RESUMEN
Hydrogen sulfide (H(2)S) depresses mitochondrial function and thereby metabolic rates in mice, purportedly resulting in a state of "suspended animation." Volatile anesthetics also depress mitochondrial function, an effect that may contribute to their anesthetic properties. In this study, we ask whether H(2)S has general anesthetic properties, and by extension, whether mitochondrial effects underlie the state of anesthesia. We compared loss of righting reflex, electroencephalography, and electromyography in mice exposed to metabolically equipotent concentrations of halothane, isoflurane, sevoflurane, and H(2)S. We also studied combinations of H(2)S and anesthetics to assess additivity. Finally, the long-term effects of H(2)S were assessed by using the Morris water maze behavioral testing 2 to 3 weeks after exposures. Exposure to H(2)S decreases O(2) consumption, CO(2) production, and body temperature similarly to that of the general anesthetics, but fails to produce a loss of righting reflex or muscle atonia at metabolically equivalent concentrations. When combined, H(2)S antagonizes the metabolic effects of isoflurane, but potentiates the isoflurane-induced loss of righting reflex. We found no effect of prior H(2)S exposure on memory or learning. H(2)S (250 ppm), not itself lethal, produced delayed lethality when combined with subanesthetic concentrations of isoflurane. H(2)S cannot be considered a general anesthetic, despite similar metabolic suppression. Metabolic suppression, presumably via mitochondrial actions, is not sufficient to account for the hypnotic or immobilizing components of the anesthetic state. Combinations of H(2)S and isoflurane can be lethal, suggesting extreme care in the combination of these gases in clinical situations.
Asunto(s)
Anestesia General/métodos , Anestésicos Generales/farmacología , Sulfuro de Hidrógeno/farmacología , Actividad Motora/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Reflejo de Enderezamiento/efectos de los fármacos , Anestésicos por Inhalación/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Temperatura Corporal , Dióxido de Carbono/metabolismo , Caspasa 3/metabolismo , Interacciones Farmacológicas , Electroencefalografía , Electromiografía , Halotano/administración & dosificación , Isoflurano/administración & dosificación , Isoflurano/antagonistas & inhibidores , Masculino , Éteres Metílicos/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Oxígeno/metabolismo , SevofluranoRESUMEN
BACKGROUND: Experimental evidence suggests that anesthetics accelerate symptomatic neurodegenerative disorders such as Alzheimer's disease (AD). Because AD pathology precedes symptoms, we asked ourselves whether anesthetic exposure in the presymptomatic interval accelerated neuropathology and appearance of symptoms. METHODS: Triple-transgenic AD mice were exposed to general aesthetics, either halothane or isoflurane, at 2, 4, and 6 months of age, they then underwent water maze cognitive testing 2 months later, and subsequently their brains were analyzed using enzyme-linked immunosorbent assay, immunoblots, and immunohistochemistry for amyloid and tau pathology and biomarkers. RESULTS: Learning and memory improved after halothane exposure in the 2-month-old group relative to controls, but no changes were noted in the isoflurane group. When gender was examined in all age groups, females exposed to halothane performed better as compared with those exposed to isoflurane or controls. Therefore, improvement in the 2-month exposure group is most likely because of a gender effect. Level of phospho-tau in the hippocampus was significantly increased 2 months after anesthesia, especially in the 6-month exposure group, but changes in amyloid, caspase, microglia, or synaptophysin levels were not detected. CONCLUSIONS: These results indicate that exposure to two different inhalation-type anesthetics during the presymptomatic phase of AD does not accelerate cognitive decline, after 2 months, and may cause a stress response, marked by hippocampal phosphorylated tau, resulting in preconditioning against the ongoing neuropathology, primarily in female mice.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/inducido químicamente , Anestésicos por Inhalación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Trastornos del Conocimiento/inducido químicamente , Femenino , Halotano/administración & dosificación , Isoflurano/administración & dosificación , Masculino , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: The number of elderly patients with frank or incipient Alzheimer's disease (AD) requiring surgery is growing as the population ages. General anesthesia may exacerbate symptoms of and the pathology underlying AD, so minimizing anesthetic exposure may be important. This requires knowledge of whether the continuing AD pathogenesis alters anesthetic potency. METHODS: We determined the induction potency and emergence time for isoflurane, halothane, and sevoflurane using the minimum alveolar anesthetic concentration for loss of righting reflex as an end point in 12- to 14-mo-old triple transgenic Alzheimer (3xTgAD) mice and wild type C57BL6 controls. 3xTgAD mice model AD by harboring three distinct mutations: the APP(Swe), Tau, and PS1 human transgenes, each of which has been associated with familial forms of human AD. RESULTS: The 3xTgAD mice exhibited mild resistance (from 8% to 30%) to volatile anesthetics but displayed indistinguishable emergence patterns from all three inhaled anesthetics. CONCLUSIONS: These results show that the genetic vulnerabilities and neuropathology associated with AD produce a small but significant decrease in sensitivity to the hypnotic actions of three inhaled anesthetics. Emergence times were not altered.