An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse.
An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse.
复制标题
酶促方法会逆转尼古丁的依赖性，减少强迫性摄入并防止复发。
DOI：
10.1126/sciadv.aat4751
复制
发表时间：
2018-10
期刊：
影响因子：
13.6
通讯作者：
George O
中科院分区：
文献类型：
--
作者：
Kallupi M;Xue S;Zhou B;Janda KD;George O
一种吃尼古丁的细菌酶可以逆转类似成瘾的行为，并提供一种帮助吸烟者戒烟的新策略。烟草使用障碍是全世界疾病和可预防死亡的主要原因，但目前基于药效学的药物疗效较低。已经使用疫苗测试了阻止尼古丁到达大脑的新药代动力学方法，但这些努力都失败了，因为抗体亲和力和浓度不足以完全阻止尼古丁到达大脑。我们提供了临床前证据，证明酶促方法可有效逆转尼古丁依赖、减少强迫性尼古丁摄入量并防止有尼古丁依赖史的大鼠复发。 NicA2-J1（一种最初从恶臭假单胞菌 S16 中分离出来的工程化尼古丁降解酶）可以完全阻止尼古丁到达大脑，并逆转具有尼古丁自我给药史的尼古丁依赖大鼠的戒断症状、痛觉过敏和易激惹样行为。 NicA2-J1 还减少了类似强迫性的尼古丁摄入量，这反映在尽管偶然发生的足部电击的不利后果下仍能做出反应，并防止尼古丁和压力（育亨宾）引起的复发。这些结果证明了酶疗法在高级动物模型中治疗尼古丁成瘾的功效，并为开发人类戒烟的生物疗法奠定了坚实的基础。
A bacterial enzyme that eats nicotine reverses addiction-like behaviors and offers a new strategy to help smokers quit. Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from Pseudomonas putida S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)–induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans.
登录
查看更多内容
影响因子：
3.4
作者：
Greenwald, Mark K.;Lundahl, Leslie H.;Steinmiller, Caren L.
通讯作者：
Steinmiller, Caren L.
影响因子：
3.4
作者：
Cohen, Ami;Soleiman, Matthew T.;Talia, Reneta;Koob, George F.;George, Olivier;Mandyam, Chitra D.
通讯作者：
Mandyam, Chitra D.
DOI：
10.1158/1055-9965.epi-11-0644
发表时间：
2012-05
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Benowitz NL;Dains KM;Hall SM;Stewart S;Wilson M;Dempsey D;Jacob P 3rd
通讯作者：
Jacob P 3rd
DOI：
10.1073/pnas.0707585104
发表时间：
2007-10-23
影响因子：
11.1
作者：
George, Olivier;Ghozland, Sandy;Koob, George F.
通讯作者：
Koob, George F.
DOI：
10.1111/acer.13484
发表时间：
2017-11
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Kimbrough A;de Guglielmo G;Kononoff J;Kallupi M;Zorrilla EP;George O
通讯作者：
George O