Sorwell K G, Urbanski H F
Departments of Neuroscience and Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
J Neuroendocrinol. 2013 Nov;25(11):1062-9. doi: 10.1111/jne.12064.
Similar to humans, rhesus macaques (Macaca mulatta) are large, long-lived diurnal primates, and show similar age-related changes in the secretion of many steroid hormones, including oestradiol, testosterone, cortisol and dehydroepiandrosterone (DHEA). Consequently, they represent a pragmatic animal model in which to examine the mechanisms by which these steroidal changes contribute to perturbed sleep-wake cycles and cognitive decline in the elderly. Using remote serial blood sampling, we have found the circulating levels of DHEA sulphate, as well as oestradiol and testosterone, decline markedly in old monkeys. Furthermore, using the real-time polymerase chain reaction, we have shown that the genes for the enzymes associated with the conversion of DHEA to oestradiol and testosterone (3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, and aromatase) are highly expressed in brain areas associated with cognition and behaviour, including the hippocampus, prefrontal cortex and amygdala. Taken together, these findings suggest that the administration of supplementary DHEA in the elderly may have therapeutic potential for cognitive and behavioural disorders, although with fewer negative side effects outside of the central nervous system. To test this, we have developed a novel steroid supplementation paradigm for use in old animals; this involves the oral administration of DHEA and testosterone at physiologically relevant times of the day to mimic the circadian hormone patterns observed in young adults. We are currently evaluating the efficacy of this steroid supplementation paradigm with respect to reversing age-associated disorders, including perturbed sleep-wake cycles and cognitive decline, as well as an impaired immune response.
与人类相似，恒河猴（猕猴）是大型、长寿的昼行性灵长类动物，在包括雌二醇、睾酮、皮质醇和脱氢表雄酮（DHEA）在内的许多甾体激素分泌方面表现出类似的年龄相关变化。因此，它们代表了一种实用的动物模型，可用于研究这些甾体变化导致老年人睡眠-觉醒周期紊乱和认知能力下降的机制。通过远程连续采血，我们发现老年猴子体内硫酸脱氢表雄酮以及雌二醇和睾酮的循环水平显著下降。此外，利用实时聚合酶链反应，我们发现与脱氢表雄酮转化为雌二醇和睾酮相关的酶（3β-羟基类固醇脱氢酶、17β-羟基类固醇脱氢酶和芳香化酶）的基因在与认知和行为相关的脑区高度表达，包括海马体、前额叶皮质和杏仁核。综上所述，这些发现表明，在老年人中补充脱氢表雄酮可能对认知和行为障碍具有治疗潜力，尽管在中枢神经系统之外的副作用较少。为了验证这一点，我们开发了一种用于老年动物的新型甾体补充模式；这包括在一天中生理相关的时间口服脱氢表雄酮和睾酮，以模拟在年轻人中观察到的昼夜激素模式。我们目前正在评估这种甾体补充模式在逆转与年龄相关的疾病方面的疗效，包括睡眠-觉醒周期紊乱、认知能力下降以及免疫反应受损。
