.05) (Figure 1). BWC nd percentge of BIA of rts Compred with shm-opertion group, the BWC in I/R group ws significntly incresed (P < 0.05). Compred with I/R group, the BWC in high-dose DEX group ws significntly decresed (P < 0.05). In ddition, compred with shm-opertion group, the other four groups presented obvious brin infrction. Compred with I/R group, the percentges of BIA in middle- nd high-dose DEX group were significntly decresed, respectively (P < 0.05) (Tble 1). Serum TNF-α nd IL-1β level of rts As shown in Tble 2, the serum levels of TNF-α nd IL-1β in I/R group were significntly higher thn those in shm-opertion group, respectively (P < 0.05). Compred with I/R group, the TNF-α level in low-, middle- nd high-dose DEX group, nd the IL-1β level in middle- nd highdose DEX group were significntly decresed, respectively (P < 0.05). SOD nd GSH-Px ctivity nd MDA level in brin tissue of rts Tble 3 showed tht, the SOD nd GSH-Px ctivity in rt brin tissue of rts in I/R group were significntly lower thn those in shmopertion, respectively (P < 0.05), nd the MDA level in I/R group ws significntly higher thn tht in shm-opertion group (P < 0.05). Compred with I/R group, the SOD nd GSH-Px ctivity in high-dose DEX group were significntly incresed, respectively (P < 0.05), nd the MDA level in high-dose DEX group ws significntly decresed (P < 0.05). COX-2 nd 5-LOX level in brin tissue of rts As shown in Tble 4, the COX-2 nd 5-LOX level in rt brin tissue in I/R group were significntly higher thn those in shm-opertion, respectively (P < 0.05). Compred with I/R group, the COX-2 level in middle- nd high-dose DEX group ws significntly decresed, respectively (P < 0.05), nd 5-LOX level in high-dose DEX group ws significntly decresed (P < 0.05). TGF-β1 nd p-smd2/3 expression in brin tissue of rts Tble 5 showed tht, the TGF-β1 nd p-smd2/ 3 expression level in brin tissue of rts in I/R, low-, middle- nd high-dose DEX group were 8482 Int J Clin Exp Med 2018;11(8):
5 Tble 3. SOD nd GSH-Px ctivity nd MDA level in brin tissue of rts in different groups Group SOD (U/mg prot) GSH-Px (U/mg prot) significntly higher thn those in shm-opertion, respectively (P < 0.05). Compred with I/R group, the TGF-β1 level in middle- nd highdose DEX group ws significntly incresed, respectively (P < 0.05), nd the p-smd2/3 level in high-dose DEX group ws significntly incresed (P < 0.05). MDA (nmol/mg prot) Shm-opertion ± ± ±1.28 I/R ± ± ±1.46 Low-dose DEX ± ± ±1.16 Middle-dose DEX ±35.72 c 65.21± ±0.98 High-dose DEX ±33.61 b,c 74.47±10.28 b,c 7.89±1.01,b P < 0.01 compred with shm-opertion group; b P < 0.05 compred with I/R group; c P < 0.05 compred with low-dose DEX group. SOD, superoxide dismutse; GSH-Px, glutthione peroxidse; MDA, mlondildehyde; I/R, ischemi-reperfusion; DEX, dexmedetomidine. Tble 4. COX-2 nd 5-LOX level in brin tissue of rts in different groups Group COX-2 (pg/g prot) 5-LOX (pg/g prot) Shm-opertion 23.23± ±0.32 I/R 32.06± ±0.53 Low-dose DEX 30.12± ±0.56 Middle-dose DEX 27.36±3.26,b 3.74±0.41 High-dose DEX 26.32±3.23,b,c 3.34±0.42,b,c,d P < 0.01 compred with shm-opertion group; b P < 0.05 compred with I/R group; c P < 0.05 compred with low-dose DEX group; d P < 0.05 compred with middle-dose DEX group. COX-2, cyclooxygense-2; 5-LOX, 5-lipoxygense; I/R, ischemi-reperfusion; DEX, dexmedetomidine. Tble 