The Antidepressant Effects Of Rosiglitazone On Rats With Depression Induced By Neuropathic Pain

Background and objective: More and more studies have reported that rosiglitazone,a PPAR gamma agonist,can release pain and prevent stress-induced depression.However,it is unclear whether rosiglitazone can prevent depression caused by neuropathic pain.This study was designed to investigate the antidepressant effect of rosiglitazone on rats with depression caused by neuropathic pain induced by L5 spinal nerve transection(SNT),and to explore the possible mechanism of action.Methods: Seventy-two male Sprague-Dawley rats(body weight 200-250 g)were randomly divided into sham operation group(sham operation + equivalent saline orally and intraperitoneal injection),L5 SNT group(L5 spinal nerve transection + equivalent saline orally and intraperitoneal injection),rosiglitazone group(L5SNT + rosiglitazone 20 mg/kg orally),Compound C group(AMPK inhibitor)(L5SNT + rosiglitazone 20 mg/kg orally + Compound C 1 mg/kg intraperitoneal injection),3-MA group(autophagy antagonist)(L5SNT + rosiglitazone 20 mg/kg orally + 3-MA 2 ?L intraperitoneal injection),morphine group(L5SNT + morphine 10 mg/kg orally).The drug intervention was started on the 7th day after surgery for 7 days.Behavioral tests such as Paw withdrawal pressure threshold test(PWPT),Open field test(OFT),Forced swimming test(FST),Sucrose preference test(SPT)and Tail suspension test(TST)were used to evaluate L5SNT-induced neuropathic pain symptoms and depression-like behavior.Then the rats were sacrificed and fresh hippocampus was harvested.Western blot was used to detect Relative protein expression levels of the Brain-derived neurotrophic factor(BDNF),Adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK),Beclin-1 and LC3 B proteins.The levels of TNF-? and IL-1? in hippocampus were detected by enzyme-linked immunosorbent assay(ELISA).The activity of Superoxide Dismutase(SOD)in hippocampus was detected by SOD activity detection kit(WST-8 method).The lipid oxidation level of hippocampus was detected by malondialdehyde(MDA)test kit.Results: 1.PWPT test results: On the 4th,6th,8th,10 th,12th and 14 th day after L5 SNT,the PWPT value of the L5 SNT group was significantly decreasd than that of the sham operation group(P<0.05).Compared with the L5 SNT group,the rosiglitazone group and the morphine group PWPT was significantly increased on the 8th,10 th,12th and 14 th postoperative day(P<0.05).Compared with the rosiglitazone group,the PWPT value of Compound C group and 3-MA group was decreased significantly(P<0.05).2.OFT test results: There were a significant difference in the crossing [F(5,66)= 73.75,P < 0.05]and rearing scores [F(5,66)= 65.65,P < 0.05]among the 6 groups of rats.The crossing and rearing scores of the L5 SNT group were significantly decreased than those of the sham operation group(P< 0.05).The crossing and rearing scores of the rosiglitazone group and the morphine group were significantly increased than those of the L5 SNT group(P < 0.05).The crossing and rearing scores of the Compound C group and 3-MA group were significantly decreased than those of the rosiglitazone group(P < 0.05).3.FST test results: There was a significant difference in the immobility time among the 6 groups of rats [F(5,66)= 40.93,P < 0.05].The immobility time of the L5 SNT group was significantly increased than that of the sham operation group(P < 0.05).The immobility time of the rosiglitazone group was significantly decreased than that of the L5 SNT group(P < 0.05).There was no significant difference between the L5 SNT operation group and morphine group,which was significantly increased than that in the rosiglitazone group(P < 0.05).The immobility time of the rats in the Compound C group and the 3-MA group was significantly increased than that in the rosiglitazone group(P< 0.05).4.SPT test results: There was a significant difference in the sucrose preference among the 6 groups [F(5,66)= 76.66,P < 0.05].The sucrose preference of the L5 SNT group was significantly decreased than that of the sham operation group(P<0.05);the sucrose preference of the rosiglitazone group was significantly increased than that of the L5 SNT group(P<0.05);There was no significant difference between the L5 SNT operation group and morphine group,which was significantly decreased than that in the rosiglitazone group(P < 0.05).The sucrose preference of the Compound C group and the 3-MA group was significantly deceased than that of the rosiglitazone group(P < 0.05).5.TST test results: There was a significant difference in the immobility time among the 6 groups of rats [F(5,66)= 71.68,P < 0.05].The immobility time of the L5 SNT group was significantly increased than that of the sham operation group(P < 0.05).The immobility time of the rosiglitazone group was significantly decresased than that of the L5 SNT group(P < 0.05).There was no significant difference between the sham operation group and morphine group,which was significantly increased than that in the rosiglitazone group(P < 0.05).The immobility time of the rats in the Compound C group and the 3-MA group was significantly increased than that in the rosiglitazone group(P< 0.05)6.Effects of rosiglitazone on the expression of AMPK,BDNF,Beclin-1 and LC3 B in rat hippocampus: One-way analysis of variance showed that There were significant differences in BDNF [F(2,15)= 15.1,P < 0.05],AMPK [F(2,15)= 17.89,P < 0.05],Beclin-1[F(2,15)= 30.91,P < 0.05],LC3 B [F(2,15)= 25.72,P < 0.05] among the sham group,the L5 SNT group,and the rosiglitazone group.The levels of BDNF,AMPK,Beclin-1 and LC3 B in the hippocampus of L5 SNT rats were significantly decreased than those in the sham group(P<0.05).While rosiglitazone significantly up-regulated BDNF,AMPK,Beclin-1,LC3 B level in the hippocampus of L5 SNT rats(P < 0.05).7.Effects of rosiglitazone on the levels of TNF-?,IL-1?,SOD and MDA in rat hippocampus: One-way analysis of variance showed that TNF-? [F(4,25)= 358.4,P < 0.05],IL-1? [F(4,25)= 115.3,P < 0.05],SOD [F(4,25)= 358.4,P < 0.05] and MDA [F(4,25)= 121.9,P < 0.05] were significant differences among the sham operation group,the L5 SNT group,the rosiglitazone group,the Compound C group,and the 3-MA group.The levels of TNF-?,IL-1?,SOD and MDA in the hippocampus of L5 SNT rats were significantly increased than those in the sham operation group(P < 0.05).After rosiglitazone treatment,the levels of TNF-?,IL-1?,MDA and SOD in the hippocampus of rats was significantly decreased than that of the L5 SNT group(P < 0.05).There was no significant difference between the Compound C group and the rosiglitazone group,while the levels of TNF-?,IL-1?,SOD and MDA in the hippocampus of the 3-MA group were significantly increased than those in the rosiglitazone group(P < 0.05).Conclusion:1.L5 SNT can induce a rat model of depression caused by neuropathic pain successfully.2.Rosiglitazone can alleviate the depressive behavior of rats caused by neuropathic pain.3.Rosiglitazone can promote the expression of AMPK,BDNF,Beclin-1 and LC3 B in hippocampus of rats with depression caused by neuropathic pain,and activate autophagy pathway.4.Rosiglitazone can alleviate the expression of IL-1?,TNF-?,SOD and MDA in hippocampus of rats with depression caused by neuropathic pain,and has anti-inflammatory and anti-oxidative effects.5.The antidepressant effect of rosiglitazone against neuropathic pain may be related to the promotion of AMPK,BDNF expression,reduction of IL-1?,TNF-?,SOD and MDA expression,and activation of autophagy pathway.