Laurens Claire, Abot Anne, Delarue Alain, Knauf Claude
Pierre Fabre Dermatologie, Lavaur, France.
Enterosys SAS, Prologue Biotech, Toulouse, France.
Front Neurosci. 2019 Jan 31;13:33. doi: 10.3389/fnins.2019.00033. eCollection 2019.
Propranolol is the first-line treatment for infants suffering from infantile hemangioma. Recently, some authors raised the question of potential neurologic side effects of propranolol due to its lipophilic nature and thus its ability to passively cross the blood-brain barrier (BBB) and accumulate into the brain. Hydrophilic beta-blockers, such as atenolol and nadolol, where therefore introduced in clinical practice. In addition to their classical mode of action in the brain, circulating factors may modulate the release of reactive oxygen/nitrogen species (ROS/RNS) from endothelial cells that compose the BBB without entering the brain. Due to their high capacity to diffuse across membranes, ROS/RNS can reach neurons and modify their activity. The aim of this study was to investigate other mechanisms of actions in which these molecules may display a central effect without actually crossing the BBB. We first performed an oral treatment in mice to measure the accumulation of propranolol, atenolol and nadolol in different brain regions . We then evaluated the ability of these molecules to induce the release of nitric oxide (NO) and hydrogen peroxide (HO) in the hypothalamus. As expected, propranolol is able to cross the BBB and is found in brain tissue in higher amounts than atenolol and nadolol. However, all of these beta-blockers are able to induce the secretion of signaling molecules (i.e., NO and/or HO) in the hypothalamus, independently of their ability to cross the BBB, deciphering a new potential deleterious impact of hydrophilic beta-blockers in the brain.
普萘洛尔是治疗婴儿血管瘤的一线药物。最近，一些作者提出了普萘洛尔可能存在神经副作用的问题，因为其具有亲脂性，因而能够被动穿过血脑屏障（BBB）并在脑中蓄积。因此，亲水性β受体阻滞剂，如阿替洛尔和纳多洛尔，被引入临床实践。除了它们在脑中的经典作用方式外，循环因子可能会调节构成血脑屏障的内皮细胞释放活性氧/氮物种（ROS/RNS），而无需进入脑内。由于ROS/RNS具有很高的跨膜扩散能力，它们可以到达神经元并改变其活性。本研究的目的是探讨这些分子可能在不实际穿过血脑屏障的情况下发挥中枢作用的其他作用机制。我们首先对小鼠进行口服治疗，以测量普萘洛尔、阿替洛尔和纳多洛尔在不同脑区的蓄积情况。然后我们评估了这些分子在下丘脑中诱导一氧化氮（NO）和过氧化氢（HO）释放的能力。正如预期的那样，普萘洛尔能够穿过血脑屏障，并且在脑组织中的含量高于阿替洛尔和纳多洛尔。然而，所有这些β受体阻滞剂都能够在下丘脑中诱导信号分子（即NO和/或HO）的分泌，而与它们穿过血脑屏障的能力无关，这揭示了亲水性β受体阻滞剂在脑中一种新的潜在有害影响。