5. TGF-β1 nd p-smd2/3 expression in brin tissue of rts in different groups Group TGF-β1/β-ctin p-smd2/3/ β-ctin Shm-opertion 0.23± ±0.02 I/R 0.87± ±0.06 Low-dose DEX 0.97± ±0.1 Middle-dose DEX 1.12±0.13,b,c 0.86±0.13 High-dose DEX 1.34±0.11,b,c,d 1.28±0.15,b,c,d P < 0.01 compred with shm-opertion group; b P < 0.05 compred with I/R group; c P < 0.05 compred with low-dose DEX group; d P < 0.05 compred with middledose DEX group. TGF-β1, trnsforming growth fctor-β1; p-smd2/3, phosphorylted Smd2/3; I/R, ischemireperfusion; DEX, dexmedetomidine. 0.05). The brin tissue MDA level ws not significntly correlted with brin tissue TGF-β1 or p-smd2/3 level (P > 0.05) (Tble 6). Discussion Reltionship between oxidtive dmge nd TGF-β1/Smd2/3 signling pthwy Person correltion nlysis showed tht, the brin tissue SOD nd GSH-Px ctivity were positively correlted with brin tissue TGF-β1 nd p-smd2/3 level, respectively (SOD with TGF-β1: r = 0.821, P < 0.01; SOD with p-smd2/3: r = 0.372, P < 0.05; GSH-Px with TGFβ1: r = 0.726, P < 0.01; GSH-Px with p-smd2/3: r = 0.235, P < Cerebrovsculr diseses re the frequentlyoccurring nd common diseses in clinic. In recent yers, the incidence rte, mortlity rte nd disbility rte of cerebrovsculr diseses re incresing, which hs become the min cuse of disbility nd deth in clinic. The ischemic cerebrovsculr disese is the most common, especilly the cerebrl I/R injury [1]. Clrifying the mechnism relted to cerebrl I/R injury hs been the focus of clinicl nd bsic reserch. In this study, the cerebrl I/R injury model of rts ws estblished, nd the protective effects of DEX pretretment on cerebrl I/R injury were investigted. Results showed tht, fter 24 h from ischemi, compred with the I/R group, the neurologicl deficit scores in middle- nd high-dose DEX group were significntly decresed, the BWC in highdose DEX group ws significntly decresed, the percentges of BIA in middle- nd highdose DEX group were significntly decresed. This indictes tht, the pretretment using DEX with certin dose cn mitigte the cerebrl I/R injury in rts. It is found tht, the production of oxygen free rdicls nd their lipid peroxidtion re one of the min mechnisms of I/R injury [12]. Under norml circumstnces, the body cn produce smll mount of free rdicls, but they re quickly eliminted by free rdicl scvenging system in the body, nd will not cuse dmge to the cells nd tissue. In cerebrl I/R ischemi, the function of free rdicl scvenging system declines. A lrge number of free rdicls re 8483 Int J Clin Exp Med 2018;11(8):
6 Tble 6. Reltionship between oxidtive dmge nd TGF-β1/Smd2/3 signling pthwy Index SOD GSH-Px MDA r P r P r P TGF-β < < > 0.05 p-smd2/ < < > 0.05 SOD, superoxide dismutse; GSH-Px, glutthione peroxidse; MDA, mlondildehyde; TGF-β1, trnsforming growth fctor-β1; p- Smd2/3, phosphorylted Smd2/3. produced, which rect with the polyunsturted ftty cids in the phospholipid on biologicl membrne, thus producing lrge mounts of toxic lipid peroxides. The toxicity of MDA is the highest mong the toxic lipid peroxides. The content of MDA cn directly reflect the degree of lipid peroxidtion, nd indirectly reflect the degree of cell injury [13]. SOD is the most importnt ntioxidnt enzyme nd free rdicl scvenger in the body. It cn cler the oxygen free rdicl nd terminte