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二甲双胍有助于小儿脑肿瘤幸存者的认知和神经恢复
作者:小柯机器人 发布时间:2020/7/28 15:29:14

加拿大多伦多病童医院Donald J. Mabbott和多伦多大学Cindi M. Morshead研究组合作的最新研究,利用一项二甲双胍的临床试验评估了小儿脑肿瘤幸存者的认知和神经恢复。2020年7月27日出版的《自然-医学》发表了这项成果。

在啮齿动物和人体放射性损伤平行研究中,研究人员探索了药物刺激内源性神经前体细胞(NPC)是否可以促进认知恢复和脑修复,特别是二甲双胍。在啮齿动物颅骨放射模型中,研究人员发现二甲双胍增强了齿状回中NPC的恢复,并对神经发生和认知具有性别依赖性。在接受颅脑放射治疗的小儿脑肿瘤幸存者中进行了一项双盲、安慰剂对照交叉试验。以白质和海马体的安全性、可行性、认知测试和MRI作为测量终点。

24名参与者允许并被随机分配完成为期12周的二甲双胍(A)和安慰剂(B)实验,以AB或BA的给药方式进行,其换药清除期为10周。抽血以监测安全性。利用招募率、药物依从性和程序依从性进行可行性评估。线性混合建模用于检查认知和MRI结果与周期、给药顺序和治疗的关系。

研究人员没有发现与临床相关的安全问题,也没有与二甲双胍相关的严重不良事件。在线性混合模型中,对所有认知结果都观察达到了序列效应。对于周期1中具有完整数据参与者的子集,在陈述和工作记忆测试中,二甲双胍的性能优于安慰剂。

研究人员提供的证据表明,在小儿脑肿瘤长期幸存者中检查二甲双胍对认知和脑结构影响的临床试验是可行的,二甲双胍在该人群中的使用是安全且可耐受的。该试验性试验并非旨在测试二甲双胍对认知恢复和脑部生长的功效,但初步结果出乎意料,因此在大型多中心3期试验中值得进一步研究。

附:英文原文

Title: Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin

Author: Ramy Ayoub, Rebecca M. Ruddy, Elizabeth Cox, Adeoye Oyefiade, Daniel Derkach, Suzanne Laughlin, Benjamin Ades-aron, Zahra Shirzadi, Els Fieremans, Bradley J. MacIntosh, Cynthia B. de Medeiros, Jovanka Skocic, Eric Bouffet, Freda D. Miller, Cindi M. Morshead, Donald J. Mabbott

Issue&Volume: 2020-07-27

Abstract: We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial. 

DOI: 10.1038/s41591-020-0985-2

Source: https://www.nature.com/articles/s41591-020-0985-2

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex