The nicotine-degrading enzyme NicA2 reduces nicotine levels in blood, nicotine distribution to brain, and nicotine discrimination and reinforcement in rats.
The nicotine-degrading enzyme NicA2 reduces nicotine levels in blood, nicotine distribution to brain, and nicotine discrimination and reinforcement in rats.
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DOI：
10.1186/s12896-018-0457-7
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发表时间：
2018-07-24
影响因子：
3.5
通讯作者：
Kalnik MW
中科院分区：
文献类型：
--
作者：
Pentel PR;Raleigh MD;LeSage MG;Thisted T;Horrigan S;Biesova Z;Kalnik MW
对从恶臭假单胞菌中分离到的尼古丁降解酶NicA2进行了研究，以评估其在烟草依赖治疗中的潜在应用。大鼠静脉注射不同剂量的生理盐水。剂量为NicA2，然后静脉注射。尼古丁剂量为0.03 mg/kg。NicA2以剂量相关的方式迅速起效，降低血液和大脑尼古丁浓度，起效迅速。与对照组相比，5毫克/公斤的尼古丁剂量在尼古丁剂量后1分钟将血液中的尼古丁浓度降低了90%； 。在尼古丁剂量后1分钟和5分钟，大脑尼古丁浓度分别下降了55%和92%。为评价尼古丁剂量相当于重度吸烟时的酶效应，大鼠静脉注射尼古丁0.03 mg/kg，尼卡2剂量为10 mg/kg。超过40分钟。第一次或第五次注射尼古丁后3分钟，血液中的尼古丁水平均低于检测限值，大脑中的尼古丁水平分别比对照组降低了82%和84%。在每天的尼古丁自我给药(NSA)之前，20 mg/kg剂量的NicA2减弱了尼古丁的歧视，并在大多数大鼠中产生了尼古丁自我给药(NSA)的消失，或其他大鼠的代偿性增加。在出现代偿的大鼠中，将NicA2剂量增加到70 mg/kg会导致NSA消失。一种作用时间更长的酶结构，通过与白蛋白结合结构域的融合，在剂量为70 mg/kg的23小时尼古丁获取模型中，类似地降低了NSA。这些数据扩展了对NICA2的S对尼古丁分布到大脑的影响以及它减轻大鼠成瘾相关行为的能力的了解，并支持将其作为治疗烟草使用障碍的进一步研究。
The bacterial nicotine-degrading enzyme NicA2 isolated from P. putida was studied to assess its potential use in the treatment of tobacco dependence. Rats were pretreated with varying i.v. doses of NicA2, followed by i.v. administration of nicotine at 0.03 mg/kg. NicA2 had a rapid onset of action reducing blood and brain nicotine concentrations in a dose-related manner, with a rapid onset of action. A 5 mg/kg NicA2 dose reduced the nicotine concentration in blood by > 90% at 1 min after the nicotine dose, compared to controls. Brain nicotine concentrations were reduced by 55% at 1 min and 92% at 5 min post nicotine dose. To evaluate enzyme effects at a nicotine dosing rate equivalent to heavy smoking, rats pretreated with NicA2 at 10 mg/kg were administered 5 doses of nicotine 0.03 mg/kg i.v. over 40 min. Nicotine levels in blood were below the assay detection limit 3 min after either the first or fifth nicotine dose, and nicotine levels in brain were reduced by 82 and 84%, respectively, compared to controls. A 20 mg/kg NicA2 dose attenuated nicotine discrimination and produced extinction of nicotine self-administration (NSA) in most rats, or a compensatory increase in other rats, when administered prior to each daily NSA session. In rats showing compensation, increasing the NicA2 dose to 70 mg/kg resulted in extinction of NSA. An enzyme construct with a longer duration of action, via fusion with an albumin-binding domain, similarly reduced NSA in a 23 h nicotine access model at a dose of 70 mg/kg. These data extend knowledge of NicA2’s effects on nicotine distribution to brain and its ability to attenuate addiction-relevant behaviors in rats and support its further investigation as a treatment for tobacco use disorder.
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DOI：
10.1093/jnci/94.2.108
发表时间：
2002-01-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Benowitz, NL;Pérez-Stable, EJ;Jacob, P
通讯作者：
Jacob, P
通过将尼古丁特异性抗体与尼古丁受体拮抗剂相结合，增强了大鼠尼古丁歧视的衰减。
影响因子：
3.6
作者：
LeSage, Mark G.;Shelley, David;Pravetoni, Marco;Pentel, Paul R.
通讯作者：
Pentel, Paul R.
DOI：
10.1016/s0378-4347(00)81033-6
发表时间：
1981-01-01
期刊：
JOURNAL OF CHROMATOGRAPHY
影响因子：
--
作者：
JACOB, P;WILSON, M;BENOWITZ, NL
通讯作者：
BENOWITZ, NL
DOI：
10.1016/b978-0-12-420118-7.00014-7
发表时间：
2014-01-01
期刊：
EMERGING TARGETS & THERAPEUTICS IN THE TREATMENT OF PSYCHOSTIMULANT ABUSE
影响因子：
--
作者：
Pentel, Paul R.;LeSage, Mark G.
通讯作者：
LeSage, Mark G.
影响因子：
4.2
作者：
Harris, Andrew C.;Tally, Laura;LeSage, Mark G.
通讯作者：
LeSage, Mark G.