the chin rection of free rdicls, so s to protect the cell nd tissue [14]. GSH-Px is kind of importnt peroxide decomposition enzyme existing widely in the body. It cn mke the reduction of toxic peroxides into non-toxic hydroxyl compounds, thus protecting the structure nd function of cell membrne from the dmge of peroxides. The ctivity of GSH-Px cn ffect the ntioxidnt cpcity of the body [15]. The results of this study showed tht, the SOD nd GSH-Px ctivity in rt brin tissue of rts in I/R group were significntly lower thn those in shm-opertion, nd the MDA level in I/R group ws significntly higher thn tht in shm-opertion group. Compred with I/R group, the SOD nd GSH-Px ctivity in rt brin tissue in high-dose DEX group were significntly incresed, nd the MDA level in high-dose DEX group ws significntly decresed. This indictes tht, the lipid peroxidtion my be one of cuses for cerebrl I/R injury, nd DEX pretretment cn resist the oxidtive dmge, thus exerting protective effects. Inflmmtory rection plys n importnt role in the pthologicl process of cerebrl ischemi. TNF-α is one of the mjor inflmmtory cytokines, nd hs wide rnge of biologicl chrcteristics. Under norml circumstnces, TNF-α hs the nti-infection, nti-tumor nd tissue repir-promotion effects, which is beneficil to the body. Under the pthologicl stte, TNF-α is persistently relesed, which will cuse the tissue dmge [16]. IL-1β is strong inflmmtory cell chemokine nd immunederived cytokine. IL-1β cn cooperte with other cytokines to promote the ctivtion of B cells nd T cells [17]. In ddition, IL-1β cn induce the production of other inflmmtory meditors nd the expression of dhesion molecules, induce genertion of free rdicls nd excittory mino cids, nd initite the cscde rection of cytokines, eventully leding to neuronl inju- ry [18]. In the present study, compred with shm-opertion group, the serum levels of TNFα nd IL-1β in I/R group were significntly incresed. This is consistent with the result of previous reserches. Compred with I/R group, the TNF-α level in low-, middle- nd high-dose DEX group, nd the IL-1β level in middle- nd highdose DEX group were significntly decresed. This indictes tht, DEX pretretment cn decrese the TNF-α nd IL-1β level in the body, which my be relted to its protective effects. Inflmmtion is cscde response of inflmmtory cells nd inflmmtory fctors. It is complex dynmic regultion process which involves the COX-2 nd 5-LOX. COX-2 nd 5-LOX re the key enzymes in the pthwy in which the rchidonic cid is trnsformed into prostglndins nd leukotriene metbolites which ply n importnt role in promoting inflmmtion, oxidtion nd the occurrence nd growth of tumor [19]. A vriety of fctors including cytokinins, growth fctors nd tumor promoting fctors cn induce the expression of COX-2, which is involved in inflmmtion, prolifertion nd differentition of cells [20]. 5-LOX nd its metbolites cn inhibit the cell poptosis, nd promote the ngiogenesis [21]. Results of this study showed tht, the COX-2 nd 5-LOX level in rt brin tissue in I/R group were significntly higher thn those in shm-opertion. Compred with I/R group, the COX-2 level in middle- nd high-dose DEX group ws significntly decresed, nd 5-LOX level in high-dose DEX group ws significntly decresed. This indictes tht, the elevtion of COX-2 nd 5-LOX level in brin my be involved in the mechnism of cerebrl I/R injury in rts, nd DEX pretretment cn lower the COX-2 nd 5-LOX level, thus llevite the injury. TGF-β1 is ubiquitous cytokine, nd Smd2/3 is its receptor [9]. TGF-β1 is not expressed or wekly expressed in norml brin tissues. In 8484 Int J Clin Exp Med 2018;11(8):
