Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABA_AR α1/GABA_AR α2 ratio

Abstract

Exposure of neonatal rat to sevoflurane leads to neurodegeneration and deficits of spatial learning and memory in adulthood. However, the underlying mechanisms remain unclear. The type A γ-aminobutyric acid receptor (GABA R) is a target receptor for sevoflurane. The present study intends to investigate the changes in GABA R α1/α2 expression and its relationship with the neurotoxicity effect due to sevoflurane in neonatal rats. After a dose-response curve was constructed to determine minimum alveolar concentration (MAC) and safety was guaranteed in our 7-day-old neonatal rat pup mode, we conducted two studies among the following groups: (A) the control group; (B) the sham anesthesia group; and (C) the sevoflurane anesthesia group and all three groups were treated in the same way as the model. First, poly(ADP-ribose) polymerase-1 protein (PARP-1) expression was determined in the different brain areas at 6 hr after anesthesia. Second, the expression of PARP-1 and GABA R α1/GABA R α2 in the hippocampus area was tested by Western blotting at 6 hr, 24 hr, and 72 hr after anesthesia in all three groups. After 4 hr, with 0.8 MAC (2.1%) sevoflurane anesthesia, the PARP-1 expression was significantly higher in the hippocampus than the other brain areas (p < .05). Compared with Groups A and B, the expression of PARP-1 in the hippocampus of Group C significantly increased at 6 hr after sevoflurane exposure (216% ± 15%, p < .05), and the ratio of the α1/α2 subunit of GABA R surged at 6 hr (126% ± 6%), 24 hr (127% ± 8%), and 72 hr (183% ± 22%) after sevoflurane exposure in the hippocampus (p < .05). Our study showed that sevoflurane exposure of 0.8 MAC (2.1%)/4 hr was a suitable model for 7-day-old rats. And the exposure to sevoflurane could induce the apoptosis of neurons in the early stage, which may be related to the transmission from GABA R α2 to GABA R α1.

Sevoflurane addiction due to workplace exposure

“…We selected the BWSQ2 scale because both sevoflurane and benzodiazepines cause addiction primarily through the activation of the γ-aminobutyric acid (GABA) A receptor. [ 6 , 15 – 17 ] A previous report also used the BWSQ2 scale to assess the withdrawal symptoms for propofol dependence, which activates the GABA A receptor. [ 18 ] In this case, there was a markedly shorter duration in the WS than the craving (Figs.…”

“…[ 3 ] Accumulated evidence indicates that sevoflurane induces neurodegeneration and apoptosis in vitro and vivo. [ 6 – 8 ] Neurons in the developing brain are specifically vulnerable to anesthetics, although the concentration of sevoflurane is 20-fold less than the recommended threshold values that induce apoptosis. [ 1 , 19 , 20 ] Second, there is a significant relationship between the rate of spontaneous abortion and occupational exposure to anesthetics.…”

WNK1 Antagonist Decreased Sevoflurane-induced Neurotoxicity in HT22 Hippocampal Neurons via the WNK1/NKCC1 Signalling Pathway

“…WNK (with no lysine) kinases are Cl − -sensing kinases, including WNK1, that regulate the activities of NKCC1 and KCC2 [17] . In our previous study, we found that sevo urane's neurotoxicity on the developing brain was related to the changes in the transition of GABA A R a1 and a2 [18] . This neuronal damage was decreased by the NKCC1 inhibitor bumetanide [18] .…”

Egr2 Upregulation Induced Mitochondrial Iron Overload Implicating in Cognitive Deficits after Sevoflurane Administration

“…Previous studies documented that sevo urane inhalation signi cantly aggravated cognitive de cits by initiating neuroin ammation and neurotoxicity in rat hippocampus [9]. Sevo urane administration triggers a series of pathophysiologic reactions comprising of mitochondrial dysfunction [10] and endoplasmic reticulum stress [11], and thereby results in cognitive dysfunction by inducing neuronal apoptosis [12], synaptogenesis impairment [13], and neuroin ammation [14].…”