Role of the GABAA receptors in the long-term cognitive impairments caused by neonatal sevoflurane exposure

Sevoflurane is a widely used inhalational anesthetic in pediatric surgeries, which is considered reasonably safe and reversible upon withdrawal. However, recent preclinical studies suggested that peri-neonatal sevoflurane exposure may cause developmental abnormalities in the brain. The present review aimed to present and discuss the accumulating experimental data regarding the undesirable effects of sevoflurane on brain development as revealed by the laboratory studies. First, we summarized the long-lasting side effects of neonatal sevoflurane exposure on cognitive functions. Subsequently, we presented the structural changes, namely, neuroapoptosis, neurogenesis and synaptogenesis, following sevoflurane exposure in the immature brain. Finally, we also discussed the potential mechanisms underlying subsequent cognitive impairments later in life, which are induced by neonatal sevoflurane exposure and pointed out potential strategies for mitigating sevoflurane-induced long-term cognitive impairments. The type A gamma-amino butyric acid (GABA(A)) receptor, the main targets of sevoflurane, is excitatory rather than inhibitory in the immature neurons. The excitatory effects of the GABA(A) receptors have been linked to increased neuroapoptosis, elevated serum corticosterone levels and epigenetic modifications following neonatal sevoflurane exposure in rodents, which might contribute to sevoflurane-induced long-term cognitive abnormalities. We proposed that the excitatory GABA(A) receptor-mediated HPA axis activity might be a novel mechanism underlying sevoflurane-induced long-term cognitive impairments. More studies are needed to investigate the effectiveness and mechanisms by targeting the excitatory GABA(A) receptor as a prevention strategy to alleviate cognitive deficits induced by neonatal sevoflurane exposure in future.