Dexmedetomidine maintains blood-brain barrier integrity by inhibiting Drp1-related endothelial mitochondrial dysfunction in ischemic stroke.

Stroke is the second leading cause of death and long-term disability worldwide, which lacks effective treatment. Perioperative stroke is associated with much higher rates of mortality and disability. The neuroprotective role of dexmedetomidine (Dex), a highly selective agonist of alpha2-adrenergic receptor, has been reported in a stroke rat model, and it was found that pretreatment of Dex before stroke could alleviate blood-brain barrier (BBB) breakdown. However, the underlying mechanisms are still unknown. As the brain endothelial cells are the main constituents of BBB and in high demand of energy, mitochondrial function of endothelial cells plays an important role in the maintenance of BBB. Given that dynamin-related protein 1 (Drp1) is a protein mediating mitochondrial fission, with mitochondrial fusion that balances mitochondrial morphology and ensures mitochondria function, the present study was designed to investigate the possible role of Drp1 in endothelial cells involved in the neuroprotective effects of Dex in ischemic stroke. Our results showed that preconditioning with Dex reduced infarction volume, alleviated brain water content and BBB damage, and improved neurological scores in middle cerebral artery occlusion rats. Meanwhile, Dex enhanced cell activity and decreased cell apoptosis in oxygen-glucose deprivation human brain microvascular endothelial cells in vitro. These protective effects of Dex were correlated with the mitochondrial morphology integrality of endothelial cells, mediated by increased phosphorylation of serine 637 in Drp1, and could be reversed by α2-adrenergic receptor antagonist Yohimbine and AMP-activated protein kinase inhibitor Compound C. These findings suggest new molecular pathways involved in the neuroprotective effects of Dex in ischemic stroke. As Dex is routinely used as a sedative drug clinically, our findings provide molecular evidence that it has perioperative neuroprotection from ischemic stroke.

Propofol differentially induces unconsciousness and respiratory depression through distinct interactions between GABAA receptor and GABAergic neuron in corresponding nuclei.

Propofol is the most commonly used intravenous anesthetic worldwide. It can induce loss of consciousness prior to the occurrence of severe respiratory suppression, which is also a pharmacodynamic feature of all general anesthetics. However, the neural mechanisms underlying this natural phenomenon are controversial and highly related to patient safety. In the present study, we demonstrated that the pharmacodynamic effects of propofol (50 and 100 µM) on suppression of consciousness-related excitatory postsynaptic currents in the medial prefrontal cortex (mPFC) and centromedian nucleus of the thalamus (CMT) were lower than those in the kernel respiratory rhythmogenesis nucleus pre-Bötzinger complex (PrBo). Furthermore, we unexpectedly found that the GABAA receptor ß3 subunit is the key target for propofol's action and that it is mutually and exclusively expressed in GABAergic neurons. It is also more abundant in the mPFC and CMT, but mainly co-localized with GABAergic neurons in the PrBo. As a result, the differentiated expression pattern should mediate more neuron suppression through the activation of GABAergic neurons in the mPFC and CMT at low doses of propofol (50 µM). However, PrBo GABAergic neurons were only activated by propofol at a high dose (100 µM). These results highlight the detailed pharmacodynamic effects of propofol on consciousness-related and respiration-related nuclei and provide the distinct interaction mechanism between the ß3 subunit and GABAergic neurons in mediating the suppression of consciousness compared to the inhibition of respiration.

Activation of anterior thalamic reticular nucleus GABAergic neurons promotes arousal from propofol anesthesia in mice.

Propofol is widely used for the induction and maintenance of anesthesia, which causes a rapid loss of consciousness. However, the mechanisms underlying the hypnosis effect of propofol are still not fully understood. The thalamic reticular nucleus (TRN) is crucial for regulating wakefulness, sleep rhythm generation, and sleep stability, while the role of TRN in the process of propofol-induced anesthesia is still unknown. Here, we investigated the function of the anterior TRN in propofol general anesthesia. Our results demonstrated that the neural activity of anterior TRN is suppressed during propofol anesthesia, whereas it is robustly activated from anesthesia by recording the calcium signals using fiber photometry technology. The results showed that the activation of anterior TRN neurons by chemogenetic and optogenetic methods shortens the emergency time without changing the induction time. Conversely, chemogenetic or optogenetic inhibition of the TRN neurons leads to a delay in the recovery time. Our study showed that anterior TRN is crucial for behavioral arousal without affecting the induction time of propofol anesthesia.

ApoE transiently regulates hippocampus amyloid-beta deposition to stable learning and memory ability in adult rats exposed in sevoflurane.

