低剂量吡格列酮通过非过氧化物酶体增殖物激活受体依赖途径保护创伤性脑损伤

Low-dose pioglitazone protects traumatic brain injury in rats through PPARγ-independent pathway

目的探讨低剂量吡格列酮(Pio)是否通过非过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor gamma,PPARγ)依赖途径对创伤性脑损伤发挥神经保护作用。方法 6周龄SD雄性大鼠30只分为假致伤组、TBI组、PPARγ拮抗剂T0070907 1.0 mg/kg组、低剂量Pio 1.0 mg/kg组、T0070907 1.0 mg/kg+Pio 1.0 mg/kg组、大剂量Pio 10.0 mg/kg组,除假致伤组外均作Feeney自由落体重物锤打击。采用HE染色、尼氏染色及TUNEL染色观察实验大鼠脑组织细胞损伤、尼氏体脱失及神经细胞凋亡程度,定量PCR技术检测PPARγmRNA表达水平。结果 1低剂量吡格列酮能减轻创伤性脑损伤后细胞损伤,Pio 1.0组、Pio 10.0组细胞损伤率明显低于T0070907组和TBI组(P<0.05),Pio 1.0组与Pio 10.0组细胞损伤率无统计学差异(P>0.05);2低剂量吡格列酮能减轻创伤性脑损伤后尼氏体脱失,Pio 1.0组、Pio 10.0组尼氏体脱失率明显低于T0070907组和TBI组(P<0.05),Pio 1.0组与Pio 10.0组尼氏体脱失率无统计学差异(P>0.05);3低剂量吡格列酮能减轻创伤性脑损伤后细胞凋亡,Pio 1.0组、Pio 10.0组凋亡细胞数明显少于T0070907组和TBI组(P<0.05),Pio 1.0组与Pio 10.0组凋亡细胞数无统计学差异(P>0.05);4大剂量Pio 10.0组PPARγmRNA表达最多,与低剂量Pio 1.0组有统计学差异(P<0.05)。结论低剂量吡格列酮可通过非PPARγ依赖途径对创伤性脑损伤发挥神经保护作用。

Objective To determine whether low-dose pioglitazone exerts its neuroprotective effect through peroxisome proliferator-activated receptor gamma（ PPARγ）-independent pathway after traumatic brain injury（ TBI）. Methods Thirty 6-week-old male SD rats were randomly divided into sham-injured group,TBI group,T0070907（ antagonist of PPARγ,1. 0 mg / kg） group,low-dose pioglitazone group（ 1. 0 mg / kg）,T0070907（ 1. 0 mg / kg） and pioglitazone（ Pio 1. 0 mg / kg） co-administrated group,high-dose Pio group（ 10. 0 mg /kg）. TBI models were established by Feeney free falling method except sham-injured group. HE,Nissl,TUNEL staining were used to observe the cellular changes,the loss of Nissl body,and the apoptosis of neuronal cells in the brain tissue of experimental rats,and the expression of PPARγ in brain tissue was detected by RT-PCR. Results（ 1） Cellular damage caused by TBI could be reduced after treatment of lowdose Pio; damage rate of cell in Pio 1. 0 group and Pio 10. 0 group were less than in T0070907 group and TBI group（ P 〈 0. 05）,while was the same in Pio 1. 0 group and Pio 10. 0 group（ P 〉 0. 05）.（ 2） Loss of nissl bodies caused by TBI was reduced after treatment of low-dose Pioglitazone; loss rates of nissl body in Pio1. 0group and Pio10. 0 group were less than in T0070907 group and TBI group（ P 〈 0. 05）,while was the same in Pio 1. 0 group and Pio 10. 0 group（ P 〉 0. 05）.（ 3） Cell apoptosis induced by TBI was reduced after treatment of low-dose Pio; apoptosis cell number in Pio 1. 0 group and Pio 10. 0 group was less than in T0070907 group and TBI group（ P 〈 0. 05）,while was the same in Pio 1. 0 group and Pio10. 0 group（ P 〉0. 05）.（ 4） PPARγ mRNA expressed highest in Pio 10. 0 group,which had significant difference with Pio1. 0 group（ P 〈 0. 05）. Conclusion Low-dose Pio exerts neuroprotection through the PPARγ-independent pathway after TBI,which plays an important part on treating TBI.