辛伐他汀对糖尿病大鼠神经病理性疼痛和全身性炎症的影响及其分子机制
|
摘要
目的探讨辛伐他汀对糖尿病大鼠神经病理性疼痛及全身性炎症的影响及其机制。方法采用随机数表法将24只SD大鼠随机分为正常+介质(NV)组、糖尿病+介质(DV)组和糖尿病+辛伐他汀(DS)组3组,每组8只,通过腹腔注射链脲佐菌素建立糖尿病大鼠模型;建模后第7、14、21、28天记录各组大鼠的血糖、体质量、机械性刺激缩足阈值(PWMT)和热刺激缩足反射潜伏期(PWTL);建模后第28天取大鼠腰段脊髓背角和血清,Western blot法检测各组大鼠脊髓背角中晚期糖基化终末产物受体(RAGE)的表达,蛋白激酶B(AKT)、细胞外调节蛋白激酶(ERK)、p38和c-Jun氨基末端激酶(JNK)的磷酸化水平,ELISA法检测各组大鼠血清中氧化型低密度脂蛋白(ox-LDL)和白细胞介素1β(IL-1β)浓度。结果建模后第14、21、28天,DV组的PWMT值分别为(8.6±0.8)、(7.1±1.6)、(7.8±0.8)g,明显低于NV组的(12.0±0.9)(q=8.482,P=0.000)、(11.6±1.5)(q=11.309,P=0.000)、(11.7±1.5)g(q=9.801,P=0.000);建模后第21、28天,DS组的PWMT值分别为(9.4±1.4)(q=5.780,P=0.000)、(9.7±0.9)g(q=4.775,P=0.003),明显高于DV组。建模后第7、14、21、28天,各组间的PWTL值差异均无统计学意义(P均>0.05)。DV组大鼠脊髓背角中RAGE的表达量明显高于NV组(q=6.299,P=0.000)和DS组(q=2.891,P=0.025);DV组大鼠脊髓背角中AKT磷酸化水平明显高于NV组(q=8.915,P=0.000)和DS组(q=4.103,P=0.003)。DV组大鼠脊髓背角中ERK(q=8.313,P=0.000)、p38蛋白(q=2.965,P=0.022)和JNK(q=7.459,P=0.000)的磷酸化水平明显高于NV组;DS组脊髓背角中JNK的磷酸化水平明显低于DV组(q=3.866,P=0.004),ERK(q=1.987,P=0.122)和p38蛋白的磷酸化水平(q=1.260,P=0.375)与DV组差异无统计学意义。DV组大鼠的血清ox-LDL和IL-1β水平分别为(41.86±13.40)ng/ml和(108.16±25.88)pg/ml,均明显高于NV组的(24.66±7.87)ng/ml(q=3.606,P=0.003)和(49.32±28.35)pg/ml(q=5.079,P=0.000);也明显高于DS组的(18.81±5.62)ng/ml(q=4.833,P=0.000)和(32.73±11.73)pg/ml(q=6.510,P=0.000)。结论辛伐他汀可在一定程度上提高糖尿病大鼠的机械痛阈,其机制可能与抑制糖尿病大鼠脊髓背角中RAGE/AKT的激活和JNK的磷酸化有关。辛伐他汀还可以显著降低糖尿病大鼠血清中ox-LDL和IL-1β的含量,减轻全身性炎症反应。
Objective To investigate the effects of simvastatin on diabetic neuropathic pain and systematic inflammation in diabetic rats and explore their molecular mechanisms.Methods Totally 24 rats were equally randomized into the normal+vehicle(NV)group,diabetic+vehicle(DV)group,and diabetic+simvastatin(DS)group using the random number table.Streptozotocin(STZ)was used to establish the rat models of diabetes.Blood glucose,body mass,paw withdrawal mechanical threshold(PWMT),and paw withdrawal thermal latency(PWTL)in each group were observed on days 7,14,21,and 28 after STZ injection.On day 28 after STZ injection,rats were sacrificed,and the lumbar spinal dorsal horn and serum were collected.Western blotting was used to detect the expression of receptor for advanced glycation end products(RAGE)and the phosphorylation levels of protein kinase B(AKT),extracellular signal-regulated kinase(ERK),p38,and c-Jun N-terminal kinase(JNK)in the