Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling

Abstract

It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors contributed to the relief of sevoflurane neurotoxicity, and the ERK1/2 MAPK signaling may be involved in this process.

Lycium�barbarum polysaccharides attenuates the apoptosis of hippocampal neurons induced by sevoflurane

“…The activation of ERK1/2 is necessary for signal transduction, from cell membrane surface receptors to nucleus. ERK1/2 MAPK signaling pathway has been reported to play essential roles in developmental neuronal survival and sevoflurane neurotoxicity (6–8), to increase dendritic spine density during synaptogenesis in hippocampal neurons, and to help improving learning and memory abilities (37,38). MEK (ERK1/2 kinase) inhibitor PD98059 is specific for ERK1/2 pathway, by noncompetitively binding to MEK, it is commonly used to block ERK1/2 pathway.…”

“…Recent researches have demonstrated that ERK1/2 plays positive roles in neuroprotective processes. Sevoflurane neurotoxicity in immature brain is related to ERK1/2 signaling pathway and apoptosis related factors such as Caspase-3, B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2 associated X (Bax) (6–8). It would be interesting to know whether LBP effects on sevoflurane-injured neurons through ERK1/2 pathway.…”

Effects of Sevoflurane on Young Male Adult C57BL/6 Mice Spatial Cognition

“…Upregulation of phosphorylated ERK1/2 (p-ERK1/2) upon NMDA stimulation promotes neuronal survival, whereas downregulation of p-ERK1/2 leads to severe neurodegeneration[ 16 , 17 ]. Sevoflurane has been reported to inhibit the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the hippocampal tissues [ 18 ]. Due to the critical role of NMDA receptors and its downstream signaling molecules in learning and memory processes[ 19 ], these receptors may play a role in sevoflurane-induced cognition change in brain.…”

Role of NR2B/ERK signaling in the neuroprotective effect of dexmedetomidine against sevoflurane induced neurological dysfunction in the developing rat brain

“…Sevo urane is an inhalational anesthetics, which is commonly used in cesarean delivery and pediatric clinical application [2]. Previous evidence has suggested that sevo urane exposure has certain harm on learning and cognitive functions, especially for children [5,11]. In the current study, the P7 rats were recruited for animal experiments to investigate the role of sevo urane in developing brain.…”

“…It is widely used in cesarean delivery and pediatric clinical application [2]. Sevo urane has some neurotoxicity for the nervous system, especially for developing brain [3][4][5]. The animal experiments have proved that volatile anesthetics at clinical concentrations can lead to neuronal apoptosis and impair the learning ability and cognitive function in neonatal and aged rodents [6][7][8].…”