Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.
Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.
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DOI：
10.1038/ncomms9466
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发表时间：
2015-10-27
影响因子：
16.6
通讯作者：
Aigner L
中科院分区：
文献类型：
--
作者：
Marschallinger J;Schäffner I;Klein B;Gelfert R;Rivera FJ;Illes S;Grassner L;Janssen M;Rotheneichner P;Schmuckermair C;Coras R;Boccazzi M;Chishty M;Lagler FB;Renic M;Bauer HC;Singewald N;Blümcke I;Bogdahn U;Couillard-Despres S;Lie DC;Abbracchio MP;Aigner L
随着工业化社会中人类预期寿命的迅速提高，与年龄相关的认知障碍提出了越来越大的挑战。针对与年龄相关的认知能力下降相关的组织病理过程，如神经炎症、低水平的神经发生、血脑屏障被破坏和神经元活动改变，可能会导致老年大脑的结构和功能复兴。本研究表明，用孟鲁司特（一种市场上销售的抗哮喘药物，能拮抗白三烯受体）对幼鼠（4个月）和老年大鼠（20个月）进行为期6周的治疗，可以减少神经炎症，促进海马神经发生，提高老年动物的学习和记忆能力。通过基因敲低和敲除方法，我们证明了这种作用是通过抑制GPR17受体介导的。这项研究表明，白三烯受体信号的抑制可能是恢复老年人认知功能的一个安全且可药物治疗的靶点，并为白三烯受体抑制治疗痴呆症的未来临床转化铺平了道路。白三烯受体拮抗剂孟鲁司特是一种抗哮喘药物。在这里，作者表明，孟鲁司特可以减少神经炎症，促进海马神经发生，并恢复患有衰老相关认知功能障碍的老年大鼠的学习和记忆。
As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood–brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias. The leukotriene receptor antagonist montelukast is an anti-asthmatic drug. Here, the authors show that montelukast reduces neuroinflammation, promotes hippocampal neurogenesis and restores learning and memory in old rats suffering from ageing-associated cognitive dysfunction.