Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA.
Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA.
Neurotoxicology. 2022 Mar;89:140-160. doi: 10.1016/j.neuro.2022.02.002. Epub 2022 Feb 9.
Accumulating evidence suggests that the detrimental effect of nicotine and tobacco smoke on the central nervous system (CNS) is caused by the neurotoxic role of nicotine on blood-brain barrier (BBB) permeability, nicotinic acetylcholine receptor expression, and the dopaminergic system. The ultimate consequence of these nicotine associated neurotoxicities can lead to cerebrovascular dysfunction, altered behavioral outcomes (hyperactivity and cognitive dysfunction) as well as future drug abuse and addiction. The severity of these detrimental effects can be associated with several biological determinants. Sex and age are two important biological determinants which can affect the pharmacokinetics and pharmacodynamics of several systemically available substances, including nicotine. With regard to sex, the availability of gonadal hormone is impacted by the pregnancy status and menstrual cycle resulting in altered metabolism rate of nicotine. Additionally, the observed lower smoking cessation rate in females compared to males is a consequence of differential effects of sex on pharmacokinetics and pharmacodynamics of nicotine. Similarly, age-dependent alterations in the pharmacokinetics and pharmacodynamics of nicotine have also been observed. One such example is related to severe vulnerability of adolescence towards addiction and long-term behavioral changes which may continue through adulthood. Considering the possible neurotoxic effects of nicotine on the central nervous system and the deterministic role of sex as well as age on these neurotoxic effects of smoking, it has become important to consider sex and age to study nicotine induced neurotoxicity and development of treatment strategies for combating possible harmful effects of nicotine. In the future, understanding the role of sex and age on the neurotoxic actions of nicotine can facilitate the individualization and optimization of treatment(s) to mitigate nicotine induced neurotoxicity as well as smoking cessation therapy. Unfortunately, however, no such comprehensive study is available which has considered both the sex- and age-dependent neurotoxicity of nicotine, as of today. Hence, the overreaching goal of this review article is to analyze and summarize the impact of sex and age on pharmacokinetics and pharmacodynamics of nicotine and possible neurotoxic consequences associated with nicotine in order to emphasize the importance of including these biological factors for such studies.
越来越多的证据表明，尼古丁和烟草烟雾对中枢神经系统 (CNS) 的有害影响是由尼古丁对血脑屏障 (BBB) 通透性、烟碱型乙酰胆碱受体表达和多巴胺系统的神经毒性作用引起的。这些与尼古丁相关的神经毒性的最终后果可能导致脑血管功能障碍、行为改变（多动和认知功能障碍）以及未来的药物滥用和成瘾。这些有害影响的严重程度可能与几个生物学决定因素有关。性别和年龄是两个重要的生物学决定因素，它们可以影响包括尼古丁在内的几种全身性物质的药代动力学和药效学。就性别而言，性腺激素的可用性受怀孕状态和月经周期的影响，导致尼古丁的代谢率发生变化。此外，与男性相比，女性戒烟率较低，这是由于性别对尼古丁药代动力学和药效学的不同影响所致。同样，也观察到尼古丁药代动力学和药效学随年龄的变化。一个这样的例子与青春期对成瘾和长期行为变化的严重脆弱性有关，这些变化可能会持续到成年期。考虑到尼古丁对中枢神经系统的可能神经毒性作用以及性别和年龄对这些吸烟神经毒性作用的决定性作用，考虑性别和年龄来研究尼古丁引起的神经毒性以及制定治疗策略来对抗尼古丁可能产生的有害影响变得非常重要。将来，了解性别和年龄对尼古丁神经毒性作用的作用可以促进个体化和优化治疗，以减轻尼古丁引起的神经毒性以及戒烟治疗。然而，遗憾的是，迄今为止，没有这样的综合研究同时考虑了尼古丁的性别和年龄依赖性神经毒性。因此，本文的总体目标是分析和总结性别和年龄对尼古丁药代动力学和药效学的影响以及与尼古丁相关的可能神经毒性后果，以强调在这些研究中包含这些生物学因素的重要性。
