Mannett Brady T, Capt Braden C, Pearman Krista, Buhlman Lori M, VandenBrooks John M, Call Gerald B
Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
OSF Neurology at University of Illinois, Peoria, IL 61637, USA.
Parkinsons Dis. 2022 Jul 8;2022:9291077. doi: 10.1155/2022/9291077. eCollection 2022.
Strong epidemiological evidence and studies in models of Parkinson's disease (PD) suggest that nicotine may be therapeutically beneficial in PD patients. However, a number of clinical trials utilizing nicotine in PD patients have had mixed results, indicating that either nicotine is not beneficial in PD patients, or an important aspect of nicotine therapy was absent. We hypothesized that nicotine must be administered early in the adult fly life in order to have beneficial effects. We show that continuous early nicotine administration improves both climbing and flight deficiencies present in homozygous mutant PD model . Using a new climbing assay, we identify several climbing deficiencies in this PD model that are improved or rescued by continuous nicotine treatment. Amongst these benefits, it appears that nicotine improves the ability of the flies to descend the climbing vial by being able to climb down more. In support of our hypothesis, we show that in order for nicotine benefits on climbing and flight to happen, nicotine administration must occur in a discrete time frame following adult fly eclosure: within one day for climbing or five days for flight. This therapeutic window of nicotine administration in this PD model fly may help to explain the lack of efficacy of nicotine in human clinical trials.
强有力的流行病学证据以及帕金森病（PD）模型研究表明，尼古丁可能对PD患者具有治疗益处。然而，多项在PD患者中使用尼古丁的临床试验结果不一，这表明要么尼古丁对PD患者无益，要么尼古丁治疗缺少一个重要方面。我们推测，尼古丁必须在成年果蝇生命早期给药才能产生有益效果。我们发现，在成年果蝇生命早期持续给予尼古丁可改善纯合突变PD模型中出现的攀爬和飞行缺陷。通过一种新的攀爬试验，我们确定了该PD模型中的几种攀爬缺陷，这些缺陷可通过持续尼古丁治疗得到改善或纠正。在这些益处中，尼古丁似乎通过能够更多地向下攀爬来提高果蝇从攀爬管下降的能力。为支持我们的假设，我们表明，为使尼古丁对攀爬和飞行产生益处，尼古丁给药必须在成年果蝇羽化后的一个离散时间段内进行：攀爬在一天内，飞行在五天内。在该PD模型果蝇中尼古丁给药的这一治疗窗口可能有助于解释尼古丁在人体临床试验中缺乏疗效的原因。