spinal dorsal horn of rats in each group.Enzyme-linked immunosorbent assay was performed to determine the serum concentrations of oxidized low density lipoprotein(ox-LDL)and interleukin-1β(IL-1β).Results On days 14,21 and 28 after STZ injection,the PWMT in DV group were(8.6 ± 0.8),(7.1 ± 1.6),and(7.8 ± 0.8)g respectively,which were significantly lower than(12.0 ± 0.9)(q=8.482,P =0.000),(11.6 ± 1.5)(q=11.309,P =0.000),and(11.7 ± 1.5)g(q=9.801,P =0.000)in NV group.The PWMT in DS group on days 21 and 28 were(9.4 ± 1.4)(q=5.780,P =0.000)and(9.7 ± 0.9)g(q=4.775,P =0.003),respectively,which were significantly improved comparing with those of DV group.On days 7,14,21,and 28,there were no significant differences in PWTL among these three groups(all P<0.05).The expression of RAGE in the spinal dorsal horn of DV group was significantly higher than those of NV group(q=6.299,P =0.000)and DS group(q=2.891,P =0.025).The phosphorylation level of AKT in the spinal dorsal horn of DV group was significantly higher than those of NV group(q=8.915,P=0.000)and DS group(q=4.103,P=0.003).The phosphorylation levels of ERK(q =8.313,P=0.000),p38(q =2.965,P =0.022),and JNK(q=7.459,P =0.000)in the spinal dorsal horn of DV group were significantly higher than those of NV group;the phosphorylation level of JNK in the spinal dorsal horn of DS group was significant lower than that of DV group(q=3.866,P =0.004);however,there were no significant differences in the phosphorylation levels of ERK(q=1.987,P=0.122)and p38(q=1.260,P=0.375)in the spinal dorsal horn between DS group and DV group.The serum concentrations of ox-LDL and IL-1β in DV group were(41.86 ± 13.40)ng/ml and(108.16 ± 25.88)pg/ml,respectively,which were significantly higher than those in NV group [(24.66 ± 7.87)ng/ml(q=3.606,P=0.003)and(49.32 ± 28.35)pg/ml(q=5.079,P=0.000)] and DS group [(18.81 ± 5.62)ng/ml(q=4.833,P =0.000)and(32.73 ± 11.73)pg/ml(q=6.510,P =0.000)].Conclusions Simvastatin can relieve the mechanical allodynia of diabetic rats possibly by inhibiting the activation of RAGE/AKT and the phosphorylation of JNK in the spinal dorsal horn.Simvastatin can also decrease the serum concentrations of ox-LDL and IL-1β in diabetic rats,which may contribute to the relief of systematic inflammation.
