Sevoflurane is an inhalational anesthetics, which is commonly used in cesarean delivery and pediatric clinical application [2]. Previous evidence has suggested that sevoflurane 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 sevoflurane in developing brain. It was found that sevoflurane exposure impaired the neurological function in rats. Additionally, western blot results suggested that sevoflurane treatment influenced the NR2B/ERK signaling related proteins. Furthermore, ifenprodil, NR2B subunit antagonist, administration reversed the effect of sevoflurane on neurological function in rats. It was concluded that NR2B/ERK signaling is involved in sevoflurane induced neurological impairment in rats.
The N-methyl-D-aspartate receptor (NMDAR) is a subtype of ionotropic glutamate receptors which mediate the neuronal plasticity and memory or learning function in the mammalian central nervous system [19]. It is observed that continued NMDAR activation can lead to neuronal injury [20]. Unbalance of NMDARs is widely suggested to be associated with the occurrence and development of various central nervous system diseases, such as ischemic stroke, Alzheimer disease, Parkinson disease and so on [19, 21]. NR2B is a subtype of NMDAR, which is associated with the over activation of NMDAR, followed by the neuronal damage [22]. NR2B overexpression can trigger cell apoptotic pathways, which may be the pathology of the neuroprotective effect of NR2B antagonists [23]. Notably NR2B activation is also closely associated with the activation of ERK signaling [24]. Moreover, NR2B-ERK signaling has been suggested to be involved in the regulation of neuronal survival and participate in the development of neurological diseases [25–27]. In the present study, sevoflurane treatment was suggested to increase the protein level of NR2B and decrease the level of phosphorylated ERK in the hippocampal tissues of rats, indicating that NR2B/ERK signaling might be involved in sevoflurane induced neurological impairment in rats. Furthermore, ifenprodil, the NMDAR antagonist, was selected to inhibit the NR2B subunit, and further verify the role of NR2B/ERK signaling. As expect, ifenprodil administration was observed to alleviate sevoflurane induced leaning and memory dysfunction via MWM test. The results confirmed that sevoflurane exposure led to neurological impairment in rats through regulating NR2B/ERK signaling. Consistently, a study about chronic intermittent hypoxia-hypercapnia (CIHH) reported that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of NR2B expression and the increased expression of ERK signaling [28]. Besides, NR2B-ERK pathway is associated with the recall of morphine-associated contextual memory [29]. All evidences reveal the crucial role of NR2B-ERK signaling in learning and memory function, which supported our present results.
DEX is a useful anesthetic adjuvant, and has been widely used in clinical area. Several studies have reported that DEX regulates the memory formation in a dose-dependent [30]. Considering the neuroprotective role of DEX in various neurological diseases, the current study further explored the role of DEX in sevoflurane induced neurological impairment. The rats were given DEX with different concentration before sevoflurane exposure, and the neurological function was evaluated by MWM test. As expected, the results demonstrated that DEX pretreatment alleviated sevoflurane induced neurological impairment in rats in a dose-dependent manner, and pretreatment with 75 µg/kg DEX had the most dramatic effect. As previous described, DEX is demonstrated to protect against anesthesia-induced neurotoxicity by several studies [31], which was consistent with the present results. Notably, in a study about drug-resistant depression, DEX is suggested to protect against learning and memory impairments caused by electroconvulsive shock in depressed rats [17], these findings supported our present results about the protective role of DEX against sevoflurane induced neurological impairment. Additionally, as the previous study reported, DEX at dose 10 and 25 µg/kg showed neuroprotective effects, and the dose of 25 µg/kg was more effective than 10 µg/kg [17]. Therefore, the current study selected higher dose of 50 and 75 µg/kg, and DEX at a dose of 75 µg/kg had a more powerful neuroprotective effect. Moreover, NR2B-ERK signaling is also reported to participate in the neuroprotective role of DEX in depressed rats [17]. In consideration of the involvement of NR2B-ERK signaling in sevoflurane induced neurological impairment, we suspected that whether NR2B-ERK signaling is involved in the neuroprotective effect of DEX in sevoflurane treated rats. It was found that DEX regulates the NR2B/ERK signaling in sevoflurane treated rats, we concluded that DEX protects against sevoflurane induced neurological dysfunction in the developing rat brain via regulating the NR2B/ERK signaling. However, other studies are needed to verify the present results, and thorough studies should be done for the mechanism exploration.
In conclusion, the present results demonstrated that NR2B/ERK signaling was involved in sevoflurane induced neurological impairment. DEX might protect against sevoflurane induced neurological dysfunction in the developing rat brain via regulating the NR2B/ERK signaling.