Repeated exposure to sevoflurane in neonatal rats impairs cognition in adulthood via the PKA-CREB-BDNF signaling pathway

Sevoflurane (Sev) anesthesia is widely used in pediatrics due to its low blood-gas partition coefficient and lack of pungency. However, Sev treatment may lead to cognitive dysfunction in later life. The current study administered Sev to neonatal rats to investigate the effects of Sev treatment on cognitive performance in adulthood. In total, 6-day-old rats received 3% Sev for 2 h daily for 3 consecutive days. The cognitive function of rats in adulthood was evaluated in 56-day-old rats by Morris water maze test. The hippocampal neuron morphology was observed by Nissl staining. Hippocampal brain-derived neurotrophic factor (BDNF) levels were measured by ELISA. The protein expression of protein kinase A (PKA), cAMP response element binding protein (CREB), phosphorylated-CREB (p-CREB) and BDNF in hippocampus were assessed by western blotting. The water maze results demonstrated that neonatal treatment with Sev resulted in a significant impairment of cognition in 56-day-old adult rats. Behavioral analysis revealed that Sev treatment increased latency to first pass the platform and decreased residence in target quadrants and across platform frequency compared with the control group in Morris water maze tests. Furthermore, compared with the control group, neonatal exposure to Sev reduced the number of neurons and the concentration of BDNF in the hippocampus, a brain region important for learning and memory. Additionally, Sev significantly decreased the expression of PKA, p-CREB, BDNF and the p-CREB/CREB ratio. Treatment with bucladesine, a selective PKA agonist, partially reversed the deleterious effects of Sev. In summary, the results indicated that PKA-CREB-BDNF signaling served an important role in the cognitive decline caused by neonatal exposure to Sev.