Cerebral Vascular Disease Research Laboratories, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL-33136, USA.
Neuroscience. 2011 May 5;181:216-25. doi: 10.1016/j.neuroscience.2011.02.036. Epub 2011 Feb 18.
The greater incidence of myocardial infarction, cardiac arrest, and ischemic stroke among women who smoke and use oral contraception (OC) compared to women who do not smoke and who do or do not use OC may be due in part to how nicotine influences endocrine function in women. For example, we recently demonstrated that chronic exposure to nicotine, the addictive agent in tobacco smoke responsible for the elevated risk of cardiac arrest, abolishes the endogenous or exogenous 17β-estradiol-conferred protection of the hippocampus against global cerebral ischemia (a potential outcome of cardiac arrest) in naive or ovariectomized female rats. In the current study we examined the hypotheses that (1) a synergistic deleterious effect of nicotine plus oral contraceptives exacerbates post-ischemic hippocampal damage in female rats, and (2) nicotine directly inhibits estrogen-mediated intracellular signaling in the hippocampus. To test first hypothesis and to simulate smoking behavior-induced nicotine levels in the human body, we implanted osmotic pumps containing nicotine in the female rats for 16 days. Furthermore, we mimicked the use of oral contraceptives in females by administering oral contraceptives orally to the rat. Rats exposed to either nicotine alone or in combination with oral contraceptives were subjected to an episode of cerebral ischemia and the resultant brain damage was quantified. These results showed for the first time that nicotine with oral contraceptives did indeed exacerbate post-ischemic CA1 damage as compared to nicotine alone in naive female rats. In ex vivo hippocampal slice cultures, we found that nicotine alone or with 17β-estradiol directly hinders estrogen receptors-mediated phosphorylation of cyclic-AMP element binding protein, a process required for neuronal survival and also exacerbates ischemic damage. Thus, nicotine can affect the outcome of cerebral ischemia by influencing brain endocrine function directly rather than through indirect systemic effects.
与不吸烟且不使用或使用口服避孕药的女性相比，吸烟且使用口服避孕药的女性心肌梗死、心脏骤停和缺血性中风的发病率更高，这可能部分归因于尼古丁如何影响女性的内分泌功能。例如，我们最近表明，慢性暴露于尼古丁（烟草烟雾中的成瘾物质，导致心脏骤停风险增加）会消除内源性或外源性 17β-雌二醇对未接受过处理或卵巢切除的雌性大鼠全脑缺血（心脏骤停的潜在后果）的保护作用。在目前的研究中，我们检验了以下假设：（1）尼古丁加口服避孕药的协同有害作用会加剧雌性大鼠缺血后海马损伤；（2）尼古丁直接抑制海马体内雌激素介导的细胞内信号转导。为了检验第一个假设并模拟人体吸烟行为引起的尼古丁水平，我们将含有尼古丁的渗透泵植入雌性大鼠体内 16 天。此外，我们通过给大鼠口服避孕药来模拟女性使用口服避孕药的行为。将单独暴露于尼古丁或与口服避孕药联合暴露于尼古丁的大鼠进行脑缺血发作，然后定量评估由此产生的脑损伤。这些结果首次表明，与单独使用尼古丁相比，尼古丁与口服避孕药联合使用确实会加剧未接受过处理的雌性大鼠缺血后 CA1 损伤。在离体海马切片培养物中，我们发现单独使用尼古丁或与 17β-雌二醇联合使用会直接阻碍雌激素受体介导的环磷酸腺苷元件结合蛋白磷酸化，这是神经元存活所必需的过程，并且还会加剧缺血性损伤。因此，尼古丁可以通过直接影响大脑内分泌功能而不是通过间接的全身作用来影响脑缺血的结果。