Objective To investigate the effects of simvastatin on diabetic neuropathic pain and systematic inflammation in diabetic rats and explore their molecular mechanisms.Methods Totally 24 rats were equally randomized into the normal+vehicle(NV)group,diabetic+vehicle(DV)group,and diabetic+simvastatin(DS)group using the random number table.Streptozotocin(STZ)was used to establish the rat models of diabetes.Blood glucose,body mass,paw withdrawal mechanical threshold(PWMT),and paw withdrawal thermal latency(PWTL)in each group were observed on days 7,14,21,and 28 after STZ injection.On day 28 after STZ injection,rats were sacrificed,and the lumbar spinal dorsal horn and serum were collected.Western blotting was used to detect the expression of receptor for advanced glycation end products(RAGE)and the phosphorylation levels of protein kinase B(AKT),extracellular signal-regulated kinase(ERK),p38,and c-Jun N-terminal kinase(JNK)in the spinal dorsal horn of rats in each group.Enzyme-linked immunosorbent assay was performed to determine the serum concentrations of oxidized low density lipoprotein(ox-LDL)and interleukin-1β(IL-1β).Results On days 14,21 and 28 after STZ injection,the PWMT in DV group were(8.6 ± 0.8),(7.1 ± 1.6),and(7.8 ± 0.8)g respectively,which were significantly lower than(12.0 ± 0.9)(q=8.482,P =0.000),(11.6 ± 1.5)(q=11.309,P =0.000),and(11.7 ± 1.5)g(q=9.801,P =0.000)in NV group.The PWMT in DS group on days 21 and 28 were(9.4 ± 1.4)(q=5.780,P =0.000)and(9.7 ± 0.9)g(q=4.775,P =0.003),respectively,which were significantly improved comparing with those of DV group.On days 7,14,21,and 28,there were no significant differences in PWTL among these three groups(all P<0.05).The expression of RAGE in the spinal dorsal horn of DV group was significantly higher than those of NV group(q=6.299,P =0.000)and DS group(q=2.891,P =0.025).The phosphorylation level of AKT in the spinal dorsal horn of DV group was significantly higher than those of NV group(q=8.915,P=0.000)and DS group(q=4.103,P=0.003).The phosphorylation levels of ERK(q =8.313,P=0.000),p38(q =2.965,P =0.022),and JNK(q=7.459,P =0.000)in the spinal dorsal horn of DV group were significantly higher than those of NV group;the phosphorylation level of JNK in the spinal dorsal horn of DS group was significant lower than that of DV group(q=3.866,P =0.004);however,there were no significant differences in the phosphorylation levels of ERK(q=1.987,P=0.122)and p38(q=1.260,P=0.375)in the spinal dorsal horn between DS group and DV group.The serum concentrations of ox-LDL and IL-1β in DV group were(41.86 ± 13.40)ng/ml and(108.16 ± 25.88)pg/ml,respectively,which were significantly higher than those in NV group [(24.66 ± 7.87)ng/ml(q=3.606,P=0.003)and(49.32 ± 28.35)pg/ml(q=5.079,P=0.000)] and DS group [(18.81 ± 5.62)ng/ml(q=4.833,P =0.000)and(32.73 ± 11.73)pg/ml(q=6.510,P =0.000)].Conclusions Simvastatin can relieve the mechanical allodynia of diabetic rats possibly by inhibiting the activation of RAGE/AKT and the phosphorylation of JNK in the spinal dorsal horn.Simvastatin can also decrease the serum concentrations of ox-LDL and IL-1β in diabetic rats,which may contribute to the relief of systematic inflammation.
引文
[1] 中华医学会糖尿病学分会.中国2型糖尿病防治指南(2017年版)[J].中华糖尿病杂志,2018,10(1):4- 67.DOI:10.3760/cma.j.issn.1674- 5809.2018.01.003.
[2] de Vries MA,Klop B,Eskes SA,et al.The postprandial situation as a pro-inflammatory condition[J].Clin Investig Arterioscler,2014,26(4):184- 192.DOI:10.1016/j.arteri.2014.02.007.
[3] Ma W,Liu Y,Wang C,et al.Atorvastatin inhibits CXCR7 induction to reduce macrophage migration[J].Biochem Pharmacol,2014,89(1):99- 108.DOI:10.1016/j.bcp.2014.02.014.
[4] Hayashi T,Hamakawa K,Nagotani S,et al.HMG CoA reductase inhibitors reduce ischemic brain injury of Wistar rats through decreasing oxidative stress on neurons[J].Brain Res,2005,1037(1- 2):52- 58.DOI:10.1016/j.brainres.2004.12.051.
[5] Pienaar IS,Schallert T,Hattingh S,et al.Behavioral and quantitative mitochondrial proteome analyses of the effects of simvastatin:implications for models of neural degeneration[J].J Neural Transm(Vienna),2009,116(7):791- 806.DOI:10.1007/s00702- 009- 0247- 4.
