Histamine 3 receptor antagonism mitigates neuroinflammation and depression-like behavior in a mouse model of food allergy

Abstract

Abstract Histamine (HA) is a major allergic response mediator as well as a neuromodulatory neurotransmitter and a blood-brain barrier (BBB) regulator. Consequently, dysregulation of the central histaminergic system could offset brain homeostasis and function. Indeed, mood and behavioral disorders are often comorbid with conditions that elevate systemic HA, such as mastocytosis and allergy. We have previously shown elevated levels of brain HA and its receptor subtype H3 (H3R) in a mouse model of cow’s milk allergy (CMA). Additionally, neuroinflammation and cortical demyelination were observed in association with depression-like behavior in CMA mice. However, whether the elevated HA and H3R were responsible for the development of these cellular and behavioral pathologies is unknown. We hypothesized that the elevated brain HA leads to central histaminergic dysfunction through H3R, ultimately resulting in cortical demyelination and aberrant behaviors. To investigate the role of H3R, CMA mice were treated daily with thioperamide, a selective BBB-permeable H3R antagonist, to block the action of HA through this receptor. Despite the production of allergen-specific IgE, thioperamide prevented depression-like behavior. Thioperamide also ameliorated CMA-associated cortical demyelination and axonal loss compared to saline-treated mice. Our findings strongly suggested that H3R signaling contributed to cortical demyelination and the development of depression-like behaviors in our CMA mice. Targeting HA production or signaling may provide a therapeutic strategy to reduce the risk of neurodegeneration and associated brain dysfunction in susceptible individuals. Supported by grants from NIH (1R01AI168563-01, P20GM113123-06, and P20GM103442).