Chronic pantoprazole exposure induces behavioral deficits and region‑specific molecular changes in the rat motor cortex and cerebellum

Abstract

Proton pump inhibitors are widely used, but their long‑term effects on the central nervous system are not well understood. In this study, we investigated whether chronic pantoprazole use alters sensorimotor function, oxidative stress, inflammatory response, and apoptosis in the motor cortex and cerebellum. Twenty‑one female Wistar rats were randomized to control (C), gavage control (GC), or pantoprazole (P; 20 mg/kg/day for 12 weeks) groups. Sensorimotor coordination (rotarod), water‑maze swim velocity, and open‑field locomotion were assessed as behavioral parameters. The cortical and cerebellar tissues were analyzed by Enzyme‑Linked Immunosorbent Assay (ELISA) for apoptosis, inflammation, and oxidative stress. Pantoprazole impaired sensorimotor coordination compared to both control groups. However, its effects on swim velocity and locomotor activity were primarily significant when compared to the naive control group, suggesting that gavage‑related stress may have contributed to these behavioral outcomes. Bcl‑2‑associated X protein (BAX) and Bcl‑2 associated agonist of cell death (BAD) protein levels and the BAX/Bcl‑2 ratio increased with pantoprazole, particularly in the motor cortex, indicating enhanced pro‑apoptotic activity. While tumor necrosis factor levels did not change, interleukin (IL)‑6 and IL‑1β levels were significantly higher in the cerebellum, suggesting neuroinflammatory activation associated with both pantoprazole and gavage‑induced stress. Furthermore, oxidative stress analyses revealed elevated malondialdehyde and oxidative stress index levels, as well as increased total antioxidant status, in specific regions, suggesting an imbalance between oxidative and antioxidant responses. Chronic pantoprazole administration resulted in modest motor deficits and region‑specific molecular alterations, including a pro‑apoptotic shift in the motor cortex. In addition, an inflammatory/compensatory antioxidant response in the cerebellum was observed due to both gavage‑induced stress and pantoprazole administration. These findings highlight the need for further studies on dose‑response, reversibility, and synaptic consequences, and suggest the importance of considering the risks of prolonged proton pump inhibitors exposure.