Histamine-4 Receptor: Emerging Target for the Treatment of Neurological Diseases

A major challenge in the field of the biogenic amine histamine is the search for new-generation histamine receptor specific drugs. Daniel Bovet and Sir James Black received their Nobel Prizes for Medicine for their work on histamine-1 receptor (H₁R) and H₂R antagonists to treat allergies and gastrointestinal disorders. The first H₃R-targeting drug to reach the market was approved for the treatment of the neurological disorder narcolepsy in 2018. The antagonists for the most recently identified histamine receptor, H₄R, are currently under clinical evaluation for their potential therapeutic effects on inflammatory diseases such as atopic dermatitis and pruritus. In this chapter, we propose that H₄R antagonists are endowed with prominent anti-inflammatory and immune effects, including in the brain. To substantiate this proposition, we combine data from transcriptional analyses of postmortem human neurodegenerative disease brain samples, human genome-wide association studies (GWAS), and translational animal model studies. The results prompt us to suggest the potential involvement of the H₄R in various neurodegenerative diseases and how manipulating the H₄R may create new therapeutic opportunities in central nervous system diseases.