School of Pharmacy, Division of Health Sciences, University of Otago, Dunedin, New Zealand; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Neuropharmacology. 2017 Apr;116:233-246. doi: 10.1016/j.neuropharm.2016.12.021. Epub 2016 Dec 23.
Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease.
The performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively.
Chronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype-independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival.
Our findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease.
对死后的人脑和遗传的小鼠模型的研究表明，胆碱能神经传递功能障碍，通过丧失激动剂而不是受体，可能是 HD 病理学的一个重要因素。如果正确，那么药理学替代可能是一种潜在的治疗策略。我们研究了慢性给予选择性烟碱部分激动剂伐仑克林是否能改善亨廷顿病转基因小鼠模型的运动、认知和情感症状。
在 YAC128 小鼠和年龄匹配的野生型同窝仔鼠 15 月龄时，通过旋转棒、T 迷宫、新物体识别、新奇抑制摄食和强迫游泳试验，在接受伐仑克林（5mg/kg/天，通过微量渗透泵持续 28 天）治疗前后进行评估。使用胸苷类似物、DARPP32 和 EM48 免疫组化分别评估伐仑克林对祖细胞增殖和存活、中脑投射神经元和聚集物形成的影响。
慢性给予伐仑克林可显著改善晚期 YAC128 小鼠的运动协调、延迟依赖记忆和减少抑郁样行为。伐仑克林还产生了与基因型无关的识别记忆改善和焦虑减少。此外，伐仑克林具有抗焦虑作用，并能改善空间记忆，而不影响其功能。功能改善伴随着神经病理学变化，包括聚集物形成增加、神经保护和祖细胞增殖和存活增加。
我们的研究结果表明，给予外源性烟碱激动剂可能对治疗晚期亨廷顿病具有临床益处。
