盐酸氟桂利嗪干预硝酸甘油致偏头痛大鼠的代谢组学研究
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摘要
目的采用代谢组学技术研究盐酸氟桂利嗪干预硝酸甘油致偏头痛模型大鼠的作用机制。方法采用皮下注射硝酸甘油致偏头痛大鼠模型,获取造模或给药后30、60、90 min 3个时间点脑组织中三叉神经颈髓复合体(trigeminocervical complex,TCC)部位及血清样本。以正常组大鼠作为对照,采用GC-TOF-MS分析各组大鼠血清及TCC部位的代谢状态。结果于同一时间点比较正常组、模型组及盐酸氟桂利嗪组,各组代谢状态存在差异。对比不同时间点的模型组或盐酸氟桂利嗪组,代谢状态随时间增加持续发生改变。与模型组相比,盐酸氟桂利嗪组血清中L-天冬酰胺、5-甲氧基色胺、α-乳糖等代谢物及脑组织TCC部位中磷酸乙醇酸、肌苷、甘油酸、D-葡萄糖等代谢物发生改变,主要涉及能量代谢通路、氨基酸代谢通路等。结论盐酸氟桂利嗪可能通过影响能量代谢、氨基酸代谢等改善硝酸甘油致偏头痛模型大鼠的代谢紊乱。
OBJECTIVE To study the mechanism of flunarizine in the nitroglycerin-induced migraine model rats by metabonomics. METHODS The nitroglycerin-induced migraine rat model was used and the brain samples and serum samples were obtained at30,60,and 90 min after model establishment or drug administration. After the isolation of TCC sites was performed,GC-TOF-MS was used to analyze the metabolic status of rat serum and TCC sites in different groups. RESULTS The metabolic status of the model group and the flunarizine group differed from that of the control group at the same time point. The metabolic state that compared with the model group or the flunarizine group at different time points changes continuously with time. Compared with those in the model group,L-asparagine,5-methoxytryptamine,α-lactose,ribitol,arachidonic acid,and glycerol in the serum samples and the phosphoglycolic acid,erythrose,inosine,glyceric acid,and D-glucose in the TCC samples were changed in the flunarizine group,indicating that the energy metabolism pathways and amino acid metabolic pathways were involved in the mechanism of flunarizine intervening migraine.CONCLUSION Flunarizine may improve metabolic disorders in nitroglycerin-induced migraine model rats by affecting energy metabolism and amino acid metabolism.
OBJECTIVE To study the mechanism of flunarizine in the nitroglycerin-induced migraine model rats by metabonomics. METHODS The nitroglycerin-induced migraine rat model was used and the brain samples and serum samples were obtained at30,60,and 90 min after model establishment or drug administration. After the isolation of TCC sites was performed,GC-TOF-MS was used to analyze the metabolic status of rat serum and TCC sites in different groups. RESULTS The metabolic status of the model group and the flunarizine group differed from that of the control group at the same time point. The metabolic state that compared with the model group or the flunarizine group at different time points changes continuously with time. Compared with those in the model group,L-asparagine,5-methoxytryptamine,α-lactose,ribitol,arachidonic acid,and glycerol in the serum samples and the phosphoglycolic acid,erythrose,inosine,glyceric acid,and D-glucose in the TCC samples were changed in the flunarizine group,indicating that the energy metabolism pathways and amino acid metabolic pathways were involved in the mechanism of flunarizine intervening migraine.CONCLUSION Flunarizine may improve metabolic disorders in nitroglycerin-induced migraine model rats by affecting energy metabolism and amino acid metabolism.
引文
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[14] MATHEW N T,KAILASAM J,SEIFERT T. Clinical recognition of allodynia in migraine[J]. Neurology,2004,63(5):848-852.
[15] CHEONG B S,CHOI D Y,CHO N H,et al. Modulation of corydalis tuber on glycine-induced ion current in acutely dissociated rat periaqueductal gray neurons[J]. Biol Pharm Bull,2004,27(8):1207-1211.
[2] UPADHYAY S K,ALI S M. Molecular recognition of flunarizine dihydrochloride andβcyclodextrin inclusion complex by NMR and computational approaches[J]. Chem Cent J,2018,12(1):33. doi:10. 1186/s13065-018-0395-4.
[3] LIU F,MA T,CHE X,et al. The efficacy of venlafaxine,flunarizine,and valproic acid in the prophylaxis of vestibular migraine[J]. Front Neurol, 2017, 8:524. doi:10. 3389/fneur. 2017. 00524.
[4] AKERMAN S,ROMERO-REYES M. Targeting the central projection of the dural trigeminovascular system for migraine prophylaxis[J]. J Cereb Blood Flow Metab, 2017, 1:271678X17729280. doi:10. 1177/0271678X17729280.
[5] JOHNSON C H,IVANISEVIC J,SIUZDAK G. Metabolomics:beyond biomarkers and towards mechanisms[J]. Nat Rev Mol Cell Biol,2016,17(7):451-459.
[6] RAMIREZ T,DANESHIAN M,KAMP H,et al. Metabolomics in toxicology and preclinical research[J]. ALTEX,2013,30(2):209-225.
[7] DEMARTINI C,TASSORELLI C,ZANABONI A M,et al. The role of the transient receptor potential ankyrin type-1(TRPA1)channel in migraine pain:evaluation in an animal model[J]. J Headache Pain,2017,18(1):94.
[8] FABJAN A,ZALETEL M,VAN B. Is there a persistent dysfunction of neurovascular coupling in migraine?[J]. Biomed Res Int,2015,2015:574186.
[9] ERDENER S E,DALKARA T. Modelling headache and migraine and its pharmacological[J]. Br J Pharmacol,2014,171(20):4575-4594.
[10] KARSAN N,PALETHORPE D,RATTANAWONG W,et al.Flunarizine in migraine-related headache prevention:results from200 patients treated in the UK[J]. Eur J Neurol,2018,25(6):811-817.
[11] KILIC K,KARATAS H,DONMEZ-DEMIR B,et al. Inadequate brain glycogen or sleep increases spreading depression susceptibility[J]. Annals Neurol,2018,83(1):61-73.
[12] COLOMBO B,SARACENO L,COMI G. Riboflavin and migraine:the bridge over troubled mitochondria[J]. Neurol Sci,2014,35(suppl 1):141-144.
[13] GASPARINI C F,GRIFFITHS L R. The biology of the glutamatergic system and potential role in migraine[J]. Int J Biomed Sci,2013,9(1):1-8.
[14] MATHEW N T,KAILASAM J,SEIFERT T. Clinical recognition of allodynia in migraine[J]. Neurology,2004,63(5):848-852.
[15] CHEONG B S,CHOI D Y,CHO N H,et al. Modulation of corydalis tuber on glycine-induced ion current in acutely dissociated rat periaqueductal gray neurons[J]. Biol Pharm Bull,2004,27(8):1207-1211.