[6] Clunn GF,Sever PS,Hughes AD.Calcium channel regulation in vascular smooth muscle cells:synergistic effects of statins and calcium channel blockers[J].Int J Cardiol,2010,139(1):2- 6.DOI:10.1016/j.ijcard.2009.05.019.
[7] Shi XQ,Lim TK,Lee S,et al.Statins alleviate experimental nerve injury-induced neuropathic pain[J].Pain,2011,152(5):1033- 1043.DOI:10.1016/j.pain.2011.01.006.
[8] Xavier AM,Serafim KG,Higashi DT,et al.Simvastatin improves morphological and functional recovery of sciatic nerve injury in Wistar rats[J].Injury,2012,43(3):284- 289.DOI:10.1016/j.injury.2011.05.036.
[9] Chu LW,Chen JY,Yu KL,et al.Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model[J].Int J Immunopathol Pharmacol,2012,25(1):219- 230.DOI:10.1177/039463201202500124.
[10] Chiu CY,Yang RS,Sheu ML,et al.Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated,AMPK-down-regulated,Akt pathway[J].J Pathol,2016,238(3):470- 482.DOI:10.1002/path.4674.
[11] Qin Q,Niu J,Wang Z,et al.Heparanase induced by advanced glycation end products(AGEs)promotes macrophage migration involving RAGE and PI3K/AKT pathway[J].Cardiovasc Diabetol,2013,12:37.DOI:10.1186/1475- 2840- 12- 37.
[12] Sharma I,Tupe RS,Wallner AK,et al.Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy[J].Am J Physiol Renal Physiol,2018,314(1):F107-F121.DOI:10.1152/ajprenal.00434.2017.
[13] Wei JY,Liu CC,Ouyang HD,et al.Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib[J].Exp Neurol,2017,296:74- 82.DOI:10.1016/j.expneurol.2017.07.010.
[14] Liu W,Lv Y,Ren F.PI3K/Akt pathway is required for spinal central sensitization in neuropathic pain[J].Cell Mol Neurobiol,2018,38(3):747- 755.DOI:10.1007/s10571- 017- 0541-x.
[15] Zhang XS,Li X,Luo HJ,et al.Activation of the RAGE/STAT3 pathway in the dorsal root ganglion contributes to the persistent pain hypersensitivity induced by lumbar disc herniation[J].Pain Physician,2017,20(5):419- 427.
[16] Li X,Yang H,Ouyang Q,et al.Enhanced RAGE expression in the dorsal root ganglion may contribute to neuropathic pain induced by spinal nerve ligation in rats[J].Pain Med,2016,17(5):803- 812.DOI:10.1093/pm/pnv035.
[17] Guo JR,Wang H,Jin XJ,et al.Effect and mechanism of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain and spinal microglia in a rat model of chronic constriction injury[J].Oncotarget,2017,8(32):52923- 52934.DOI:10.18632/oncotarget.17629.
[18] Guan X,Fu Q,Xiong B,et al.Activation of PI3Kgamma/Akt pathway mediates bone cancer pain in rats[J].J Neurochem,2015,134(3):590- 600.DOI:10.1111/jnc.13139.
[19] Daulhac L,Mallet C,Courteix C,et al.Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms[J].Mol Pharmacol,2006,70(4):1246- 1254.DOI:10.1124/mol.106.025478.
[20] Lopes-Virella MF,Baker NL,Hunt KJ,et al.High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes[J].Diabetes Care,2012,35(6):1333- 1340.DOI:10.2337/dc11- 2040.
[21] Hunt KJ,Baker N,Cleary P,et al.Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes[J].Atherosclerosis,2013,231(2):315- 322.DOI:10.1016/j.atherosclerosis.2013.09.027.
[22] Lopes-Virella MF,Baker NL,Hunt KJ,et al.Oxidized LDL immune complexes and coronary artery calcification in type 1 diabetes[J].Atherosclerosis,2011,214(2):462- 467.DOI:10.1016/j.atherosclerosis.2010.11.012.
