目的:观察鞘内注射P2Y13受体阻断剂MRS2211对慢性坐骨神经结扎(CCI)大鼠热痛阈及脊髓背角P2X4受体、P38MAPK表达变化的影响,探讨脊髓P2Y13受体在神经病理性疼痛中的作用。方法:成年SD大鼠随机分为3组(n=8):假手术组、CCI模型组(鞘内注...目的:观察鞘内注射P2Y13受体阻断剂MRS2211对慢性坐骨神经结扎(CCI)大鼠热痛阈及脊髓背角P2X4受体、P38MAPK表达变化的影响,探讨脊髓P2Y13受体在神经病理性疼痛中的作用。方法:成年SD大鼠随机分为3组(n=8):假手术组、CCI模型组(鞘内注射生理盐水)、MRS2211(100 pmol/L)处理组(CCI+鞘内注射MRS2211)。CCI模型组及MRS2211处理组大鼠均于鞘内置管7 d之后行慢性坐骨神经结扎,连续14 d鞘内注射生理盐水、MRS2211(100 pmol/L),2次/d。分别在术前1 d、术后第1,3,5,7,10,14 d测定给药1h后热缩足潜伏期(TWL);分别在第7,14 d处死大鼠,取脊髓背角做Western Blot检测,观察背角P2X4受体和P38MAPK的表达变化。结果:与假手术组相比,CCI组大鼠第1,3,5,7,10,14 d TWL明显缩短(P<0.01);与CCI组相比,MRS2211处理组大鼠术后第1,3,5,7,10,14 d TWL明显延长(P<0.05)。Western Blot结果观察到,与假手术组相比,CCI组第7 d P2X4受体表达上调(P<0.05),在第14 d P2X4受体表达上调更为明显(P<0.05);与假手术组相比,CCI组第7 d P38MAPK表达明显上调(P<0.05),在第14 d P38MAPK表达有所下降,但与假手术组相比仍具有统计学意义(P<0.05);与CCI组相比,MRS2211处理组大鼠第7 d后背角P38MAPK表达上调明显减弱(P<0.05),但在第14 d P38MAPK表达有所上升,但与CCI组相比仍具有统计学意义(P<0.05);此外,鞘内注射MRS2211并不影响CCI大鼠背角P2X4受体表达变化。结论:鞘内注射P2Y13受体拮抗剂MRS2211可以明显抑制CCI大鼠热痛敏症状和脊髓背角P38MAPK表达的上调,但并不影响CCI大鼠P2X4受体表达变化。这提示MRS2211可以抑制小胶质细胞P38MAPK活化但不影响小胶质细胞P2X4受体表达,这可能是其在脊髓水平发挥镇痛作用的机制之一。展开更多
Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surfa...Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.展开更多
文摘目的:观察鞘内注射P2Y13受体阻断剂MRS2211对慢性坐骨神经结扎(CCI)大鼠热痛阈及脊髓背角P2X4受体、P38MAPK表达变化的影响,探讨脊髓P2Y13受体在神经病理性疼痛中的作用。方法:成年SD大鼠随机分为3组(n=8):假手术组、CCI模型组(鞘内注射生理盐水)、MRS2211(100 pmol/L)处理组(CCI+鞘内注射MRS2211)。CCI模型组及MRS2211处理组大鼠均于鞘内置管7 d之后行慢性坐骨神经结扎,连续14 d鞘内注射生理盐水、MRS2211(100 pmol/L),2次/d。分别在术前1 d、术后第1,3,5,7,10,14 d测定给药1h后热缩足潜伏期(TWL);分别在第7,14 d处死大鼠,取脊髓背角做Western Blot检测,观察背角P2X4受体和P38MAPK的表达变化。结果:与假手术组相比,CCI组大鼠第1,3,5,7,10,14 d TWL明显缩短(P<0.01);与CCI组相比,MRS2211处理组大鼠术后第1,3,5,7,10,14 d TWL明显延长(P<0.05)。Western Blot结果观察到,与假手术组相比,CCI组第7 d P2X4受体表达上调(P<0.05),在第14 d P2X4受体表达上调更为明显(P<0.05);与假手术组相比,CCI组第7 d P38MAPK表达明显上调(P<0.05),在第14 d P38MAPK表达有所下降,但与假手术组相比仍具有统计学意义(P<0.05);与CCI组相比,MRS2211处理组大鼠第7 d后背角P38MAPK表达上调明显减弱(P<0.05),但在第14 d P38MAPK表达有所上升,但与CCI组相比仍具有统计学意义(P<0.05);此外,鞘内注射MRS2211并不影响CCI大鼠背角P2X4受体表达变化。结论:鞘内注射P2Y13受体拮抗剂MRS2211可以明显抑制CCI大鼠热痛敏症状和脊髓背角P38MAPK表达的上调,但并不影响CCI大鼠P2X4受体表达变化。这提示MRS2211可以抑制小胶质细胞P38MAPK活化但不影响小胶质细胞P2X4受体表达,这可能是其在脊髓水平发挥镇痛作用的机制之一。
基金Supported by An INSERM Avenir Grant (Martinez LO)ANR (Martinez LO and Lichtenstein L, #GENO 102 01)+1 种基金the French Association pour la Recherche sur le Cancer (Vantourout P and Champagne E, #3711-3913-4847)An INSERM young scientist fellowship (Pons V)
文摘Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.
