The Possible Role of Endozepines in Sleep Regulation and Biomarker of Process S of the Borbély Sleep Model

ABSTRACT

The well-known Two-Process Model of Sleep Regulation describes the integration of the circadian rhythm of arousal and sleep – Process C, and the homeostatic pressure to sleep – Process S. Presently, the known biological markers for Process C are melatonin and core body temperature; whereas, for Process S, there is no biological marker except that of aspects of the electroencephalogram (EEG). Endozepines are a class of endogenous compounds that act like benzodiazepines (BZ), i.e., serving as ligands for the BZ binding sites on GABA_A receptors. Not much is known about the role of endozepines, in particular non-peptide endozepines, in the sleep field except very few reports about high concentrations observed in endozepine stupor, a rare phenomenon of idiopathic recurring stupor. We focused on hypoxanthine and thromboxane A2, which are considered to have endozepine function. This study aimed to examine the effect of 24 h of acute sleep deprivation on blood levels of hypoxanthine and thromboxane A2 of healthy subjects without sleep problems or disorders. The results showed a significant decrease of both compounds in the morning after sleep deprivation in comparison to the unrestricted normal sleep condition, thereby suggesting that these endozepines are secreted regularly while asleep, and, thus, are necessary for the sleep process. This study is the first to suggest a connection between specific biological markers – endozepines and Process S – in the Two-Process Model of Sleep Regulation and, furthermore, it sheds light on the possible role of endozepines in sleepiness and fatigue.

KEYWORDS:

• Endozepines
• GABA_a receptor
• hypoxanthine
• sleep deprivation
• sleep homeostasis
• thromboxane A2
• two-process model of sleep regulation

Disclosure statement

Ms. Simona Sher, Dr. Amit Green, Professor Soliman Khatib, and Professor Yaron Dagan declare that they have no conflict of interest. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.