[Effects of Simvastatin on Diabetic Neuropathic Pain and Systematic Inflammation in Diabetic Rat Models and Their Molecular Mechanisms].

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.