[23] Hong D,Bai YP,Gao HC,et al.Ox-LDL induces endothelial cell apoptosis via the LOX- 1-dependent endoplasmic reticulum stress pathway[J].Atherosclerosis,2014,235(2):310- 317.DOI:10.1016/j.atherosclerosis.2014.04.028.
[24] Wang YC,Hu YW,Sha YH,et al.Ox-LDL upregulates IL- 6 expression by enhancing NF-kappaB in an IGF2-dependent manner in THP- 1 macrophages[J].Inflammation,2015,38(6):2116- 2123.DOI:10.1007/s10753- 015- 0194- 1.
[25] Jiang Y,Wang M,Huang K,et al.Oxidized low-density lipoprotein induces secretion of interleukin- 1beta by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation[J].Biochem Biophys Res Commun,2012,425(2):121- 126.DOI:10.1016/j.bbrc.2012.07.011.
[26] Bhalla S,Singh N,Jaggi AS.Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats[J].Food Chem Toxicol,2015,80:32- 40.DOI:10.1016/j.fct.2015.02.016.
[27] Cameron N,Cotter M,Inkster M,et al.Looking to the future:diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models[J].Diabetes Res Clin Pract,2003,61(Suppl 1):S35-S39.
[28] Ii M,Nishimura H,Kusano KF,et al.Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy[J].Circulation,2005,112(1):93- 102.DOI:10.1161/CIRCULATIONAHA.104.511964.
[29] Ohsawa M,Aasato M,Hayashi SS,et al.RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice[J].Pain,2011,152(1):114- 122.DOI:10.1016/j.pain.2010.10.005.
[30] Daugherty DJ,Marquez A,Calcutt NA,et al.A novel curcumin derivative for the treatment of diabetic neuropathy[J].Neuropharmacology,2018,129:26- 35.DOI:10.1016/j.neuro-pharm.2017.11.007.
[31] 龚亚红.曲马多和对乙酰氨基酚联合应用在糖尿病大鼠神经病理性疼痛治疗中的作用[D].北京:万方硕博论文数据库,2007.
[32] Kiasalari Z,Rahmani T,Mahmoudi N,et al.Diosgenin ameliorates development of neuropathic pain in diabetic rats:Involvement of oxidative stress and inflammation[J].Biomed Pharmacother,2017,86:654- 661.DOI:10.1016/j.biopha.2016.12.068.
[33] Rondon LJ,Farges MC,Davin N,et al.L-arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration[J].Eur J Nutr,2018,57(7):2353- 2363.DOI:10.1007/s00394- 017- 1508-x.
[34] Huang YH,Hou SY,Cheng JK,et al.Pulsed radiofrequency attenuates diabetic neuropathic pain and suppresses formalin-evoked spinal glutamate release in rats[J].Int J Med Sci,2016,13(12):984- 991.DOI:10.7150/ijms.16072.
[35] Ji RR,Gereau RW 4h,Malcangio M,et al.MAP kinase and pain[J].Brain Res Rev,2009,60(1):135- 148.DOI:10.1016/j.brainresrev.2008.12.011.
[36] Rains JL,Jain SK.Oxidative stress,insulin signaling,and diabetes[J].Free Radic Biol Med,2011,50(5):567- 575.DOI:10.1016/j.freeradbiomed.2010.12.006.
[37] Arai H.Oxidative modification of lipoproteins[J].Subcell Biochem,2014,77:103- 114.DOI:10.1007/978- 94- 007- 7920- 4_9.
[2] de Vries MA,Klop B,Eskes SA,et al.The postprandial situation as a pro-inflammatory condition[J].Clin Investig Arterioscler,2014,26(4):184- 192.DOI:10.1016/j.arteri.2014.02.007.
[3] Ma W,Liu Y,Wang C,et al.Atorvastatin inhibits CXCR7 induction to reduce macrophage migration[J].Biochem Pharmacol,2014,89(1):99- 108.DOI:10.1016/j.bcp.2014.02.014.
