PPARγ agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes

OBJECTIVE Pioglitazone,known as a peroxisome proliferator-activated receptor γ(PPARγ) agonist,is used to treat type 2 diabetes(T2DM).T2DM has been associated with reduced performance on numerous domains of cognitive function.Here,we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion,namely high-fat diet(HFD) streptozotocin(STZ)-induced diabetic mice.METHODS ICR mice were fed an HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks.The diabetic mice were orally administered with pioglitazone(9,18 mg·kg-1) for 4-5 weeks.Y-maze test and Morris water maze test(MWM) were employed for testing learning and memory.Serum glucose,serum insulin,serum triglyceride,brain amyloid peptide-β(Aβ),brain β-site amyloid precursor protein cleaving enzyme(BACE1),brain nuclear factor κB(NF-κB),brain receptor for advanced glycation end products(RAGE) were also tested.RESULTS The STZ/HFD diabetic mice,characterized by hyperglycemia,hyperlipemia and hypoinsulinemia,performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of Aβ40/Aβ42,BACE1,NF-κB,and RAGE in brain.Treatment of PPARγ agonist,pioglitazone,significantly reversed diabetes-induced impairment of learning and memory behavior,which is involved in decreases of Aβ40/Aβ42 via inhibition of NF-κB,BACE1 and RAGE in brain as well as attenuation of hyperglycemia,hyperlipemia and hypoinsulinemia.CONCLUSION It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.     

吡格列酮抑制人胶质瘤SNB19细胞生长及诱导其凋亡

目的 探讨吡格列酮(PGZ)对人神经胶质瘤细胞株SNB19增殖和凋亡的影响及其机制。方法 用MTT、流式细胞仪、Tunel和Western blot分析技术。结果 吡格列酮能够抑制SNB19细胞增殖和诱导其凋亡,同时伴有Bax表达的增高和pRb、Bcl-2表达的降低。结论 PGZ能够在体外抑制胶质瘤SNB19细胞的生长并诱导其凋亡,提示PGZ有可能成为一种新的治疗胶质瘤药物。     

吡格列酮对脂多糖引起的大鼠海马有丝分裂原激活蛋白激酶p38信号传导通路的影响

<正>吡格列酮(pioglitazone,Pio)能抑制脂多糖诱导的原代培养的星形胶质细胞炎症因子的释放[1],对抗谷氨酸诱导的神经细胞损伤[2],也有研究显示Pio通过抑制p38MAPK信号传导通路抑制LPS诱导的小胶质细胞炎症反应[3]。但关于Pio对大鼠脑内炎症反应的抑制作用是否与p38MAPK信号传导通路有关目前尚未见报道,本研究通过大鼠脑室内注     

盐酸吡格列酮胶囊的人体相对生物利用度

目的:评价盐酸吡格列酮胶囊的人体生物等效性.方法:18名男性健康志愿者随机交叉口服受试制剂盐酸吡格列酮胶囊和参比制剂盐酸吡格列酮片30 mg,采用反相高效液相色谱-紫外检测法测定血浆药物浓度.结果:受试制剂和参比制剂的Tmax分别为(1.9±0.5),(2.1±0.6)h;Cmax分别为(1 480.0±234.9),(1 436.5±206.4)μg·L-1;t1/2β分别为(6.0±1.4),(6.4±1.4)h;AUC0→24分别为(8 893.6±1979.9),(8893.2±1913.8)μg·L-1·h;AUC0→∞.分别为(9 706.4±2 394.5),(9928.3±2512.4)μg·L-1·h,盐酸吡格列酮胶囊的相对生物利用度为(101.4±17.5)%.结论:经统计学分析,盐酸吡格列酮胶囊与盐酸吡格列酮片具有生物等效性.     

吡格列酮联合二甲双胍治疗2型糖尿病效果的meta分析

目的：系统评价吡格列酮联合二甲双胍治疗2型糖尿病的疗效和安全性。方法：检索Cochrane Library、PubMed、EMbase、CBM、CNKI、VIP、WanFang Data共7个数据库,收集主题为吡格列酮联合二甲双胍治疗2型糖尿病的文献;根据排除标准筛选确定最终文献,并根据Cochrane手册评价纳入研究质量,最后提取结局指标数据运用RevMan 5.2进行meta分析。结果：纳入15篇文献,包含T2DM患者1881例,其中联合组941例,二甲双胍单用组940例。结果显示,联合组更能有效降低血糖和糖化血红蛋白,改善胰岛素及血脂,但体质指数无显著差异;不良反应方面,两组在胃肠道事件发生率方面无显著差异;但联合组的水肿发生率略高于单用组。结论：联合用药效果优于二甲双胍单用,且安全性良好。     

有限采样法估算口服吡格列酮制剂的生物等效性

目的建立有限采样法模型估算盐酸吡格列酮(PGT)制剂的生物等效性。方法以健康志愿者口服PGT参比制剂后的血药浓度数据建模，有限采样法建立多元回归模型估算C_max和AUC_0-t。模型的内部和外部验证分别以Jackknife法和Monte Carlo法生成的模拟数据进行。选择最佳模型进行生物等效性评价。结果给药后1.5 h和2.5 h血药浓度(C_1.5和C_2.5)估算C_max的准确性较好，C_1.5和C₉估算AUC_0-t的准确性较好，平均预测误差<5%、平均绝对误差<9%，参数预测误差超过±20％的样本数<5%。生物等效性评价结果与经典法一致。结论有限采样法估算口服PGT制剂的生物等效性是可行的，为生物等效性研究提供新的思路和方法。     

