Histamine N-Methyltransferase in the Brain

Takeo Yoshikawa,Kazuhiko Yanai,Tadaho Nakamura

doi:10.3390/ijms20030737

Abstract

Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood–brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.

Highlights

Histamine (2-[4-imidazolyl]ethylamine) was discovered by Sir Henry Hallet Dale and Sir Patrick Playfair Laidlaw in 1910 [1]
Zhu et al examined the importance of organic cation transporter 3 (OCT3) in brain histamine concentration [30]. They showed that OCT3 is not involved in brain histamine concentration in normal conditions, whereas histamine content in the brain cortex is elevated in Oct3-deficient mice after cerebral ischemia
These results might indicate the minor contribution of these transporters to brain histamine concentration, further studies are essential to examine the importance of plasma membrane monoamine transporter (PMAT) and OCT3 in histamine clearance

Summary

Introduction

Histamine (2-[4-imidazolyl]ethylamine) was discovered by Sir Henry Hallet Dale and Sir Patrick Playfair Laidlaw in 1910 [1]. Dysfunctional neurotransmitter clearance plays a causative role in various neurological disorders, including SCZ and depression Various drugs, such as tricyclic antidepressants, serotonin norepinephrine re-uptake inhibitors, and monoamine oxidase inhibitors, block neurotransmitter clearance and exert their therapeutic actions in patients suffering from brain diseases. Several reports suggested that PMAT plays a role in serotonin clearance [23,24], and that mutations in the human PMAT genes coupled with low transport activity are related to autism spectrum disorders [25], indicating the involvement of PMAT in brain monoamine concentration. They showed that OCT3 is not involved in brain histamine concentration in normal conditions, whereas histamine content in the brain cortex is elevated in Oct3-deficient mice after cerebral ischemia These results might indicate the minor contribution of these transporters to brain histamine concentration, further studies are essential to examine the importance of PMAT and OCT3 in histamine clearance.

HNMT and Human Brain Diseases

Pharmacological Analysis Using HNMT Inhibitors

Phenotyping of Hnmt-deficient Mice

Future Perspectives