BackgroundConsiderable evidences support the finding that the anesthesia reagent isoflurane increases neuronal cell death in young rats. Recent studies have shown that dexmedetomidine can reduce isoflurane-induced neuronal injury, but the mechanism remains unclear. We investigated whether isoflurane cause neurotoxicity to the central nervous system by regulating the N-methyl-D-aspartate receptor (NMDAR) and excitatory amino acid transporter1 (EAAT1) in young rats. Furthermore, we examined if dexmedetomidine could decrease isoflurane-induced neurotoxicity.MethodsNeonatal rats (postnatal day 7, n=144) were randomly divided into four groups of 36 animals each: control (saline injection without isoflurane); isoflurane (2% for 4 h); isoflurane + single dose of dexmedetomidine (75 µg/kg, 20 min before the start of 2% isoflurane for 4 h); and isoflurane + dual doses of dexmedetomidine (25 µg/kg, 20 min before and 2 h after start of isoflurane at 2% for 4 h). Six neonates from each group were euthanatized at 2 h, 12 h, 24 h, 3 days, 7 days and 28 days post-anesthesia. Hippocampi were collected and processed for protein extraction. Expression levels of the NMDAR subunits NR2A and NR2B, EAAT1 and caspase-3 were measured by western blot analysis.ResultsProtein levels of NR2A, EAAT1 and caspase-3 were significantly increased in hippocampus of the isoflurane group from 2 h to 3 days, while NR2B levels were decreased. However, the -induced increase in NR2A, EAAT1 and caspase-3 and the decrease in NR2B in isoflurane-exposed rats were ameliorated in the rats treated with single or dual doses of dexmedetomidine. Isoflurane-induced neuronal damage in neonatal rats is due in part to the increase in NR2A and EAAT1 and the decrease in NR2B in the hippocampus.ConclusionDexmedetomidine protects the brain against the use of isoflurane through the regulation of NR2A, NR2B and EAAT1. However, using the same amount of dexmedetomidine, the trend of protection is basically the same.

To investigate the mechanism dexmedetomidine in relieving the neurotoxicity of a developing brain induced by sevoflurane. Sprague-Dawley rats, 6 days old, were randomly divided into three groups. Rats in the control group were inhaled with air after injection of normal saline; rats in the sevoflurane group were injected with normal saline and inhaled with 3% sevoflurane for 2 h in three consecutive day; rats in the dexmedetomidine group were inhaled with 3% sevoflurane after intraperitoneal injection of dexmedetomidine 25 μg/kg. WB results showed that mBDNF, pTrkB/TrkB, and CREB were significantly decreased in the hippocampus of the sevoflurane group, which are significantly upregulated in the dexmedetomidine group. In the sevoflurane group, proBDNF, P75NRT, and RhoA were significantly increased, which were significantly lower than those in the dexmedetomidine group than those in the sevoflurane group. The expression BDNF was downregulated in the sevoflurane group, while the proBDNF was upregulated in the sevoflurane group. In the Morris water maze test, the escape latency of the sevoflurane group was significantly prolonged. In sevoflurane groups, the number of crossing platform was significantly reduced, the synaptic protein decreased significantly, and this effect was reversed in rats of the dexmedetomidine group. Dexmedetomidine could reduce synaptic plasticity decline in developing rats induced by sevoflurane, through downregulating the proBDNF-p75NTR-RhoA pathway and upregulating BDNF-TrkB-CREB.

Background Many studies have reported that sevoflurane can increase neuronal apoptosis and result in cognitive deficits in rodents. Although neurotoxicity may be associated with mitochondrial dysfunction and oxidative stress, the exact mechanism remains unclear. In order to evaluate potential treatment therapies, we studied the effects of hemin on neurotoxicity of neonatal rat sevoflurane exposure. Methods Postnatal day (P) seven rats were assigned randomly to four groups; (1) group C: non-anesthesia, (2) group H: intraperitoneal hemin (50 mg kg −1 ) treatment on days 5 and 6, (3) group S: 3% sevoflurane exposure for 4 h, and (4) group SH: hemin treatment + sevoflurane exposure. The expression of neuroglobin in neonatal hippocampus was determined by western blot and immunohistochemistry. Neuroglobin was localized by immunofluorescence. Western blot for the expression of cleaved caspase-3 and TUNEL were used to detect neonatal hippocampal apoptosis, and cytochrome c was used to evaluate mitochondrial function. Drp-1 and Mfn-2 immunoblotting were used to assess mitochondrial dynamics. The Morris water maze test was performed to detect cognitive function in the rats on P30. Results Exposure to sevoflurane increased the expression of cleaved caspase-3, cytochrome c , and Drp1 in the neonatal hippocampus and resulted in cognitive deficiency but decreased expression of Mfn2. Hemin reduced apoptosis, improved mitochondrial dynamics and ameliorated the cognitive impairment caused by sevoflurane exposure. Conclusion Hemin reduced neuronal apoptosis, improved mitochondrial dynamics and protected against cognitive deficits induced by sevoflurane in neonatal rats. This neuroprotective effect may be achieved by increasing the expression of neuroglobin.

Numerous studies have demonstrated that general anesthetics might damage the nervous system, thus, the effect of general anesthetics on the developing brain has attracted much attention. Dexmedetomidine (Dex) exhibits a certain neuroprotective effect, but the mechanism is obscure. In our study, pregnant rats on gestational day 20 (G20) were exposed to 3% sevoflurane for 2 h or 4 h, and the neuronal apoptosis in hippocampal CA1 region of the offspring rats was detected by quantification of TUNEL positive cells and cleaved-caspase3 (cl-caspase3). Different doses of Dex were intraperitoneally injected before sevoflurane anesthesia; then, the expression of apoptotic-related proteins including BCL-2, BAX and cl-caspase3 as well as amyloid precursor protein (APP, a marker of axonal injury), p-CRMP-2 and CRMP-2 were measured at postnatal days 0, 1and 3 (P0, P1, and P3, respectively). As an antagonist of the bone morphgenetic proteins (BMP) receptor, DMH1 was co-administered with sevoflurane plus Dex to investigate whether BMP/SMAD is associated with the neuroprotective effects of Dex. The results showed that prenatal sevoflurane anesthesia for 4 h activated apoptosis transiently, as manifested by the caspase3 activity peaked on P1 and disappeared on P3. In addition, the expressions of APP and p-CRMP-2/CRMP-2 in postnatal rat hippocampus were significantly increased, which revealed that prenatal sevoflurane anesthesia caused axonal injury of offspring. The long-term learning and memory ability of offspring rats was also impaired after prenatal sevoflurane anesthesia. These damaging effects of sevoflurane could be mitigated by Dex and DMH1 reversed the neuroprotective effect of Dex. Our results indicated that prenatal exposure to 3% sevoflurane for 4 h increased apoptosis and axonal injury, even caused long-term learning and memory dysfunction in the offspring rats. Dex dose-dependently reduced sevoflurane- anesthesia-induced the neurotoxicity by activating the BMP/SMAD signaling pathway.

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