Tackling Neuroinflammation in Cognitive Disorders with Single-targeted and Multi-targeted Histamine H3 Receptor Modulators

Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H₃ receptor (H₃R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H₃R ligands for various brain diseases. H₃R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H₃R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H₃R antagonists/inverse agonists for the treatment of these conditions is discussed here.