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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Structural basis of neurosteroid anesthetic action on GABAA receptors

Type A γ-aminobutyric acid receptors (GABA A Rs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABA A R transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABA A R structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABA A R (ELIC-α1GABA A R). The chimera retains the functional and pharmacological properties of GABA A Rs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1–TM2 linker. The study provides a framework to discover new GABA A R modulators with therapeutic potential.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Amide-linked local anesthetics preferentially target leukemia stem cell through inhibition of Wnt/β-catenin

Highlights: • Local anaesthetics target malignant (LSC) and normal stem cells (HSC). • HSC are less sensitive than LSC to local anaesthetics. • Lidocaine and bupivacaine is more potent than ropivacaine. • Local anaesthetics acts on LSC and HSC via Wnt/β-catenin-dependent manner. The anti-cancer activities of amide-linked local anesthetics have been demonstrated in various types of bulky/differentiated cancer cells. However, whether these anesthetics also affect biological functions of cancer stem cells is largely unknown. In this study, we systematically investigated the effects of three commonly used amide-linked local anesthetics (ropivacaine, lidocaine and bupivacaine) on leukemia stem cell (LSC) derived from two different leukemia diseases (acute myeloid leukemia, n = 8 and chronic myeloid leukemia, n = 8) as well as normal hematopoietic stem cell (HSC) derived from cord blood donors (n = 8) as comparison. We show that all three local anesthetics at clinically achievable concentrations significantly inhibit colony formation and serial replating of LSC in a dose-dependent manner, suggesting their inhibitory effects on LSC differentiation, proliferation and self-renewal. In addition, lidocaine and bupivacaine are more potent than ropivacaine. However, local anesthetics at the same concentrations do not affect LSC and HSC survival, demonstrating the differentiation and self-renewal as the primary effects of local anesthetics on LSC and HSC. Interestingly, local anesthetics display certain selectivity between LSC and HSC by having higher efficacy on LSC than HSC. Mechanism studies using both pharmacological and genetic approaches demonstrate that these local anesthetics target LSC via inhibiting Wnt/β-catenin but not Hedgehog or NF-ĸB signaling. Our work is the first to demonstrate the possible influence of amide-linked local anesthetics on cancer as well as normal stem cells via inhibiting Wnt/β-catenin signaling. Our findings contribute to the comprehensive understanding of potential implication of amide-linked local aesthesis in tumor biology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

A Unitary Anesthetic Binding Site at High Resolution

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABA{sub A} receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABA{sub A} receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show that apoferritin also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABA{sub A} receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.

08 HYDROGEN↗
DOE OSTI2023

Structural interplay of anesthetics and paralytics on muscle nicotinic receptors

General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic

We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray crystallography. Additionally, we obtained the {sup 3}H-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC{sub 50} approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(-)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human {alpha}1{beta}2/3{gamma}2L GABA{sub A} receptors. Finally, R-(-)-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both {alpha}1 and {beta}3 subunits of human {alpha}1{beta}3 GABAA receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2012

Piriformis Syndrome: Long-Term Follow-up in Patients Treated with Percutaneous Injection of Anesthetic and Corticosteroid Under CT Guidance

