Examining the mechanisms of dexmedetomidine's protective effect against ketamine-induced neurotoxicity in neonatal rats

Neurotoxicity caused by the repeated or long-term administration of anesthetics and sedatives during the neurodevelopmental period, leading to behavioral and cognitive impairments, continues to be a matter of concern. This study aimed to investigate the neurobiological and histological changes in the brain as well as the potential long-term neurocognitive dysfunction associated with the repeated administration of ketamine (KET) and dexmedetomidine (DEX), commonly used anesthetics and sedatives in the clinic, during the neonatal period in rats. Postnatal day 7 (PND7) rat pups were divided into 4 injection groups: %0,9 NaCl (control group); KET (50 mg/kg); DEX (25 μg/kg); DEX (25 μg/kg) and KET (50 mg/kg). Intraperitoneal injections were performed for 3 consecutive days (PND8-10). To assess developmental neurotoxicity in the hippocampus, which is highly susceptible to anesthetic-induced effects, apoptotic activity was evaluated using caspase-3, Bax, and Bcl-2, while the presence of pyroptosis, an inflammatory-programmed cell death pathway, assessed by measuring caspase-1, gasdermin D, IL-1b, and IL-18 protein levels using ELISA assays on PND11 and PND45. Long-term histological changes were examined in whole brain tissues taken on PND45. Long-term effects on cognitive functions such as learning, memory, and attention were evaluated on PND40 using the Barnes maze and object recognition tests. The combined administration of DEX and KET enhanced deeper sedation. This study concluded that KET, when administered at a dose of 50 mg/kg and repeated for 3 days, did not show significant neurotoxic effects at the protein and histological levels. However, Both KET and DEX, when administered individually, led to impaired object recognition memory and attention in the long term. It has been demonstrated that dexmedetomidine can exhibit acute neuroprotective properties at the protein level. This study shows that the combined administration of DEX and KET may provide more advantageous use in both cognitive functions and enhancing sedative effects.