[4] Hayashi T,Hamakawa K,Nagotani S,et al.HMG CoA reductase inhibitors reduce ischemic brain injury of Wistar rats through decreasing oxidative stress on neurons[J].Brain Res,2005,1037(1- 2):52- 58.DOI:10.1016/j.brainres.2004.12.051.
[5] Pienaar IS,Schallert T,Hattingh S,et al.Behavioral and quantitative mitochondrial proteome analyses of the effects of simvastatin:implications for models of neural degeneration[J].J Neural Transm(Vienna),2009,116(7):791- 806.DOI:10.1007/s00702- 009- 0247- 4.
[6] Clunn GF,Sever PS,Hughes AD.Calcium channel regulation in vascular smooth muscle cells:synergistic effects of statins and calcium channel blockers[J].Int J Cardiol,2010,139(1):2- 6.DOI:10.1016/j.ijcard.2009.05.019.
[7] Shi XQ,Lim TK,Lee S,et al.Statins alleviate experimental nerve injury-induced neuropathic pain[J].Pain,2011,152(5):1033- 1043.DOI:10.1016/j.pain.2011.01.006.
[8] Xavier AM,Serafim KG,Higashi DT,et al.Simvastatin improves morphological and functional recovery of sciatic nerve injury in Wistar rats[J].Injury,2012,43(3):284- 289.DOI:10.1016/j.injury.2011.05.036.
[9] Chu LW,Chen JY,Yu KL,et al.Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model[J].Int J Immunopathol Pharmacol,2012,25(1):219- 230.DOI:10.1177/039463201202500124.
[10] Chiu CY,Yang RS,Sheu ML,et al.Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated,AMPK-down-regulated,Akt pathway[J].J Pathol,2016,238(3):470- 482.DOI:10.1002/path.4674.
[11] Qin Q,Niu J,Wang Z,et al.Heparanase induced by advanced glycation end products(AGEs)promotes macrophage migration involving RAGE and PI3K/AKT pathway[J].Cardiovasc Diabetol,2013,12:37.DOI:10.1186/1475- 2840- 12- 37.
[12] Sharma I,Tupe RS,Wallner AK,et al.Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy[J].Am J Physiol Renal Physiol,2018,314(1):F107-F121.DOI:10.1152/ajprenal.00434.2017.
[13] Wei JY,Liu CC,Ouyang HD,et al.Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib[J].Exp Neurol,2017,296:74- 82.DOI:10.1016/j.expneurol.2017.07.010.
[14] Liu W,Lv Y,Ren F.PI3K/Akt pathway is required for spinal central sensitization in neuropathic pain[J].Cell Mol Neurobiol,2018,38(3):747- 755.DOI:10.1007/s10571- 017- 0541-x.
[15] Zhang XS,Li X,Luo HJ,et al.Activation of the RAGE/STAT3 pathway in the dorsal root ganglion contributes to the persistent pain hypersensitivity induced by lumbar disc herniation[J].Pain Physician,2017,20(5):419- 427.
[16] Li X,Yang H,Ouyang Q,et al.Enhanced RAGE expression in the dorsal root ganglion may contribute to neuropathic pain induced by spinal nerve ligation in rats[J].Pain Med,2016,17(5):803- 812.DOI:10.1093/pm/pnv035.
[17] Guo JR,Wang H,Jin XJ,et al.Effect and mechanism of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain and spinal microglia in a rat model of chronic constriction injury[J].Oncotarget,2017,8(32):52923- 52934.DOI:10.18632/oncotarget.17629.
[18] Guan X,Fu Q,Xiong B,et al.Activation of PI3Kgamma/Akt pathway mediates bone cancer pain in rats[J].J Neurochem,2015,134(3):590- 600.DOI:10.1111/jnc.13139.
[19] Daulhac L,Mallet C,Courteix C,et al.Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms[J].Mol Pharmacol,2006,70(4):1246- 1254.DOI:10.1124/mol.106.025478.
[20] Lopes-Virella MF,Baker NL,Hunt KJ,et al.High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes[J].Diabetes Care,2012,35(6):1333- 1340.DOI:10.2337/dc11- 2040.