Purpose: This study was designed to evaluate the efficacy of CT-guided injection of anesthetic and corticosteroid for the treatment of pain in patients with piriformis syndrome unresponsive to conservative treatment. Methods: We enrolled 23 patients with piriformis syndrome, proposing a percutaneous intramuscular injection of methylprednisone-lidocaine. Among them, 13 patients accepted and 10 refused to undergo the procedure; the second group was used as a control group. Clinical evaluation was performed with four maneuvers (Lasegue sign, FAIR test, Beatty and Freiberg maneuver) and a VAS questionnaire before the injection, after 5-7 days, and after 2 months. A telephonic follow-up was conducted to 3, 6, and 12 months. Results: Procedural success was achieved in all patients who were treated without any complications. After 2 months, among 13 treated subjects, 2 of 13 patients showed positivity to FAIR test (hip flexion, adduction, and internal rotation), 2 of 13 were positive to Lasegue sign, and the Beatty maneuver was positive in 1 patient. Patients who underwent conservative treatment were positive respectively in 7 of 10 (p = 0.01), 6 of 10 (p = 0.03), and 6 of 10 (p = 0.01). The VAS score showed a difference between patients treated with percutaneous approach and those managed with conservative therapy at the baseline evaluation (p = 0.04), after 2 months (p = 0.02), and 12 months (p = 0.002). We observed a significant reduction in pain for patients treated percutaneously, who were evaluated with the VAS scale at 5-7 days, 2 months, 3, 6, and 12 months (p < 0.001). Conclusions: Our findings suggested potential benefit from the percutaneous injection of anesthetics and corticosteroids under CT guidance for the treatment of piriformis syndrome.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Effect of Topical Anesthetic Cream on Pain During Periareolar Injection of Technetium Tc99m Sulfur Colloid for Sentinel Lymph Node Biopsy in Breast Cancer: A Randomized Control Trial

Injection of Tc99m to localize nodes for sentinel lymph node biopsy is reported by patients as very painful. The purpose of this study was to determine if anesthetic cream reduces pain associated with periareolar injection of Tc99m and to help elucidate conflicting literature regarding the efficacy of anesthetic cream for this procedure.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Rapid 18 F-FDG Uptake in Brain of Awake, Behaving Rat and Anesthetized Chicken has Implications for Behavioral PET Studies in Species With High Metabolisms

Brain-behavior studies using 18 F-FDG PET aim to reveal brain regions that become active during behavior. In standard protocols, 18 F-FDG is injected, the behavior is executed during 30–60 min of tracer uptake, and then the animal is anesthetized and scanned. Hence, the uptake of 18 F-FDG is not itself observed and could, in fact, be complete in very little time. This has implications for behavioral studies because uptake is assumed to reflect concurrent behavior. Here, we utilized a new, miniature PET scanner termed RatCAP to measure uptake simultaneously with behavior. We employed a novel injection protocol in which we administered 18 F-FDG (i.v.) four times over two 2 h to allow for repeated measurements and the correlation of changes in uptake and behavioral activity. Furthermore, using standard PET methods, we explored the effects of injection route on uptake time in chickens, a model for avians, for which PET studies are just beginning. We found that in the awake, behaving rat most of the 18 F-FDG uptake occurred within minutes and overlapped to a large extent with 18F-FDG data taken from longer uptake periods. By contrast, behavior which occurred within minutes of the 18 F-FDG infusion differed markedly from the behavior that occurred during later uptake periods. Accordingly, we found that changes in 18 F-FDG uptake in the striatum, motor cortex and cerebellum relative to different reference regions significantly predicted changes in behavioral activity during the scan, if the time bins used for correlation were near the injection times of 18 F-FDG. However, when morphine was also injected during the scan, which completely abolished behavioral activity for over 50 min, a large proportion of the variance in behavioral activity was also explained by the uptake data from the entire scan. In anesthetized chickens, tracer uptake was complete in about 80 min with s.c. injection, but 8 min with i.v. injection. In conclusion, uptake time needs to be taken into account to more accurately correlate PET and behavioral data in mammals and avians. Additionally, RatCAP together with multiple, successive injections of 18 F-FDG may be useful to explore changes in uptake over time in relation to changes in behavior.