Objective: Post-operative cognitive dysfunction (POCD) is a common central nervous system complication after surgery. Inhaled anesthetic sevoflurane is thought to have harmful effects on the developing and aged nerves, but its effects on adults' nervous system are less studied and the mechanism is not clear. Methods: Male adult rats were divided into control group and sevoflurane group. Rats from sevoflurane group were received 3.2% sevoflurane + carrier gas (1 L/min O2+1 L/min air) for 2 h, while control group received carrier gas for 2 h. Each group was subsequently divided into 3 subgroups according to the Day 1, Day 3, Day 7 after sevoflurane anesthesia. Morris Water Maze, amyloid-beita (Abeta) and apolipoprotein E (ApoE) mRNA in hippocampus were analyzed. Then, adult ApoE-/- rats were also divided into control group and sevoflurane group. Each group was divided into 3 subgroups according to Day 1, Day 3 and Day 7. Abeta mRNA and protein expression in hippocampus were analyzed. Results: Compared with the control group, hippocampal Abeta mRNA and protein expression in rats from sevoflurane group significantly increased in hippocampus on Day 7, while ApoE mRNA and protein expression increased on Day 1 and Day 3. There was no difference in times of crossing platforms, time during platform, times across platform quadrant and time percent during platform quadrant between each group. Compared with the control group, hippocampal Abeta and ApoE-/- rats in sevoflurane group did not change. Conclusion: ApoE modulates hippocampal Abeta deposition and stabilizes learning and memory ability in adult rats after sevoflurane exposure, but this effect is not constant.

Effect of multiple neonatal sevoflurane exposures on hippocampal apolipoprotein E levels and learning and memory abilities.

BACKGROUND: Sevoflurane anesthesia is widely used in pediatric patients. In this study, we investigated whether early multiple exposures to sevoflurane induced cognitive dysfunction by altering the hippocampal expression of ApoE later in development. METHODS: Sprague-Dawley rats were exposed to 2.6% sevoflurane at postnatal day 7 (P7), P14, and P21 for 2 h. The ability of learning and memory was assessed using the Morris water maze at P37 and P97. The hippocampal volume was measured by magnetic resonance imaging (MRI) at P37 and P97. The hippocampal expression of ApoE was assessed by immunohistochemical analyses and real-time polymerase chain reaction (PCR). RESULTS: Behavioral testing revealed that the ability of learning and memory in the sevoflurane-exposed rats was decreased compared with the control animals; however, there was no significant difference (P > 0.05). The MRI results showed a significant decrease in the left hippocampal volume, left maximum hippocampal length, and right maximum hippocampal length in the sevoflurane young group compared with the control young group (P < 0.05). The brain volume, left maximum hippocampal length, right hippocampal volume, and maximum brain length were significantly lower in the sevoflurane adult group than in the control adult group (P < 0.05). In young animals, the ApoE expression in the hippocampal CA1 and CA3 regions and the ApoE mRNA level were significantly higher compared with the control group (P < 0.05), but not in the dentate gyrus region (P > 0.05). Among the adult animals, there was no significant difference between the groups in any parameter tested (P > 0.05). CONCLUSION: Multiple exposures to sevoflurane during the neonatal period decreased the volume of the hippocampus and increased the hippocampal expression of ApoE. The differential expression level of ApoE in different hippocampal subdivisions suggested that the expression of ApoE was regionally specific and reversible.

Pharmacologic studies on ET-26 hydrochloride in a rat model of lipopolysaccharide-induced sepsis.

BACKGROUND: ET-26 hydrochloride (ET-26 HCl) is a promising sedation-hypnotic compound with stable hemodynamic features that elicits virtually no adrenocortical suppression. However, whether it preserves better pharmacologic characteristics in a rat model of sepsis is not known. This study compared the survival rate, levels of corticosterone and pro-inflammatory cytokines, and histologic injury in the lungs and kidneys of rats suffering from sepsis treated with ET-26 HCl, etomidate, or normal saline (NS). METHODS: Rats were given lipopolysaccharide (1mg/kg body weight, i.v.) to establish a sepsis model. Thirty minutes after lipopolysaccharide administration, ET-26 HCl, etomidate or NS were given as a bolus injection at equivalent doses. Plasma levels of corticosterone, interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α were measured 1, 2, 4, 6 and 24h after administration. Histologic injury was observed at the time of death or 24h after drug administration. RESULTS: The survival rate for rats in the etomidate, ET-26 HCl and NS groups was 40%, 90% and 90%, respectively. Corticosterone concentrations in the etomidate group were lower than those in the other groups 1h after administration of hypnotic compounds. Concentrations of pro-inflammatory cytokines in the ET-26 HCl group and NS group were not significantly different, but were significantly lower than those in the etomidate group. The injury scores of kidneys and lungs in the etomidate group were higher than those in ET-26 HCl and NS groups. CONCLUSIONS: ET-26 HCl showed virtually no suppression of corticosterone synthesis, lower concentrations of pro-inflammatory cytokines, higher survival rate, and less organ injury in rats suffering from sepsis compared with the etomidate group. It may be safer to induce anesthesia using ET-26 HCl, rather than etomidate, in patients suffering from sepsis.

