Children exposed to general anesthetics such as isoflurane are maybe at an increased risk of cognitive impairment. Recent studies have indicated that this kind of cognitive decline is associated with neuroinflammation in the hippocampus of neonatal rodents. Glycyrrhizin is a naturally available compound for the treatment of inflammatory and neurodegenerative diseases. We therefore aimed to investigate the effects of glycyrrhizin on the isoflurane-induced cognitive deficits and hippocampal neuroinflammation in the neonatal rats. Seven day-old rats were exposed to 1.8% isoflurane for 4 h. Saline and glycyrrhizin solution was injected intraperitoneally 30 min prior to isoflurane or control gas exposure. The effects of isoflurane and glycyrrhizin treatment on memory performance were examined using Morris Water Maze (MWM) task. The protein expression of high-mobility group box 1 (HMGB1), NF kappa B, Bcl-2, Bax and cleaved (active) caspase-3 were determined by Western blot assay. The protein levels of TNF-alpha and IL-1 beta were detected by enzyme-linked immunosorbent assay (ELISA). The combination of ELISA and Western blot results showed that glycyrrhizin attenuated isoflurane-induced increases of pro-inflammatory cytokines (TNF-alpha and IL-1 beta) and activation of HMGB1/NF kappa B signaling pathway in the hippocampus of neonatal rats. Furthermore, glycyrrhizin treatment prevented the deficits in spatial memory induced by neonatal exposure to isoflurane. Consistent with these observations, we found that glycyrrhizin alleviated isoflurane-induced neuroapoptosis and down-regulations of PSD-95 and SNAP-25 in the hippocampus of neonatal rats. These results suggest that glycyrrhizin may be a potential therapeutic agent for developmental neurotoxicity and subsequent cognitive decline induced by neonatal exposure to general anesthetics. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.