Neonatal Sevoflurane-induced Cognitive Impairments Were Associated With Adverse Environment In Later Acquired Life

Background. The neurotoxicity of clinical inhalation anesthetics has always been controversial. Animal studies have shown that sevoflurane (sevoflurane, SEV) exposure on newborn mice have certain central nerve toxicity, which can cause cognitive decline in the later life. Since the selection of anesthesia or the differences in acquired environment after anesthesia, the cognitive impairment after SEV vary widely. The influence of SEV on children’s cognitive function is still a big debate. The present study tested the hypothesis that developmental effects of neonatal exposure to SEV in rats are associated with adverse environment in later acquired life.Methods. Sprague-Dawley male rats received repeated exposures to 3% SEV (FiO2 50%) for 2 h on postnatal days (P) 6,7, and 8 (SEV group). Control group received repeated exposures to 50% FiO2 for 2 h on postnatal days (P) 6,7, and 8 (SEV group). In the first set of experiments:the acute effects of SEV were studied by assessing apoptotic neuronal profiles, levels of BDNF and synaptic markers in the hippocampus of the SEV-exposed and control rats 6 h after the last SEV exposure (n=6) or last maternal separation only (n=6), respectively. To determine the effect of SEV on neural progenitor proliferation in the hippocampus, the SEV-exposed (n=6) and control (n=6) rat pups received the thymidine analog, bromodeoxyuridine (BrdU,75 mg/kg, i.p.), over three consecutive days from P8 to P10. The BrdU+cells were determined at P11 using immunohistochemistry. In the second set of experiments:the effects of the adverse and enriched environments (AE and EE, respectively) on SEV-induced changes in brain biochemical markers and neurocognitive function were studied. The rats were divided into four treatment groups:SEV-exposed rats housed in the AE (SEV+AE); SEV-exposed rats housed in the EE (SEV+EE); control rats housed in the AE (CON+AE); and control rats housed in the EE (CON+EE). Subset of animals (n=6) from each treatment group received BrdU (75 mg/kg, i.p.) for six consecutive days from P22 to P27. At P53, the survival of BrdU+ cells, the levels of BDNF and synaptic markers in the hippocampus were evaluated (n=6 per measurement per treatment group). Separately, the neurocognitive function tests were performed at P49 to P53 (n=10 per treatment group). Upon completion of these tests, the rats were not used in any other experiments and were euthanized as described above. In the third set of experiments:the effects of 2-APB on the SEV-induced acute neuroapoptosis in the hippocampus and neurocognitive function in rats housed in the AE conditions were determined. One-half of SEV-exposed and control rats were pretreated with 2-APB [10 mg/kg, i.p.] 15 min prior to induction of anaesthesia; the other half of the rat pups received an equal volume of vehicle (VEH).2-APB was first dissolved in dimethyl sulfoxide to 20 mg/mL and then diluted with saline to 0.5 mg/mL (1:40 dilution). The brain tissue samples were isolated 6 h after the last SEV exposure as described below (brain tissue harvest and protein level quantification). Apoptotic neuronal profiles in the hippocampus of rats from the CON+VEH, CON+2-APB, SEV+VEH and SEV+2-APB groups (n=6 per treatment group) were determined. The neurocognitive function was evaluated at P49 to P53 (n=10). These animals were not used in any other experiments and were euthanized as described above.Results. SEV acutely increased levels of cleaved caspase-3 and reduced levels of BDNF, synaptic markers and neural progenitor proliferation. The SEV group housed in the AE conditions (SEV+AE) had decreased levels of BDNF and synaptic markers, and survival of new granule cells and cognitive function compared to the CON+AE, CON+EE, and SEV+EE groups. The neurobehavioral parameters in the SEV+EE and CON+EE groups were similar. Pretreatment with 2-APB reduced acute increase in levels of cleaved caspase-3 but did not affect SEV-induced neurocognitive dysfunction.Conclusions. Neonatal SEV-induced long-term cognitive impairments were associated with adverse environment in later acquired life.