7 cute cerebrl ischemic injury, TGF-β1 plys role in nti-oxidtion, preventing poptosis, nd modulting the inflmmtory response through phosphoryltion of downstrem fctor Smd2/ 3, thus regulting the microgli nd strocyte rection. The incresed expression of TGF-β in cerebrl I/R injury my be due to the stress of nerve cells nd glil cells induced by hypoxi nd hypoxi [22]. TGF-β1 firstly ctivtes the Smd2/3 pthwy, nd then ctivtes inflmmtory fctors COX-2 nd 5-LOX, thus regultes the inflmmtory response [23, 24]. Results of this study showed tht, the TGF-β1 nd p- Smd2/3 expression level in brin tissue of rts in I/R were significntly higher thn those in shm-opertion. This is consistent with the result of previous reserches. Compred with I/R group, the TGF-β1 level in middle- nd highdose DEX group ws significntly incresed, nd the p-smd2/3 level in high-dose DEX group ws significntly incresed. This indictes tht, DEX pretretment cn further increse the expressions of TGF-β1 nd p-smd2/3 in brin tissue, thus exerting protective effects. In conclusion, DEX preconditioning cn llevite the cerebrl I/R injury in rts. The possible mechnism my be relted to its resistnce of oxidtive dmge nd up-regultion of TGF-β1/ Smd2/3 signling pthwy in brin tissue. This study hs provided bsis for further clrifying the mechnism of DEX in prevention nd tretment of cerebrl I/R injury. However, the reltionship of oxidtive dmge nd TGF-β1/ Smd2/3 signling pthwy in cerebrl I/R injury nd other mechnisms in protective effects of DEX on cerebrl I/R injury need to be further studied. Disclosure of conflict of interest None. Address correspondence to: Dr. Ruiqing Sun, Tinjin Eye Hospitl, Tinjin Key Lbortory of Ophthlmology nd Vision Science, Tinjin Eye Institute, Clinicl College of Ophthlmology, Tinjin Medicl University, 4 Gnsu Rod, Heping District, Tinjin , Chin. Tel: ; E-mil: sunruiqing12@sin.com References [1] Lnier WL, Perkins WJ. Periopertive cerebrl nd myocrdil ischemi nd injury in surgicl ptients hving known crotid rtery stenosis. Anesthesiology 2014; 121: [2] Schller B, Grf R. Cerebrl ischemi nd reperfusion: the pthophysiologic concept s bsis for clinicl therpy. J Cereb Blood Flow Metb 2004; 24: [3] Husenloy DJ, Yellon DM. Myocrdil ischemireperfusion injury: neglected therpeutic trget. J Clin Invest 2013; 123: [4] Crollo DS, Nossmn BD, Rmdhyni U. Dexmedetomidine: review of clinicl pplictions. Curr Opin Anesthesiol 2008; 21: [5] Singh S, Singh A. Dexmedetomidine induced ctecholmine suppression in pheochromocytom. J Nt Sci Biol Med 2014; 5: [6] Hwng L, Choi IY, Kim SE, Ko IG, Shin MS, Kim CJ, Kim SH, Jin JJ, Chung JY, Yi JW. Dexmedetomidine meliortes intrcerebrl hemorrhgeinduced memory impirment by inhibiting poptosis nd enhncing brin-derived neurotrophic fctor expression in the rt hippocmpus. Int J Mol Med 2013; 31: [7] de Groot H, Ruen U. Ischemi-reperfusion injury: processes in pthogenetic networks: review. Trnsplnt Proc 2007; 39: [8] Wng JM, Hyshi T, Zhng WR, Ski K, Shiro Y, Abe