Abstract
Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, causes neurodegeneration in the developing animal brains. Recent studies showed that dexmedetomidine, a selective α2-adrenergic agonist, reduced isoflurane-induced cognitive impairment and neuroapoptosis. However, the mechanisms for the effect are not completely clear. Thus, we investigated whether exposure to isoflurane or sevoflurane at an equivalent dose for anesthesia during brain development causes different degrees of neuroapoptosis and whether this neuroapoptosis is reduced by dexmedetomidine via effects on PI3K/Akt pathway that can regulate cell survival. Seven-day-old (P7) neonatal Sprague-Dawley rats were randomly exposed to 0.75% isoflurane, 1.2% sevoflurane or air for 6 h. Activated caspase-3 was detected by immunohistochemistry and Western blotting. Phospho-Akt, phospho-Bad, Akt, Bad and Bcl-xL proteins were detected by Western blotting in the hippocampus at the end of exposure. Also, P7 rats were pretreated with various concentrations of dexmedetomidine alone or together with PI3K inhibitor LY294002, and then exposed to 0.75% isoflurane. Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) and activated caspase-3 were used to detect neuronal apoptosis in their hippocampus. Isoflurane, not sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased the levels of phospho-Akt and phospho-Bad proteins, increased the expression of Bad protein and reduced the ratio of Bcl-xL/Bad in the hippocampus. Dexmedetomidine pretreatment dose-dependently inhibited isoflurane-induced neuroapoptosis and restored protein expression of phospho-Akt and Bad as well as the Bcl-xL/Bad ratio induced by isoflurane. Pretreatment with single dose of 75 µg/kg dexmedetomidine provided a protective effect similar to that with three doses of 25 µg/kg dexmedetomidine. Moreover, LY294002, partly inhibited neuroprotection of dexmedetomidine. Our results suggest that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.
Highlights
Volatile anesthetics, such as isoflurane and sevoflurane, are used in millions of young children every year during surgical procedures and imaging studies [1]
Our results found that isoflurane at low concentration (0.75%) did not decrease the level of blood glucose significantly (Table 1), which indicates that the neuroapoptosis and protein change induced by isoflurane as described below are not related to hypoglycemia
The present study demonstrated that isoflurane, not sevoflurane, at equivalent low dose, induced neuroapoptosis in the neonatal rat hippocampus and that dexmedetomidine pretreatment provided neuroprotection against isoflurane-induced neuroapoptosis in a dose-dependent manner
Summary
Volatile anesthetics, such as isoflurane and sevoflurane, are used in millions of young children every year during surgical procedures and imaging studies [1]. Recent studies have demonstrated that prolonged exposure to isoflurane and sevoflurane causes neurodegeneration in the developing animal brains and persistent learning deficits [2,3,4,5,6,7,8]. Some clinical retrospective studies have indicated that anesthesia and surgery in children younger than 4 years probably increase their probability of developing disabilities in reading, writing and math learning [10,11]. These findings have led to the concern about the possible detrimental effects of anesthesia and sedation in the pediatric population. It is important to explore the mechanisms of anesthesia-induced neurodegeneration and to develop potential protective strategies for it
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