Pioglitazone opposes neurogenic vascular dysfunction associated with chronic hyperinsulinaemia

BACKGROUND AND PURPOSE: We previously demonstrated that chronic hyperinsulinaemia induced by drinking high levels of fructose augments adrenergic nerve-mediated vasoconstriction and suppresses vasodilatation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. In this study, the effects of pioglitazone on vascular responses induced by stimulation of adrenergic nerves, CGRPergic nerves and vasoactive agents were investigated in pithed rats given 15% fructose solution to drink (FDR). EXPERIMENTAL APPROACH: To assess the effect of pioglitazone on the altered vascular responsiveness in the hyperinsulinaemic state in vivo, changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin II and CGRP were evaluated in pithed control rats and FDR either untreated or treated with pioglitazone.Key results: In the pithed FDR, vasoconstrictor responses to SCS and to injections of noradrenaline and angiotensin II were significantly greater than those of pithed control rats. In pithed FDR with artificially increased blood pressure and blockade of the autonomic ganglia, the vasodilator responses to SCS and CGRP injection were significantly smaller than those of pithed control rats. Oral administration of pioglitazone to FDR for two weeks markedly decreased plasma levels of insulin, triglycerides and blood glucose. In FDR pioglitazone diminished the augmented vasoconstrictor responses to SCS, noradrenaline and angiotensin II, and ameliorated the decrease in vasodilator responses to SCS. CONCLUSIONS AND IMPLICATIONS: The present results suggest that pioglitazone improves not only insulin resistance, but also the dysfunctions in vascular control regulated by adrenergic and CGRPergic nerves in the hyperinsulinaemic state.     

丹芪参杞降糖汤和盐酸吡格列酮联合治疗糖尿病疗效观察

目的:探讨丹芪参杞降糖汤和盐酸吡格列酮联合治疗糖尿病的临床疗效。方法:选择我院2009年6月～2011年10月采用丹芪参杞降糖汤联合盐酸吡格列酮治疗的72例糖尿病患者作为观察组,另选择同期单纯应用盐酸吡格列酮治疗的72例患者为对照组,对两组患者的临床资料进行回顾性分析,比较两组患者临床治疗总有效率及不良反应发生率。结果:治疗3个月后,观察组总有效率为94.44%,明显高于对照组的81.94%;差异有统计学意义(P0.05)。两组不良反应率比较,差异无统计学意义(P0.05)。结论:联合应用丹芪参杞降糖汤和盐酸吡格列酮治疗糖尿病疗效明显,优于单纯西药治疗。     

吡格列酮对老年糖耐量低减患者内皮功能的影响

目的:探讨吡格列酮对老年糖耐量低减患者（IGT）内皮功能的影响。方法：选取56例老年糖耐量正常者（NGT）及60例老年糖耐量低减患者（IGT），将IGT患者随机分两组进行治疗，每组30例，疗程为6月。非药物干预组，仅改变生活模式；综合治疗组，生活模式改变基础上服吡格列酮（每天30 mg），观察内皮依赖舒张功能（EDD）变化。结果：EDD在IGT患者明显低于NGT个体；在非药物干预组和综合治疗组EDD治疗前无明显差别，6月后EDD在非药物干预组无明显改变，在综合治疗组明显升高（P＜0.05），EDD变化值与糖化血红蛋白（HbA1C）变化值 、胰岛素抵抗指数（HOMA-IR）变化值、高敏感C反应蛋白（HsCRP）变化值呈负相关。结论：在改变生活模式基础上，吡格列酮可进一步改善老年IGT患者内皮功能，其机制可能是通过降低血糖、改善胰岛素抵抗，抑制炎症反应等。     

噻唑烷二酮类药物对氯米芬抵抗型的多囊卵巢综合征不孕患者治疗有效性的Meta分析

目的:系统评价罗格列酮、吡格列酮等噻唑烷二酮类药物(TZD)治疗氯米芬(CC)抵抗型多囊卵巢综合征(PCOS)不孕患者的疗效。方法:计算机检索Pubmed、Embase、Cochrane Library、Web of Science、CNKI、维普、生物医学文献、万方等数据库,检索时间截止至2015年1月。由两名评价者按照纳入与排除标准独立筛选文献、提取资料并评价纳入研究的方法学质量后,采用Rev Man 5.3软件进行Meta分析。结果:最终纳入4个随机对照研究,222例CC抵抗型PCOS不孕患者。Meta分析结果表明,TZD组在排卵率、妊娠率、成熟卵泡数、改善卵泡刺激素(FSH)、黄体生成素(LH)、睾酮(T)方面均优于对照组,其中提高排卵率[MD=2.14;95%CI(1.16,3.95),P=0.02]、妊娠率[MD=2.02;95%CI(1.14,3.58),P=0.02]、增加成熟卵泡数[MD=0.82;95%CI(0.61,1.04),P<0.01]及降低LH值[MD=-1.18;95%CI(-1.76,-0.60),P<0.01]等4个结局指标的两组间差异具有统计学意义。结论:对于生育要求较强、经济条件好且胰岛素抵抗较严重的CC抵抗型PCOS患者,可首选TZD预治疗。