K. Reduction of ischemic brin injury by topicl ppliction of insulin-like growth fctor- I fter trnsient middle cerebrl rtery occlusion in rts. Brin Res 2000; 859: [9] Brown KA, Pietenpol JA, Moses HL. A tle of two proteins: differentil roles nd regultion of Smd2 nd Smd3 in TGF-bet signling. J Cell Biochem 2007; 101: [10] Long EZ, Weinstein PR, Crlson S, Cummins R. Reversible middle cerebrl rtery occlusion without crniectomy in rts. Stroke 1989; 20: [11] Liou KT, Shen YC, Chen CF, Tso CM, Tsi SK. Honokiol protects rt brin from focl cerebrl ischemi-reperfusion injury by inhibiting neutrophil infiltrtion nd rective oxygen species production. Brin Res 2003; 992: [12] Alluri H, Ansooy Shji C, Dvis ML, Thrkn B. Oxygen-glucose deprivtion nd reoxygention s n in vitro ischemi-reperfusion injury model for studying blood-brin brrier dysfunction. J Vis Exp 2015: e [13] Lv L, Meng Q, Xu J, Gong J, Cheng Y, Jing S. Ligustrzine ttenutes myocrdil ischemi reperfusion injury in rts by ctivting the phosphtidylinositol 3-kinse/Akt pthwy. Ann Clin Lb Sci 2012; 42: [14] Djordjevic A, Spsic S, Jovnovic-Glovic A, Djordjevic R, Grubor-Ljsic G. Oxidtive stress in dibetic pregnncy: SOD, CAT nd GSH-Px ctivity nd lipid peroxidtion products. J Mtern Fetl Neontl Med 2004; 16: [15] Lin W, Wng W, Lio D, Chen D, Zhu P, Ci G, Kiyoshi A. Polyscchrides from enteromorph 8485 Int J Clin Exp Med 2018;11(8):
8 prolifer improve glucose metbolism in dibetic rts. J Dibetes Res 2015; 2015: [16] Ingegnoli F, Fntini F, Griffini S, Soldi A, Meroni PL, Cugno M. Anti-tumor necrosis fctor lph therpy normlizes fibrinolysis impirment in ptients with ctive rheumtoid rthritis. Clin Exp Rheumtol 2010; 28: [17] Scpigliti G, Ghir P, Brtlini M, Tglibue A, Borschi D. Differentil binding of IL-1 lph nd IL-1 bet to receptors on B nd T cells. FEBS Lett 1989; 243: [18] Wng P, Rothwell NJ, Pinteux E, Brough D. Neuronl injury induces the relese of pro-interleukin-1bet from ctivted microgli in vitro. Brin Res 2008; 1236: 1-7. [19] de Getno G, Donti MB, Cerletti C. Prevention of thrombosis nd vsculr inflmmtion: benefits nd limittions of selective or combined COX-1, COX-2 nd 5-LOX inhibitors. Trends Phrmcol Sci 2003; 24: [20] Smd TA, Moore KA, Spirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ. Interleukin-1bet-medited induction of Cox-2 in the CNS contributes to inflmmtory pin hypersensitivity. Nture 2001; 410: [21] Kim TY, Kim J, Choo HY, Kwon HJ. Inhibition of 5-lipoxygense suppresses vsculr endothelil growth fctor-induced ngiogenesis in endothelil cells. Biochem Biophys Res Commun 2016; 478: [22] Wng S, Yin J, Ge M, Di Z, Li Y, Si J, M K, Li L, Yo S. Trnsforming growth-bet 1 contributes to isoflurne postconditioning ginst cerebrl ischemi-reperfusion injury by regulting the c-jun N-terminl kinse signling pthwy. Biomed Phrmcother 2016; 78: [23] Eligini S, Brbieri SS, Arenz I, Tremoli E, Colli S. Prcrine up-regultion of monocyte cyclooxygense-2 by pltelets: role of trnsforming growth fctor-bet1. Crdiovsc Res 2007; 74: [24] Härle D, Rådmrk O, Smuelsson B, Steinhilber D. Clcitriol nd trnsforming growth fctor-bet upregulte 5-lipoxygense mrna expression by incresing gene trnscription nd mrna mturtion. Eur J Biochem 1998; 254: Int J Clin Exp Med 2018;11(8):
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