Promising Drug Candidate Reverses Age-Related Memory Loss in Mice
ScienceDaily (Oct. 13, 2010) — Researchers at the University of Edinburgh report a new experimental compound that can improve memory and cognitive function in aging mice. The compound is being investigated with a view to developing a drug that could slow the natural decline in memory associated with aging.
A new experimental compound that can improve memory and cognitive function in aging mice, researchers report. (Credit: iStockphoto)
With support from a Wellcome Trust Seeding Drug Discovery award, the team has identified a preclinical candidate that they hope to take into human trials within a year.
Many people find they become more forgetful as they get older and we generally accept it as a natural part of the aging process. Absent mindedness and a difficulty to concentrate are not uncommon, it takes longer to recall a person's name, and we can't remember where we left the car keys. These can all be early signs of the onset of dementia, but for most of us it's just part of getting old.
Such memory loss has been linked with high levels of 'stress' steroid hormones known as glucocorticoids which have a deleterious effect on the part of the brain that helps us to remember. An enzyme called 11beta-HSD1 is involved in making these hormones and has been shown to be more active in the brain during aging.
In a study published in the Journal of Neuroscience, the team reports the effects of a new synthetic compound that selectively blocks 11beta-HSD1 on the ability of mice to complete a memory task, called the Y maze.
Professor Jonathan Seckl from the University of Edinburgh, who discovered the role of 11beta-HSD1 in the brain, described the findings: "Normal old mice often have marked deficits in learning and memory just like some elderly people. We found that life-long partial deficiency of 11beta-HSD1 prevented memory decline with aging. But we were very surprised to find that the blocking compound works quickly over a few days to improve memory in old mice suggesting it might be a good treatment for the already elderly."
The effects were seen after only 10 days of treatment.
Professor Brian Walker and Dr Scott Webster from the University of Edinburgh are leading the drug development programme. Professor Walker added: "These results provide proof-of-concept that this class of drugs could be useful to treat age-related decline in memory. We previously showed that carbenoxolone, an old drug that blocks multiple enzymes including 11beta-HSD1, improves memory in healthy elderly men and in patients with type 2 diabetes after just a month of treatment, so we are optimistic that our new compounds will be effective in humans. The next step is to conduct further studies with our preclinical candidate to prove that the compound is safe to take into clinical trials, hopefully within a year."
The 11beta-HSD1 enzyme has also been implicated in metabolic diseases including diabetes and obesity by the Edinburgh team, and similar drugs that block its activity outside of the brain are already under investigation.
This study was supported by the Wellcome Trust and the Medical Research Council (MRC). The drug development programme in Edinburgh is supported by a Seeding Drug Discovery award from the Wellcome Trust.
Dr Rick Davis of the Wellcome Trust commented: "Developing drugs that can selectively inhibit this enzyme has been a challenge to the pharmaceutical industry for nearly 10 years. Advancing this compound towards clinical trials takes us a step closer to finding a drug that could have far reaching implications as the population ages."
Promising Drug Candidate Reverses Age-Related Memory Loss in Mice
新的候选药逆转小鼠老年性记忆丧失
译者:Docofsoul
ScienceDaily (Oct. 13, 2010) — Researchers at the University of Edinburgh report a new experimental compound that can improve memory and cognitive function in aging mice. The compound is being investigated with a view to developing a drug that could slow the natural decline in memory associated with aging.
With support from a Wellcome Trust Seeding Drug Discovery award, the team has identified a preclinical candidate that they hope to take into human trials within a year.
这项研究得到惠康信托新药研究投资计划(Wellcome Trust Seeding Drug Discovery)的支持。研究小组业已确认了一种临床前候选药物,并希望能够在一年内进行人类试验。
Many people find they become more forgetful as they get older and we generally accept it as a natural part of the aging process. Absent mindedness and a difficulty to concentrate are not uncommon, it takes longer to recall a person's name, and we can't remember where we left the car keys. These can all be early signs of the onset of dementia, but for most of us it's just part of getting old.
Such memory loss has been linked with high levels of 'stress' steroid hormones known as glucocorticoids which have a deleterious effect on the part of the brain that helps us to remember. An enzyme called 11beta-HSD1 is involved in making these hormones and has been shown to be more active in the brain during aging.
