Intermittent Hypoxia Protects Brain from Ethanol Withdrawal Mechanisms and Therap

描述（由申请人提供）：停止乙醇消费是困难的，而且经常不成功，即使对高度积极的患者也是如此。突然停止酒精暴露会使大脑容易产生神经系统后遗症，包括感觉运动障碍、震颤和抽搐，这使患者停止饮酒的努力受挫。乙醇戒断（EW）困扰的唯一可用治疗方法是苯二氮卓类药物，但其副作用（如依赖性和呼吸抑制）限制了这种治疗的临床应用。在乙醇中毒和戒断的大鼠模型中，我们最近证明了5-10分钟、间歇性、常压、中度（FIO2 9.5-10%）缺氧（IH）的每日循环对大脑有深远的保护作用。在我们的初步研究中，当在乙醇饮食的最后20天应用IH治疗时，它减弱了EW的明显行为体征（例如震颤和僵硬）；ew诱导线粒体膜肿胀；和细胞毒性。特别是，EW引起凋亡前激酶P38增加6倍以上；IH条件作用几乎完全抑制了乙醇戒断大鼠的这种增加。有趣的是，所有这些IH保护在EW期间比在乙醇暴露期间更有效，这意味着IH抵消了介导EW的因素。这些显著的结果表明，适应间歇性常压缺氧可以提供一种安全有效的治疗方法，补充传统的苯二氮卓类药物。使用重复戒断模式，我们打算用不同的IH治疗窗口和涉及P38的细胞机制来定义IH保护的行为表型，IH通过P38保护免受重复EW。我们假设，在电挫伤的初始周期中应用的IH条件反射在重复电挫伤中对行为和脑损伤具有持续的保护作用。大鼠将接受2个周期的乙醇饮食（7.5%），持续5周，然后突然停药20天。IH条件作用将应用于电子束的初始循环或乙醇暴露阶段。我们将确定1)在EW的初始周期中IH治疗是否可以防止EW的明显行为体征和小脑/海马相关的行为缺陷，以及这种保护是否在重复EW中持续存在；2) ih诱导的P38活性抑制是否介导对凋亡（程序性细胞死亡）脑损伤的保护，以及这种保护是否以一种与行为保护相关的方式持续存在于重复EW中。部分动物将接受P38抑制剂SB203580，以确定P38抑制剂在IH保护中的作用。明确ih诱导的行为和脑保护以对抗EW损伤，并确定最佳治疗窗口，可能为EW治疗替代方案的开发提供必要的基础数据。

DESCRIPTION (provided by applicant): The cessation of ethanol consumption is difficult and often unsuccessful, even for highly motivated patients. Abrupt termination of ethanol-exposure renders the brain vulnerable to neurological sequelae, including sensorimotor impairment, tremor, and convulsions, which discourage the patient's efforts to stop consuming alcohol. The only available treatment for the ethanol withdrawal (EW) distress is benzodiazepines but the side effects (e.g. dependency and respiratory depression) limit clinical use of this treatment. In a rat model of ethanol intoxication and withdrawal, we recently demonstrated profound brain protection by daily cycles of 5-10 minutes, intermittent, normobaric, moderate (FIO2 9.5-10%) hypoxia (IH). In our pilot studies, when IH treatment was applied during the last 20 days of an ethanol diet, it attenuated the overt behavioral signs of EW (e.g. tremor and rigidity); EW-induced mitochondrial membrane swelling; and cytotoxicity. In particular, EW provoked a more than 6-fold increase in the proapoptotic kinase P38; IH conditioning almost completely suppressed this increase in ethanol withdrawn rats. Interestingly, all of these IH protections were more effective during EW than during ethanol-exposure, implicating that IH counteracts factors mediating EW. These remarkable results suggest that adaptation to intermittent normobaric hypoxia could provide a safe and effective treatment complementary to conventional benzodiazepines. Using a repeated withdrawal paradigm, we intend to define behavioral phenotypes of IH protection with various treatment windows of IH and cellular mechanisms involving P38 by which IH protects against repeated EW. We hypothesize that IH conditioning applied during the initial cycle of EW exerts persistent protection against behavioral and brain injury throughout repeated EW. Rats will receive two cycles of an ethanol diet (7.5%) for 5 weeks and abrupt withdrawal for 20 days. IH conditioning will be applied to the initial cycle of the EW or the ethanol-exposure phase. We will determine 1) whether IH treatment during the initial cycle of EW protects against overt behavioral signs of EW and cerebellum-/hippocampus-related behavioral deficit and whether the protection persists throughout the repeated EW; 2) whether IH-induced suppression of P38 activity mediates protection against apoptotic (programmed cell death) brain injury and whether the protection persists throughout the repeated EW in a manner that correlates with behavioral protection. Some animals will receive the P38 inhibitor SB203580 to define the role of P38-inhibition in the IH protection. Defining the IH-induced behavioral and brain protection against EW insults and identifying an optimal treatment window may establish foundation data necessary for the development of an alternative management of EW. PUBLIC HEALTH RELEVANCE: Alcoholics failed to achieve complete abstinence due to distress associated with sudden termination of drinking. We observed that cycles of intermittent brief (5 to 8 min) and moderate hypoxia (9 to 10% oxygen) conditioning reduced signs of ethanol withdrawal (e.g. tremor and rigidity) and oxidative stress in rats. Information on intermittent hypoxia-evoked brain protection from ethanol withdrawal distress resulting will establish an empirical foundation to support eventual clinical application for a better management of alcoholism in which ethanol withdrawal plays a key role.