Therapeutic potential of histamine N-methyltransferase inhibition for the treatment of hypersomnia

Abstract

Histamine plays a crucial role in maintaining wakefulness. Decreased histamine levels in the cerebrospinal fluid have been reported in patients with hypersomnia, including narcolepsy and idiopathic hypersomnia. Histamine N-methyltransferase (HNMT) is a key enzyme responsible for histamine degradation in the brain. In this study, we examined the effects of pharmacological HNMT inhibition on animal models of hypersomnia disorders. Metoprine, an HNMT inhibitor, significantly increased brain histamine levels and produced robust wake-promoting effects and suppressed cataplexy in narcolepsy model mice. The arousal effects of metoprine were mainly mediated through activation of histamine H1 receptors. Metoprine also promoted wakefulness in Sleepy mice, a model of idiopathic hypersomnia, and in drug-induced Parkinson’s disease model mice. Compared with pitolisant, an H3 receptor inverse agonist that has been approved in EU and US for treatment of narcolepsy, metoprine exhibited stronger and more sustained wake-promoting effects. Our findings indicate that HNMT inhibitors increase brain histamine levels and promote wakefulness in various types of hypersomnia. Therefore, HNMT inhibitors may represent a novel and effective therapeutic approach for hypersomnia. To further advance drug development, we have performed high-throughput screening based on mass spectrometry, through which approximately 1,000 hit compounds have been identified.