Pharmacological Inhibition of Histamine N ‐Methyltransferase Markedly Improves Hypersomnia in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. In addition to motor symptoms, excessive daytime sleepiness (EDS) occurs frequently in patients with PD and severely impairs their quality of life. Current pharmacotherapies for EDS in PD are often associated with adverse effects. However, clinical studies have yielded inconsistent results, underscoring the need for safer, more effective treatment strategies. Histamine plays a pivotal role in maintaining wakefulness in the brain and is primarily inactivated by histamine N ‐methyltransferase (HNMT), the major enzyme responsible for histamine clearance in the central nervous system. We previously demonstrated that pharmacological inhibition of HNMT markedly elevates brain histamine levels and potently promotes wakefulness in mouse models of narcolepsy and idiopathic hypersomnia, suggesting that targeting HNMT may also be beneficial for treating hypersomnia in PD. Here, we investigated whether pharmacological inhibition of HNMT ameliorates hypersomnia in a 6‐hydroxydopamine‐induced mouse model of PD. We first confirmed dopaminergic neuronal loss and hypersomnia during the active phase in a mouse model of PD. Pharmacological inhibition of HNMT with metoprine robustly increased wakefulness, markedly reduced NREM and REM sleep, and prolonged sleep latency. Metoprine also reduced sleep–wake bout fragmentation, indicating the sustained consolidation of wakefulness. In direct comparison, metoprine produced stronger and more sustained wake‐promoting effects than other wake‐promoting agents. These findings indicate that HNMT inhibition represents a promising and mechanistically distinct therapeutic approach for EDS in PD.