Sevoflurane-Induced Neuroapoptosis in Rat Dentate Gyrus Is Activated by Autophagy Through NF-κB Signaling on the Late-Stage Progenitor Granule Cells

Abstract

ObjectiveThe mechanisms by which exposure of the late-stage progenitor cells to the anesthesia sevoflurane alters their differentiation are not known. We seek to query whether the effects of sevoflurane on late-stage progenitor cells might be regulated by apoptosis and/or autophagy.MethodsTo address the short-term impact of sevoflurane exposure on granule cell differentiation, we used 5-bromo-2-deoxyuridine (BrdU) to identify the labeled late-stage progenitor granule cells. Male or female rats were exposed to 3% sevoflurane for 4 h when the labeled granule cells were 2 weeks old. Differentiation of the BrdU-labeled granule cells was quantified 4 and 7 days after exposure by double immunofluorescence. The expression of apoptosis and autophagy in hippocampal dentate gyrus (DG) was determined by western blot and immunofluorescence. Western blot for the expression of NF-κB was used to evaluate the mechanism. Morris water maze (MWM) test was performed to detect cognitive function in the rats on postnatal 28–33 days.ResultsExposure to sevoflurane decreased the differentiation of the BrdU-labeled late-stage progenitor granule cells, but increased the expression of caspase-3, autophagy, and phosphorylated-P65 in the hippocampus of juvenile rats and resulted in cognitive deficiency. These damaging effects of sevoflurane could be mitigated by inhibitors of autophagy, apoptosis, and NF-κB. The increased apoptosis could be alleviated by pretreatment with the autophagy inhibitor 3-MA, and the increased autophagy and apoptosis could be reduced by pretreatment with NF-κB inhibitor BAY 11-7085.ConclusionThese findings suggest that a single, prolonged sevoflurane exposure could impair the differentiation of late-stage progenitor granule cells in hippocampal DG and cause cognitive deficits possibly via apoptosis activated by autophagy through NF-κB signaling. Our results do not preclude the possibility that the affected differentiation and functional deficits may be caused by depletion of the progenitors pool.

Propofol and Sevoflurane Anesthesia in Early Childhood Do Not Influence Seizure Threshold in Adult Rats

“…In order to test the hypothesis that neuropathological alterations induced by propofol and sevoflurane during synaptogenesis in rats may lead to changes in seizure threshold during adulthood, we adopted protocols described by Bercker et al and Tong et al [ 4 , 13 ].…”

“…The exposure of rats to sevoflurane was carried out according to Tong et al [ 13 ] with minor modification. In our study rats were younger (D6 vs. D21) and time of exposure was longer (6 h vs. 4 h).…”

“…They have proven that sevoflurane anesthesia in juvenile rats has caused a significant increase in apoptosis in newly-born granule cells of dentate gyrus in rats 2 h, 24 h, 4 days, and 7 days after exposure. Additionally, they demonstrated that exposure to sevoflurane decreased the differentiation of the BrdU-labeled late-stage progenitor granule cells but increased the expression of caspase-3, autophagy, and phosphorylated-P65 in the hippocampus of juvenile rats and resulted in cognitive deficiency [ 13 ]. Noteworthy, dentate gurus, which is a region of the hippocampus, is strictly associated with epileptogenesis [ 42 ].…”

“…According to protocol described by Tong et al [ 13 ] the rats in the sevoflurane group (30 rats) were placed in a plastic chamber (EZ Anesthesia, Palmer, MA, USA) and exposed to 2.5–3.5% sevoflurane (Abbott Laboratories, Abott Park, IL, USA) for 6 h with oxygen and air mixture (30% oxygen) as a carrier at a gas flow of 2 L/min. During sevoflurane exposure, the rats were placed on a warming device heated to 38 °C (NPS A3; Midea Group Co., Ltd., Foshan, China).…”

“…Substances that act on the GABA or NMDA receptor during a BGS could potentially influence the process of synaptogenesis. Prolonged exposure of developing rats to sevoflurane and propofol has been proven to cause neurodegeneration and apoptosis in the brain [ 4 , 13 ]. When given during synaptogenesis, ethanol, a non-specific GABA agonist, impacts not only the neurotransmitter production, but also the receptor density in various brain regions [ 14 , 15 ].…”