| Objective:Post-stroke depression(PSD)damages the neurological function of patients with stroke,often accompanied by different degrees of mental disorders,which significantly reduces the quality of life.PSD is the result of multiple mechanisms.The inflammatory immune response is still a hot topic in the etiology of PSD.Salvia polyphenolic acid(SAFI)for injection can effectively improve depressive behavior,and has many pharmacological activities,including anti-inflammatory in vivo and vitro,antioxidant and neuroprotective effects,but its role in PSD is unknown.Abundantly expressed in the nervous system,tumor necrosis factor-like weak apoptosis inducer(TWEAK)in conjuction with its receptor fibroblast growth factor–inducible-14(Fn14)can activate the NF-kB pathway to promote inflammatory response,participating in the occurrence and development of PSD.In the present study,a PSD rat model was established by middle cerebral artery occlusion(MCAO)combined with chronic unpredictable mild stimulation(CUMS).Using this model,we investigate that whether SAFI can improve the inflammatory response in PSD rats through the TWEAK/Fn14-NF-kB signaling pathway and explore the possible inflammatory mechanism.Methods:Sixty male Sprague-Dawley(SD)rats which weighs approximately 290-310 g were randomly divided into a sham operation group(Control group,n = 12),a stroke group(MCAO group,n = 12),a MCAO + CUMS group(PSD group,n = 12),a MCAO + CUMS + SAFI 20 mg / kg group(PSD + SAFI 20 group,n = 12),a MCAO + CUMS + SAFI 30 mg / kg group(PSD + SAFI 30 group,n = 12).The model of acute ischemic stroke was established by the method of embolization with fishing line.After 3 days of postoperative recovery,the PSD group,PSD + SAFI 20 group and PSD + SAFI 30 group were given CUMS for 18 days to establish the PSD model.Then the PSD + SAFI 20 group and PSD + SAFI 30 group were injected intraperitoneally SAFI while the Control group,MCAO group and PSD group were admistrated intraperitoneally the corresponding doses of normal saline.During the period of establishing the model,rats in each group were regularly weighed and had behavior tests.After being finished the model,the serum and hippocampal brain tissues were collected.The serum TWEAK,IL-1? and TNF-? concentrations were measured by ELISA kits.The expression of Ionized calcium binding adaptor molecule 1(Iba-1,the biomarker of microglial activation)and aquaporins-4(AQP-4)in the hippocampus were determined using immumohistochemical staining.The protein expression levels of TWEAK,NF-kBp65,p-NF-kBp65,Iba-1 and AQP-4 were detected in all hippocampal tissues by Western blot.Results:(1)Weight: No difference was found between rats body weight in each group from pre-stress to week 1 of stress(P> 0.05).Compared with the PSD group,the body weight of the Control group and the MCAO group were decreased from the second week of stress to the end of the stress(P <0.05);With SAFI admistration,a drammatic increase was found in the body weight of the PSD + SAFI 20 group and the PSD + SAFI 30 group(P <0.01),and there was no difference with different doses of SAFI treatment(P> 0.05);(2)Behavioral test:(1)Sucrose preference test: Before stress,there was no difference in sucrose consumption between rats in each group(P >0.05);From the first week of stress to the end of stress,the sucrose consumption in the Control group and the MCAO group were increased when compared with the PSD group(P <0.05);With SAFI admistration,the sucrose consumption of the PSD + SAFI 20 group and the PSD + SAFI 30 group were increased significantly compared with the PSD group(P <0.01).Surprisely,the sucrose consumption of the low-dose SAFI group was increased more prominent(P <0.01);(2)Open field test: Compared to the Control and the MCAO group,the activity scores in the PSD group were reduced dramatically(P <0.05);However,they were improved with SAFI admistration(P <0.05),but there was no difference in the scores with different doses of SAFI(P> 0.05);(3)Forced swimming test: The immobility time of the PSD group was significantly increased when conpared with the Control group and MCAO group(P <0.01);With SAFI admistration,the immobility time was significantly shortened(P <0.01),and there was no difference with different doses of SAFI(P> 0.05);(3)Compared to the Control group,the serum level of TWEAK,IL-1?,and TNF-? in the MCAO and the PSD group were obviously increased(P <0.01);Compared to the MCAO group,there was no difference as regard to the serum IL-1? level(P> 0.05)while the serum TNF-? and TWEAK level were significantly increased(P <0.05)in the PSD group;Compared to the PSD group,the serum level of TWEAK and TNF-? in the PSD + SAFI 20 group and PSD + SAFI 30 group were obviously reduced(P <0.01),and there was no difference in expression with different doses of SAFI(P> 0.05).However,the serum level of IL-1? was only decreased in the PSD + SAFI 20 group(P <0.05);(4)Compared with the Control group,the Iba-1 and AQP-4 level in the hippocampal in the MCAO and the PSD group were dramatically enhanced(P <0.05);Compared to the MCAO group,the Iba-1 and AQP-4 level in the hippocampal in the PSD group were dramatically enhanced(P <0.01);Compared to the PSD group,the Iba-1 and AQP-4 level in the hippocampal of the PSD + SAFI 20 group and the PSD + SAFI 30 group were decreased(P <0.01),and the effect of low-dose SAFI was more significant than that of high-dose SAFI(P <0.01);(5)Compared with the Control group,the expressions of TWEAK,p-NF-kBp65,Iba-1,and AQP-4 proteins in the hippocampus of the MCAO and the PSD group were significantly increased(P <0.05);Compared with the MCAO group,the expressions of TWEAK,p-NF-kBp65,Iba-1,and AQP-4 were significantly increased(P <0.01);With SAFI admistration,the expressions of TWEAK,p-NF-kBp65,Iba-1 and AQP-4 proteins were somewhat significantly reduced(P <0.01),and the effect of low-dose SAFI was more significant than that of high-dose SAFI(P <0.05).Conclusion:1.SAFI can improve the depression behavior of rats after stroke,and it has obvious effect on sucrose preference test;2.SAFI can improve the inflammatory response in PSD rats.The mechanism may be achieved by inhibiting the TWEAK / Fn14-NF-kB signaling pathway to reduce the release of inflammatory cytokines;3.SAFI may also improve the inflammatory response of PSD by regulating the viability of microglia and protecting the permeability of the blood-brain barrier(BBB). |
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