Histamine H3 Receptor Antagonist, Thioperamide, Improves Behavioral and Neuropathological Changes Associated with Subclinical Hypersensitivity to a Cow’s Milk Allergen

Mood and behavior-related comorbidities are often reported with food allergies, an atopic condition that elevates histamine (HA) levels in tissues and circulation. However, whether allergy-induced HA directly affects the central nervous system is unclear. Previously, we demonstrated that the levels of HA and its receptor subtype, H3 receptor (H3R), were elevated in the brains of mice with subclinical cow's milk allergy (CMA) generated by sensitizing C57BL/6J mice to a bovine whey allergen, β-lactoglobulin (BLG, Bos d 5). Furthermore, these BLG-sensitized CMA mice showed depression-like behavior associated with mast cell activation, neuroinflammation, and cortical demyelination, leading us to postulate that peripheral immune responses raised brain HA and dysregulated the neuronal histaminergic system. Hypothesizing that the autoregulatory function of H3R signaling is pivotal in eliciting altered behavior and neuropathologies, we investigated whether thioperamide, a brain-permeable H3R-selective antagonist, would attenuate the changes observed in CMA mice. Male and female CMA mice were fed a whey-containing diet for 2 weeks without or with thioperamide. While sensorimotor functions were not impaired in CMA mice of either sex, some aspects of affective and cognitive behaviors were significantly altered in males. Male CMA mice also showed more IgE-immunopositive, degranulated mast cells in the dura mater than females, regardless of thioperamide treatment. Importantly, thioperamide reduced CMA-associated behavioral and neuropathological changes in male mice, although it also uniquely affected female mice. Our results suggest that thioperamide ameliorates CMA-associated behavioral changes and neuropathologies via H3R inhibition in a sex-dependent manner.