Effects of long-term pioglitazone treatment on peripheral and central markers of aging.
Effects of long-term pioglitazone treatment on peripheral and central markers of aging.
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DOI：
10.1371/journal.pone.0010405
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发表时间：
2010-04-29
期刊：
影响因子：
3.7
通讯作者：
Thibault O
中科院分区：
文献类型：
--
作者：
Blalock EM;Phelps JT;Pancani T;Searcy JL;Anderson KL;Gant JC;Popovic J;Avdiushko MG;Cohen DA;Chen KC;Porter NM;Thibault O
噻唑烷二酮类药物(TZD)可激活过氧化物酶体增殖物激活受体γ(PPARγ)，临床上用于帮助2型糖尿病(T2 DM)患者恢复外周胰岛素敏感性。有趣的是，用TZDS长期治疗阿尔茨海默病(AD)小鼠模型也被证明可以减少AD的几个成熟的脑生物标志物，包括炎症、氧化应激和Aβ积聚。虽然TZD在AD模型中的作用有助于阐明其对AD患者潜在有益影响的机制，但TZD在正常衰老动物模型中的功能后果知之甚少。由于衰老是AD和T2 DM的共同危险因素，我们研究了TZD、吡格列酮在非病理条件下是否能改变脑老化。我们使用F344大鼠的衰老模型，并监测了行为、电生理和分子变量，以评估吡格列酮(PIO-Actos®a TZD)对几种外周(血液和肝脏)和中枢(海马区)衰老生物标志物的影响。从3个月或17个月龄开始，雄性大鼠接受4-5个月的治疗，要么是对照组，要么是含PIO的饮食(最终剂量约为2.3 mg/kg体重/天)。老年动物的钙依赖性后超极化显著减少，对长时程增强维持或学习记忆能力无明显影响。血胰岛素水平不随年龄增长而变化，但受PIO影响显著降低。最后，对海马区组织的微阵列分析和基于血清的多重细胞因子分析的组合显示，PIO不能逆转年龄相关性炎症增加。虽然目前的研究努力继续确定导致正常衰老期间认知功能进行性下降的潜在过程，但可用的医疗治疗仍然非常有限。由于TZD已被证明在T2 DM和AD等与年龄相关的疾病中具有益处，我们的研究旨在阐明PIO在正常衰老中的潜在有益作用。使用与临床相关的剂量和给药方法，长期PIO治疗能够钝化几个衰老指标，但显然既不影响与年龄相关的认知能力下降，也不影响与外周/中枢年龄相关的炎症信号增加。
Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARγ) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer's disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Aβ accumulation. While TZD's actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions. We used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos® a TZD) on several peripheral (blood and liver) and central (hippocampal) biomarkers of aging. Starting at 3 months or 17 months of age, male rats were treated for 4–5 months with either a control or a PIO-containing diet (final dose approximately 2.3 mg/kg body weight/day). A significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals, with no significant change in long-term potentiation maintenance or learning and memory performance. Blood insulin levels were unchanged with age, but significantly reduced by PIO. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory increases were not reversed by PIO. While current research efforts continue to identify the underlying processes responsible for the progressive decline in cognitive function seen during normal aging, available medical treatments are still very limited. Because TZDs have been shown to have benefits in age-related conditions such as T2DM and AD, our study was aimed at elucidating PIO's potentially beneficial actions in normal aging. Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling.
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影响因子：
4.8
作者：
Dasu, Mohan R.;Park, Samuel;Jialal, Ishwarlal
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