Suppression of ERK phosphorylation through oxidative stress is involved in the mechanism underlying sevoflurane-induced toxicity in the developing brain

Abstract

In animal models, neonatal exposure to general anesthetics significantly increased neuronal apoptosis with subsequent behavioral deficits in adulthood. Although the underlying mechanism is largely unknown, involvement of extracellular signal-regulated kinases (ERKs) is speculated since ERK phosphorylation is decreased by neonatal anesthetic exposure. Importance of ERK phosphorylation for neuronal development is underscored by our recent finding that transient suppression of ERK phosphorylation during the neonatal period significantly increased neuronal apoptosis and induced behavioral deficits. However, it is still unknown as to what extent decreased ERK phosphorylation contributes to the mechanism underlying anesthetic-induced toxicity. Here we investigated the causal relationship of decreased ERK phosphorylation and anesthetic-induced toxicity in the developing brain. At postnatal day 6 (P6), mice were exposed to sevoflurane (2%) or the blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) (50 mg/kg). Transient suppression of ERK phosphorylation by an intraperitoneal injection of SL327 at P6 significantly increased apoptosis similar to sevoflurane-induced apoptosis. Conversely, SL327 administration at P14 or P21 did not induce apoptosis, even though ERK phosphorylation was inhibited. Restoring ERK phosphorylation by administration of molecular hydrogen ameliorated sevoflurane-induced apoptosis. Together, our results strongly suggests that suppressed ERK phosphorylation is critically involved in the mechanism underlying anesthetic-induced toxicity in the developing brain.

Sevoflurane improves respiratory mechanics and gas exchange in a case series of infants with severe bronchiolitis‐induced acute respiratory distress syndrome

“…Preclinical data suggest that anesthetic and hypnotic drugs such as halogenated agents and midazolam may affect brain development [24]. The GAS study [25] found no increase in adverse neurodevelopmental outcome in infants exposed to a short period of sevoflurane anesthesia.…”

“…The GAS study [25] found no increase in adverse neurodevelopmental outcome in infants exposed to a short period of sevoflurane anesthesia. Long-term use of sevoflurane in children and its effect on neurological development remains unclear (24).…”

The effect of Cyanidin-3-o-glucoside on UVA-induced damage in human dermal fibroblasts

“…Therefore, it appears that the phosphorylation levels of ERK may be related to the dose of UVA and incubation time, although further study will be required for verification of this hypothesis. Decreased ERK phosphorylation induced by oxidative stress leads to toxic effects on brain development . Additionally, mouse neuronal apoptosis within 6 days after birth can be induced by the transient blockade of ERK activation .…”

Phosphodiesterase 4 Inhibitor Roflumilast Protects Rat Hippocampal Neurons from Sevoflurane Induced Injury via Modulation of MEK/ERK Signaling Pathway

“…Neuronal ERK activation is a central mean of transducing neurotransmitter and neurotrophic signals, and thereby participates in a wide range of activities including neural survival, protection, and stress-related behavioral responses [23]. Suppression of MEK/ERK and mTOR phosphorylation is critically involved in the mechanism underlying anesthetic-induced toxicity in the developing brain [24-26]. In the current study, by performing western blot analysis, we found that sevoflurane inhibited the activation of MEK/ERK signaling, but has no impact on mTOR signaling.…”