[21] Hunt KJ,Baker N,Cleary P,et al.Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes[J].Atherosclerosis,2013,231(2):315- 322.DOI:10.1016/j.atherosclerosis.2013.09.027.
[22] Lopes-Virella MF,Baker NL,Hunt KJ,et al.Oxidized LDL immune complexes and coronary artery calcification in type 1 diabetes[J].Atherosclerosis,2011,214(2):462- 467.DOI:10.1016/j.atherosclerosis.2010.11.012.
[23] Hong D,Bai YP,Gao HC,et al.Ox-LDL induces endothelial cell apoptosis via the LOX- 1-dependent endoplasmic reticulum stress pathway[J].Atherosclerosis,2014,235(2):310- 317.DOI:10.1016/j.atherosclerosis.2014.04.028.
[24] Wang YC,Hu YW,Sha YH,et al.Ox-LDL upregulates IL- 6 expression by enhancing NF-kappaB in an IGF2-dependent manner in THP- 1 macrophages[J].Inflammation,2015,38(6):2116- 2123.DOI:10.1007/s10753- 015- 0194- 1.
[25] Jiang Y,Wang M,Huang K,et al.Oxidized low-density lipoprotein induces secretion of interleukin- 1beta by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation[J].Biochem Biophys Res Commun,2012,425(2):121- 126.DOI:10.1016/j.bbrc.2012.07.011.
[26] Bhalla S,Singh N,Jaggi AS.Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats[J].Food Chem Toxicol,2015,80:32- 40.DOI:10.1016/j.fct.2015.02.016.
[27] Cameron N,Cotter M,Inkster M,et al.Looking to the future:diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models[J].Diabetes Res Clin Pract,2003,61(Suppl 1):S35-S39.
[28] Ii M,Nishimura H,Kusano KF,et al.Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy[J].Circulation,2005,112(1):93- 102.DOI:10.1161/CIRCULATIONAHA.104.511964.
[29] Ohsawa M,Aasato M,Hayashi SS,et al.RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice[J].Pain,2011,152(1):114- 122.DOI:10.1016/j.pain.2010.10.005.
[30] Daugherty DJ,Marquez A,Calcutt NA,et al.A novel curcumin derivative for the treatment of diabetic neuropathy[J].Neuropharmacology,2018,129:26- 35.DOI:10.1016/j.neuro-pharm.2017.11.007.
[31] 龚亚红.曲马多和对乙酰氨基酚联合应用在糖尿病大鼠神经病理性疼痛治疗中的作用[D].北京:万方硕博论文数据库,2007.
[32] Kiasalari Z,Rahmani T,Mahmoudi N,et al.Diosgenin ameliorates development of neuropathic pain in diabetic rats:Involvement of oxidative stress and inflammation[J].Biomed Pharmacother,2017,86:654- 661.DOI:10.1016/j.biopha.2016.12.068.
[33] Rondon LJ,Farges MC,Davin N,et al.L-arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration[J].Eur J Nutr,2018,57(7):2353- 2363.DOI:10.1007/s00394- 017- 1508-x.
[34] Huang YH,Hou SY,Cheng JK,et al.Pulsed radiofrequency attenuates diabetic neuropathic pain and suppresses formalin-evoked spinal glutamate release in rats[J].Int J Med Sci,2016,13(12):984- 991.DOI:10.7150/ijms.16072.
[35] Ji RR,Gereau RW 4h,Malcangio M,et al.MAP kinase and pain[J].Brain Res Rev,2009,60(1):135- 148.DOI:10.1016/j.brainresrev.2008.12.011.
[36] Rains JL,Jain SK.Oxidative stress,insulin signaling,and diabetes[J].Free Radic Biol Med,2011,50(5):567- 575.DOI:10.1016/j.freeradbiomed.2010.12.006.
[37] Arai H.Oxidative modification of lipoproteins[J].Subcell Biochem,2014,77:103- 114.DOI:10.1007/978- 94- 007- 7920- 4_9.