Minimum infusion rate and adrenocortical function after continuous infusion of the novel etomidate analog ET-26-HCl in rats.

BACKGROUND: Because etomidate induces prolonged adrenal suppression, even following a single bolus, its use as an infused anesthetic is limited. Our previous study indicated that a single administration of the novel etomidate analog methoxyethyletomidate hydrochloride (ET-26-HCl) shows little suppression of adrenocortical function. The aims of the present study were to (1) determine the minimum infusion rate of ET-26-HCl and compare it with those for etomidate and cyclopropyl-methoxycarbonylmetomidate (CPMM), a rapidly metabolized etomidate analog that is currently in clinical trials and (2) to evaluate adrenocortical function after a continuous infusion of ET-26-HCl as part of a broader study investigating whether this etomidate analog is suitable for long infusion in the maintenance of anesthesia. METHOD: The up-and-down method was used to determine the minimum infusion rates for ET-26-HCl, etomidate and CPMM. Sprague-Dawley rats (n = 32) were then randomly divided into four groups: etomidate, ET-26-HCl, CPMM, and vehicle control. Rats in each group were infused for 60 min with one of the drugs at its predetermined minimum infusion rate. Blood samples were drawn initially and then every 30 min after drug infusion to determine the adrenocorticotropic hormone-stimulated concentration of serum corticosterone as a measure of adrenocortical function. RESULTS: The minimum infusion rates for etomidate, ET-26-HCl and CPMM were 0.29, 0.62, and 0.95 mg/kg/min, respectively. Compared with controls, etomidate decreased serum corticosterone, as expected, whereas serum corticosterone concentrations following infusion with the etomidate analogs ET-26-HCl or CPMM were not significantly different from those in the control group. CONCLUSION: The corticosterone concentrations tended to be reduced for the first hour following ET-26-HCl infusion (as compared to vehicle infusion); however, this reduction did not reach statistical significance. Thus, further studies are warranted examining the practicability of using ET-26-HCl as an infused anesthetic.

[Pollution characterization and source apportionment of polybrominated diphenyl ethers in autumn air of Xi'an].

Air samples in gas and particle phases were collected using a high volume active sampler from August to October in 2008 at Xi'an for evaluating the pollution level of polybrominated diphenyl ethers (PBDEs). Lower brominated PBDEs and BDE-209 were analyzed via GC-MS and GC/ECD, respectively. The total concentrations (gas plus particle phases) of 12 PBDEs were ranged from 37.43 to 620.30 pg/m3, with an average of 216.28 pg/m3, while tri- to hexa-brominated congeners (Sigma11 PBDEs) ranged from 16.32 to 86. 49 pg/m3, BDE-209 ranged from 16. 34 to 576.01 pg/m3. Tri- to tetra-brominated congeners existed mainly in gas phase, tetra- to hexa-brominated congeners were predominated in particle phase, and BDE-209 was detected only in particle phase. The proportion of PBDEs in particle phase increased with bromine number. Gas-particle partition coefficient of PBDEs was well correlated with sub-cooled liquid vapor pressure, and the partitioning of PBDEs between gas and particle phases were close to equilibrium. Correlation analysis indicated that all the PBDEs have good coefficients except BDE-85. Source analysis indicated that PBDEs in the atmosphere of Xi'an were mainly from the Penta-BDE and Deca-BDE contamination.

[Pollution characterizations and source apportionment of polycyclic aromatic hydrocarbons in air during domestic heating season of Xi'an].

TSP samples and gas phase air samples were collected by an improved high volume active air sampler during domestic heating season in Xi'an, and the concentrations of polycyclic aromatic hydrocarbons (PAHs) were analyzed via GC-MS. The results showed that average concentrations of sigma 16 PAHs in TSP and gas phase were (108.15 +/- 41.44) ng/m3, (260.14 +/- 99.84) ng/m3, respectively. Two and three ring PAHs dominated in the gas phase, while more than four ring PAHs were mainly adsorbed on the particle phase. Good correlation was found between gas-particle partition coefficient and the respective sub-cooled vapor pressures of PAHs. A significant correlation was also found between partition coefficient and temperature, and the regression equation was put forward by stepwise linear regression method. Ratio analysis illustrated that coal burning and vehicle exhaust were the main source of PAHs in Xi' an. Contribution of each source was calculated by factor analysis and multiple linear regression. Partial correlation analysis was applied to study the relationship between air pollution indexes and some representative PAHs of individual factors, which indicated some PAH had same source to SO2 and NO2.