In a study published in the Journal of Neuroscience, the team reports the effects of a new synthetic compound that selectively blocks 11beta-HSD1 on the ability of mice to complete a memory task, called the Y maze.
在一项发表于《神经科学杂志》(Journal of Neuroscience)的研究中,研究小组报告了一种新的合成化合物的(记忆改善)效应。该化合物可选择性阻止11beta-HSD1,从而对小鼠完成Y迷宫记忆任务的能力产生影响。
Professor Jonathan Seckl from the University of Edinburgh, who discovered the role of 11beta-HSD1 in the brain, described the findings: "Normal old mice often have marked deficits in learning and memory just like some elderly people. We found that life-long partial deficiency of 11beta-HSD1 prevented memory decline with aging. But we were very surprised to find that the blocking compound works quickly over a few days to improve memory in old mice suggesting it might be a good treatment for the already elderly."
The effects were seen after only 10 days of treatment.
(准确地说,)仅仅10天的治疗,效果就出来了。
Professor Brian Walker and Dr Scott Webster from the University of Edinburgh are leading the drug development programme.
来自爱丁顿大学的Brian Walker 教授与 Scott Webster 博士眼下正领导着该药物的开发计划。
Professor Walker added:"These results provide proof-of-concept that this class of drugs could be useful to treat age-related decline in memory. We previously showed that carbenoxolone, an old drug that blocks multiple enzymes including 11beta-HSD1, improves memory in healthy elderly men and in patients with type 2 diabetes after just a month of treatment, so we are optimistic that our new compounds will be effective in humans. The next step is to conduct further studies with our preclinical candidate to prove that the compound is safe to take into clinical trials, hopefully within a year."
The 11beta-HSD1 enzyme has also been implicated in metabolic diseases including diabetes and obesity by the Edinburgh team, and similar drugs that block its activity outside of the brain are already under investigation.作者: shkudo 时间: 2013-12-9 20:48
This study was supported by the Wellcome Trust and the Medical Research Council (MRC). The drug development programme in Edinburgh is supported by a Seeding Drug Discovery award from the Wellcome Trust.
本研究得到了惠康信托(Wellcome Trust)与医学研究委员会(MRC)的支持。爱丁顿的药物开发计划得到来自惠康信托的药物研究投资计划(Seeding Drug Discovery)的支持。
Dr Rick Davis of the Wellcome Trust commented: "Developing drugs that can selectively inhibit this enzyme has been a challenge to the pharmaceutical industry for nearly 10 years. Advancing this compound towards clinical trials takes us a step closer to finding a drug that could have far reaching implications as the population ages."
1.Karen Sooy, Scott P. Webster, June Noble, Margaret Binnie, Brian R. Walker, Jonathan R. Seckl, and Joyce L. W. Yau. Partial Deficiency or Short-Term Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Cognitive Function in Aging Mice. Journal of Neuroscience, 2010; 30: 13867-13872 DOI: 10.1523/JNEUROSCI.2783-10.2010 作者: shkudo 时间: 2013-12-9 20:53
Partial Deficiency or Short-Term Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Cognitive Function in Aging Mice
Karen Sooy,2 Scott P. Webster,2 June Noble,2 Margaret Binnie,2 Brian R. Walker,2 Jonathan R. Seckl,1,2 and Joyce L. W. Yau1,2
1Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, and 2Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom
Correspondence should be addressed to Dr. Joyce L. W. Yau, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Email: Joyce.Yau@ed.ac.uk
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. Excess GC action exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency of 11β-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11β-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11β-HSD1 knock-out mice, with 60% reduction in hippocampal 11β-reductase activity throughout life, were protected against spatial memory impairments in the Y-maze compared to age-matched congenic C57BL/6J controls. Pharmacological treatment of aged C57BL/6J mice with a selective 11β-HSD1 inhibitor (UE1961) for 10 d improved spatial memory performance in the Y-maze (59% greater time in novel arm than vehicle control). These data support the use of selective 11β-HSD1 inhibitors in the treatment of age-related cognitive impairments.