Chronic pantoprazole administration impairs memory behavior and motor function in mice independent of serum nutrient changes.

Long-term proton pump inhibitor use is associated with cognitive and motor impairments and nutrient deficiencies. Whether these impairments result directly from proton pump inhibitors or indirectly from nutrient deficiencies remains unclear. Chronic pantoprazole treatment (0 or vehicle, 1, 10, or 100 mg/kg/day, by mouth, 38 days) was evaluated across tests of anxiety-like behavior, learning and memory behavior, and motor function and coordination in 4-month-old male C57BL/6 mice. Serum levels of holotranscobalamin and magnesium, as well as poly(A) RNA sequencing of brain tissue, were subsequently evaluated. Pantoprazole (100 mg/kg) reduced the percentage of spontaneous alternations in the Y-maze (P < .05 vs 0 and 1 mg/kg) and decreased the distance traveled in Rotarod testing (P < .05 vs vehicle), suggesting that it impaired short-term working memory behavior and motor coordination, respectively. All pantoprazole doses increased anxiety-like behavior in the open field (P < .05 vs vehicle). In novel (N) object recognition testing, pantoprazole (1 mg/kg) reduced the discrimination index at 24 hours (P < .05, vs vehicle), suggesting it impaired recognition memory behavior. Magnesium levels were similar across chronic pantoprazole groups. Holotranscobalamin, the bioavailable form of vitamin B12, was lower at 10 mg/kg pantoprazole (P < .05 vs vehicle). Poly(A) RNA sequencing identified 15 differentially expressed genes in hippocampus (10 upregulated and 5 downregulated) and 32 in FC (14 upregulated and 18 downregulated) with 100 mg/kg pantoprazole treatment compared to vehicle. There was no correspondence between behavioral changes and alterations in serum nutrient levels with the respective doses of pantoprazole. SIGNIFICANCE STATEMENT: Long-term proton pump inhibitor use may affect cognition, motor function, and nutrient status. This study examined the behavioral impact of chronic pantoprazole treatment in young male mice and whether declines in serum magnesium or holotranscobalamin levels could explain behavioral changes. Doses of chronic pantoprazole that altered behavior were not associated with declines in either nutrient.