Cognitive and Pyroptotic Outcomes of Neonatal Ketamine and Dexmedetomidine: Potential Neuroprotection via Caspase‐1 Modulation

ABSTRACT

Neurotoxicity induced by the repeated anesthetic exposure during the neurodevelopmental period and its potential long‐term cognitive consequences remain a matter of concern. This study investigated the neurobiological and histological changes in the hippocampus as well as potential long‐term neurobehavioral alterations, following repeated administration of ketamine (KET) and dexmedetomidine (DEX) in neonatal rats. Postnatal Day 7 (PND7) rat pups were randomly assigned to four groups: Control (0.9% NaCl), KET (50 mg/kg), DEX (25 µg/kg), and DEXKET (DEX (25 µg/kg) + KET (50 mg/kg)). Intraperitoneal (i.p.) injections were performed for three consecutive days (PND8‐10). Developmental neurotoxicity was assessed by measuring apoptotic markers (caspase‐3, Bax, and Bcl‐2) and pyroptosis‐related proteins (caspase‐1, gasdermin D, IL‐1β, and IL‐18) in hippocampus via ELISA. Western blotting was used to analyze long‐term hippocampal caspase‐1, brain‐derived neurotrophic factor (BDNF), and growth associated protein 43 (GAP43) levels. Long‐term cognitive effects, including learning, memory, and attention, were evaluated on PND40 using the Barnes maze and the novel object recognition (NOR) tests. Hippocampal morphology was examined by Nissl staining. Although KET or DEX alone did not alter classical apoptotic pathways, they significantly reduced caspase‐1. However, both KET and DEX alone impaired recognition memory and attention in the long term, without altering spatial learning. Notably, the combined administration of KET and DEX enhanced sedation while maintaining caspase‐1, BDNF, and GAP43 levels close to control values, preserving recognition memory and spatial learning. These findings indicate that co‐administration of KET and DEX during the neonatal period may provide a safer anesthetic strategy by reducing cognitive side effects and modulating neuroinflammatory pathways.