Characterization of an endogenous GABA-ergic mechanism underlying hypersomnia

 描述(由申请人提供)：尽管长时间睡眠(即睡眠过度)持续的嗜睡对发病率和死亡率有负面影响。睡眠和昼夜节律科学已经确定了影响睡眠过多的环境、生物和遗传因素，然而，这些知识很少被转化到临床上。有效 缺乏可靠的评估手段和高睡眠的生物标志物(S)。增强觉醒的精神刺激剂仍然是默认的治疗主体。它们的有效性依赖于增强大脑的兴奋性单胺信号，但它们可能无效，并充满副作用。它们是例行公事的处方，这强化了启发式结构，即假设大脑的促进觉醒网络功能丧失，作为睡眠过多的主要仲裁者。另一种假说--即睡眠过多反映了为睡眠服务的大脑机制的功能增强--有其支持者。在限制睡眠后，自然产生的假定睡眠激素包括腺苷、前列腺素、细胞因子、安定结合抑制物(DBI)和油酰胺，但没有一种被证明会导致人类病理性嗜睡。因此，所获得的知识并没有转化为治疗睡眠症的合理的替代疗法。出现睡眠过多的人类条件，例如“原发性睡眠过多”(PH)，提供了一个独特的机会，可以从机制上对“自然”睡眠本身产生新的见解，因为它们绕过了包括睡眠限制在内的实验范式的解释混乱。在排除了32名PH患者睡眠过多的已知原因后，我们报告了他们脑脊液中的一种内源性多肽生物活性，它模仿镇静-催眠药和麻醉的作用。这种生理学在体外用苯二氮(BZD)拮抗剂是可逆的，并在体内转化为警觉改善，似乎优于传统药物。我们在这里的主要目标是通过确定其在PH和Kleine-Levin综合征中分别对持续性和发作性睡眠障碍与阻塞性睡眠呼吸暂停相关的嗜睡的特异性，从机制上促进对这种假定的睡眠诱导的GABA能生物活性的理解；2)依赖于a-1 GABAA受体亚单位，在体内介导镇静，以及通过体外分子工程受体变体的生理询问，相对于该受体的BZD结合口袋起作用位置；以及3)同一性。病理性睡眠症的这些机械性细节有望通过改进诊断和治疗来改变医疗实践。

 DESCRIPTION (provided by applicant): Sleepiness that persists despite episodes of prolonged sleep (viz., hypersomnolence) negatively impacts morbidity and mortality. The sleep and circadian sciences have identified environmental, biological, and genetic factors that influence hypersomnolence, yet, little of this knowledge has been translated into the clinic. Valid and reliable means of assessment and biomarker(s) for hypersomnolence are lacking. Psychostimulants that enhance wake remain the default mainstays of treatment. Their efficacies depend on heightening the brain's excitatory monoamine signaling, but they can be ineffective and fraught with side effects. They are prescribed routinely which reinforces heuristic constructs that posit loss of function in the brain's wake- promoting networks as the principal arbiter of hypersomnolence. The alternative hypothesis - namely, that hypersomnolence reflects a gain in function in brain mechanisms subserving sleep - has its advocates. Naturally occurring putative somnogens that accumulate after restricting sleep include adenosine, prostaglandins, cytokines, the diazepam binding inhibitor (DBI), and oleamides, but none are proven to cause pathological sleepiness in humans. The knowledge gained has therefore not translated into rational, treatment alternatives for hypersomnolence. Human conditions in which hypersomnolence emerges sui generis, e.g., the `primary hypersomnias' (PH), afford a unique opportunity to derive novel mechanistic insights into `natural' sleep per se, because they bypass interpretative confounds of experimental paradigms that include sleep restriction. After excluding known causes of hypersomnolence in 32 PH patients, we have reported on an endogenous peptidergic bioactivity in their cerebrospinal fluids that mimics the actions of sedative-hypnotics and anesthesia. This physiology is reversible with benzodiazepine (BZD) antagonists in vitro, and translates in vivo to vigilance improvements that appear superior to conventional medications. Our major goal here is to advance mechanistic understanding of this putative sleep-inducing GABA-ergic bioactivity by determining its: 1) specificity to persistent and episodic hypersomnolence in PH and Kleine-Levin syndrome, respectively, vs. sleepiness associated with obstructive sleep apnea; 2) reliance upon the a-1 GABAA receptor subunit known to mediate sedation in vivo, and site of action relative to this receptor's BZD binding pocket through physiological interrogation of molecularly engineered receptor variants in vitro ; and 3) identity. These mechanistic details of pathological hypersomnolence promise to change medical practice by way of improved diagnostics and therapeutics.