Histamine N-methyltransferase inhibition as a novel therapeutic strategy for idiopathic hypersomnia

Idiopathic hypersomnia (IH) is a sleep disorder characterised by excessive daytime sleepiness despite adequate night-time sleep. Although current treatments, including low-sodium oxybate and modafinil, are readily available for IH, they are associated with side effects such as drug dependence and abuse. Histamine, a key neurotransmitter, plays a critical role in promoting wakefulness and reducing the risk of drug dependence. Clinical studies have found reduced histamine levels in the cerebrospinal fluid of patients with hypersomnia, suggesting that enhanced histaminergic neurotransmission could alleviate IH symptoms. In our recent study, we demonstrated that the pharmacological inhibition of histamine N-methyltransferase (HNMT), the enzyme responsible for histamine degradation, significantly increased brain histamine levels and improved hypersomnolence and sleep attacks in a mouse model of narcolepsy. Based on these findings, we hypothesised that HNMT inhibitors could serve as novel therapeutic agents for IH treatment. In this study, we examined the effects of metoprine, a potent HNMT inhibitor, on sleep-wake behaviour in Sik3^Sleepy mutant mice, a mouse model of IH. Our results show that metoprine significantly increased brain histamine levels without altering dopamine, norepinephrine, or serotonin levels. Sleep analysis revealed that metoprine markedly promoted wakefulness and prolonged sleep latency, likely through the activation of the histamine receptor H1. Furthermore, the wake-up promoting effect of metoprine was more pronounced than that of other agents, including a histamine receptor H3 inverse agonist and an orexin receptor agonist. These findings suggest that the pharmacological inhibition of HNMT represents a promising therapeutic strategy for IH.