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AMPA受体正向调节剂IDRA 21对幼年和老年恒河猴延迟匹配表现的影响。

The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys.

作者信息

Buccafusco Jerry J, Weiser Thomas, Winter Karin, Klinder Klaus, Terry Alvin V

机构信息

Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912, USA.

出版信息

Neuropharmacology. 2004 Jan;46(1):10-22. doi: 10.1016/j.neuropharm.2003.07.002.

Abstract

IDRA 21, a positive allosteric modulator of the glutamate AMPA receptor, produced a concentration-dependent inhibition of glutamate-induced inactivation of membrane currents in recombinant HEK 293 (human embryonic kidney) cells stably transfected with human GluR1/2 flip receptors. IDRA 21 doubled the charge transfer at a concentration of 70 microM, suggesting that this compound can facilitate excitatory neurotransmission via GluR 1/2 receptors. We next sought to exploit this mechanism of action by examining the drug as a potential cognition-enhancing agent in non-human primates. Oral administration of IDRA 21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMTS) task by young adult rhesus monkeys. The pattern of task improvement over the dose range 0.15-10 mg/kg was maintained to 48 hr after the single dose administration. For sessions run after administration of the individualized Best Dose of IDRA 21, task accuracy for Long delay (most difficult) trials was increased by 34% of vehicle. Animals were randomly assigned fixed doses of IDRA 21 to determine whether the positive mnemonic response could be maintained. The repeated doses were separated by 3 days, thus allowing for potential cumulative effects. IDRA 21 produced a gradual increase in task accuracy that was maintained on average above vehicle performance levels over an intermittent dosing schedule during a total period of 3 weeks. A separate group of aged monkeys (>20 y) were, as a group, impaired (during vehicle testing) in DMTS performance efficiency relative to the young cohort. IDRA 21 also improved task accuracy by aged rhesus monkeys over the same dose range, but the responses were not as robust as those exhibited by young animals. Aged subjects also appeared to be more individually sensitive to drug dose, and they exhibited shorter task latencies than did the young group. Despite these differences, when the individualized Best Doses were considered, IDRA 21 produced a robust increase in DMTS accuracy of up to 18% of vehicle for trials associated with Medium delay intervals. For both study groups, no obvious untoward effects of IDRA 21 were noted. These findings support the use of AMPA modulators like IDRA 21 in the treatment of cognitive/memory disorders, including those associated with aging. They also indicate that the drug is associated with long-term effects that could limit dosing regimens to one dose every two or three days. The nature of the protracted mnemonic effects produced by the compound remains to be elucidated.

摘要

IDRA 21是一种谷氨酸AMPA受体的正变构调节剂,它能浓度依赖性地抑制在稳定转染人GluR1/2翻转受体的重组HEK 293(人胚胎肾)细胞中谷氨酸诱导的膜电流失活。在浓度为70微摩尔时,IDRA 21使电荷转移增加了一倍,这表明该化合物可通过GluR 1/2受体促进兴奋性神经传递。接下来,我们试图通过将该药物作为非人类灵长类动物中潜在的认知增强剂来利用这一作用机制。口服IDRA 21使年轻成年恒河猴在延迟匹配样本(DMTS)任务中的表现有了非常显著的改善。在0.15 - 10毫克/千克剂量范围内,单次给药后任务改善模式持续到48小时。对于给予个体化最佳剂量的IDRA 21后进行的实验,长延迟(最难)试验的任务准确性比给予赋形剂时提高了34%。动物被随机分配固定剂量的IDRA 21,以确定阳性记忆反应是否能够维持。重复给药间隔为3天,从而允许潜在的累积效应。在总共3周的间歇性给药方案期间,IDRA 21使任务准确性逐渐提高,平均维持在高于赋形剂表现水平之上。相对于年轻组,另一组老年猴子(>20岁)在(赋形剂测试期间)DMTS表现效率受损。在相同剂量范围内,IDRA 21也提高了老年恒河猴的任务准确性,但反应不如年轻动物强烈。老年受试者似乎对药物剂量更具个体敏感性,并且他们的任务潜伏期比年轻组短。尽管存在这些差异,但考虑到个体化最佳剂量时,对于与中等延迟间隔相关的试验,IDRA 21使DMTS准确性大幅提高,最高可达赋形剂组的18%。对于两个研究组,均未观察到IDRA 21有明显的不良影响。这些发现支持使用像IDRA 21这样的AMPA调节剂来治疗认知/记忆障碍,包括与衰老相关的障碍。它们还表明该药物具有长期效应,这可能将给药方案限制为每两到三天一剂。该化合物产生的持久记忆效应的性质仍有待阐明。

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