Behavioral Sciences↗
DOE OSTI2011

The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease

Isoflurane is known to increase {beta}-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh{sup Q111/Q111}) and wild type (STHdh{sup Q7/Q7}) striatal neurons. The primary cultured neurons were exposed for 24 h to equipotent concentrations of isoflurane, sevoflurane, and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP{sub 3}) receptor antagonist. Aggregation of huntingtin protein, cell viability, and calcium concentrations were measured. Isoflurane, sevoflurane, and desflurane all increased the aggregation of huntingtin in STHdh{sup Q111/Q111} cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdh{sup Q111/Q111} huntingtin cells than in the wild type STHdh{sup Q7/Q7} striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh{sup Q111/Q111} cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP{sub 3} receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh{sup Q111/Q111} striatal cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [ 11 C]GSK189254 in anesthetized baboon

Rationale The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4- cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin3-yl)methanone) as a high-affinity histamine H3 receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors. Objective This study measured brain histamine H3 receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon. Methods Positron emission tomography imaging and [ 11 C] GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H3 receptor, was used to measure histamine H3 receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H3 receptor availability was estimated as the total distribution volume (VT) in brain regions. The sensitivity of [ 11 C]GSK189254 binding to injected mass and carryover effects was determined. Results JNJ-39220675 produces robust (ca. 90 %) blockade of [ 11 C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1 mg/kg), the fractional receptor occupancy was >0.9 at 90 min with a slight increase from 90 to 240 min. Similar to prior studies in humans, VT was highly sensitive to the mass of GSK189254 with ED50 estimated to be 0.16 μg/kg. Conclusions The robust blockade of binding of [ 11 C] GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood–brain barrier and occupies the histamine H3 receptor after oral administration at low plasma concentrations (~1 ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [ 11 C]GSK189254 to injected mass at doses >0.1 μg/kg.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

Acute Cor Pulmonale and Right Heat Failure Complicating Ethanol Ablative Therapy: Anesthetic and Radiologic Considerations and Management

Ethanol is an effective ablative agent used for the treatment of certain solid organ tumors and vascular malformations (VMs). The egress of ethanol beyond the target tissue can be associated with significant changes to the cardiopulmonary system that can lead to cardiac arrest. This article reviews the contemporary role of ethanol in tumor and VM treatment and discusses the physiological mechanisms of acute pulmonary hypertension and cardiovascular collapse. The importance of periprocedural recognition of the hemodynamic changes that can occur with the use of ethanol and the treatment of this condition are discussed.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo

An overdose and a prolonged treatment of propofol may cause cellular cytotoxicity in multiple organs and tissues such as brain, heart, kidney, skeletal muscle, and immune cells; however, the underlying mechanism remains undocumented, particularly in vascular endothelial cells. Our previous studies showed that the activation of glycogen synthase kinase (GSK)-3 is pro-apoptotic in phagocytes during overdose of propofol treatment. Regarding the intravascular administration of propofol, we therefore hypothesized that propofol overdose also induces endothelial cytotoxicity via GSK-3. Propofol overdose (100 μg/ml) inhibited growth in human arterial and microvascular endothelial cells. After treatment, most of the endothelial cells experienced caspase-independent necrosis-like cell death. The activation of cathepsin D following lysosomal membrane permeabilization (LMP) determined necrosis-like cell death. Furthermore, propofol overdose also induced caspase-dependent apoptosis, at least in part. Caspase-3 was activated and acted downstream of mitochondrial transmembrane potential (MTP) loss; however, lysosomal cathepsins were not required for endothelial cell apoptosis. Notably, activation of GSK-3 was essential for propofol overdose-induced mitochondrial damage and apoptosis, but not necrosis-like cell death. Intraperitoneal administration of a propofol overdose in BALB/c mice caused an increase in peritoneal vascular permeability. These results demonstrate the cytotoxic effects of propofol overdose, including cathepsin D-regulated necrosis-like cell death and GSK-3-regulated mitochondrial apoptosis, on endothelial cells in vitro and the endothelial barrier dysfunction by propofol in vivo. Highlights: ► Propofol overdose causes apoptosis and necrosis in endothelial cells. ► Propofol overdose triggers lysosomal dysfunction independent of autophagy. ► Glycogen synthase kinase-3 facilitates propofol overdose-induced apoptosis. ► Propofol overdose causes an increase in peritoneal vascular permeability.

60 APPLIED LIFE SCIENCES↗