Linagliptin, a Selective DPP-4 Inhibitor, Attenuates Ketamine- and Diazepam-Induced Deficits in Passive Avoidance Performance in Mice

Background: Linagliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes, enhances glucagon-like peptide-1 (GLP-1) signaling. Because GLP-1 receptors are widely expressed in the brain, DPP-4 inhibitors have emerged as potential modulators of central nervous system function. The present study investigated the effects of linagliptin (10 and 20 mg/kg, i.p.) on ketamine- (10 mg/kg, i.p.) and diazepam-induced (2 mg/kg, i.p.) deficits in passive avoidance performance in mice. Behavioral effects were assessed using the passive avoidance test, and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex and hippocampus were determined by enzyme-linked immunosorbent assay (ELISA). Linagliptin attenuated ketamine- and diazepam-induced deficits in passive avoidance performance. In addition, both acute and chronic administration of linagliptin increased BDNF levels in the prefrontal cortex but not in the hippocampus. These findings provide preliminary evidence that linagliptin modulates passive avoidance performance in mice and is associated with increased BDNF levels in the prefrontal cortex. Further studies employing complementary behavioral paradigms and additional molecular approaches are required to clarify the neuropharmacological mechanisms underlying these effects.