Colas Damien, Chuluun Bayarsaikhan, Garner Craig C, Heller H Craig
Biology Department, Stanford University, Stanford, CA 94305-5020, USA.
Neurobiol Learn Mem. 2017 Apr;140:11-16. doi: 10.1016/j.nlm.2017.02.006. Epub 2017 Feb 12.
Down syndrome (DS) is a common genetic cause of intellectual disability yet no pro-cognitive drug therapies are approved for human use. Mechanistic studies in a mouse model of DS (Ts65Dn mice) demonstrate that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits are normalized by chronic, short-term low doses of GABA receptor (GABAR) antagonists in adult animals, but none of the compounds investigated are approved for human use. We explored the therapeutic potential of flumazenil (FLUM), a GABAR antagonist working at the benzodiazepine binding site that has FDA approval. Long-term memory was assessed by the Novel Object Recognition (NOR) testing in Ts65Dn mice after acute or short-term chronic treatment with FLUM. Short-term, low, chronic dose regimens of FLUM elicit long-lasting (>1week) normalization of cognitive function in both young and aged mice. FLUM at low dosages produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS.
唐氏综合征（DS）是导致智力残疾的常见遗传病因，但目前尚无获批用于人类的促认知药物疗法。在唐氏综合征小鼠模型（Ts65Dn小鼠）中的机制研究表明，认知功能受损是由于神经元抑制性张力过高所致。在成年动物中，长期、短期低剂量的GABA受体（GABAR）拮抗剂可使这些缺陷恢复正常，但所研究的化合物均未获批用于人类。我们探究了氟马西尼（FLUM）的治疗潜力，它是一种作用于苯二氮䓬结合位点的GABAR拮抗剂，已获得美国食品药品监督管理局（FDA）批准。在用FLUM进行急性或短期慢性治疗后，通过新颖物体识别（NOR）测试评估Ts65Dn小鼠的长期记忆。短期、低剂量、慢性给药方案的FLUM可使年轻和老年小鼠的认知功能持久（>1周）恢复正常。低剂量的FLUM可产生持久的认知改善，并有潜力满足唐氏综合征中未得到满足的治疗需求。
