Determination of minimum alveolar concentration for isoflurane and sevoflurane in a rodent model of human metabolic syndrome.

BACKGROUND: Morbid obesity affects the pharmacokinetics and pharmacodynamics of anesthetics, which may result in inappropriate dosing. We hypothesized that obesity significantly alters the minimum alveolar concentration (MAC) for isoflurane and sevoflurane. To test this hypothesis, we used a rodent model of human metabolic syndrome developed through artificial selection for inherent low aerobic capacity runners (LCR) and high aerobic capacity runners (HCR). The LCR rats are obese, display phenotypes homologous to those characteristic of human metabolic syndrome, and exhibit low running endurance. In contrast, HCR rats have high running endurance and are characterized by improved cardiovascular performance and overall health. METHODS: Male and female LCR (n = 10) and HCR (n = 10) rats were endotracheally intubated and maintained on mechanical ventilation with either isoflurane or sevoflurane. A bracketing design was used to determine MAC; sensory stimulation was induced by tail clamping. An equilibration period of 30 minutes was provided before and between the consecutive tail clamps. Two-tailed parametric (unpaired t test) and nonparametric (Mann-Whitney test) statistics were used for the comparison of MAC between LCR and HCR rats. The data are reported as mean ± sd along with the 95% confidence interval. A P value of <0.05 was considered statistically significant. RESULTS: The MAC for isoflurane in LCR rats (1.52% ± 0.13%) was similar to previously reported isoflurane-MAC for normal rats (1.51% ± 0.12%). The HCR rats showed a significantly higher isoflurane-MAC (1.90% ± 0.19%) than did the LCR rats (1.52% ± 0.13%) (P = 0.0001). The MAC for sevoflurane was not significantly different between LCR and HCR rats and was similar to the previously published sevoflurane-MAC for normal rats (2.4% ± 0.30%). There was no influence of sex on the MAC of either isoflurane or sevoflurane. CONCLUSION: Obesity and associated comorbidities do not affect anesthetic requirements as measured by MAC in a rodent model of metabolic syndrome. By contrast, high aerobic capacity is associated with a higher MAC for isoflurane and may be a risk factor for subtherapeutic dosing.

State-specific effects of sevoflurane anesthesia on sleep homeostasis: selective recovery of slow wave but not rapid eye movement sleep.

BACKGROUND: Prolonged propofol administration does not result in signs of sleep deprivation, and propofol anesthesia appears to satisfy the homeostatic need for both rapid eye movement (REM) and non-REM (NREM) sleep. In the current study, the effects of sevoflurane on recovery from total sleep deprivation were investigated. METHODS: Ten male rats were instrumented for electrophysiologic recordings under three conditions: (1) 36-h ad libitum sleep; (2) 12-h sleep deprivation followed by 24-h ad libitum sleep; and (3) 12-h sleep deprivation, followed by 6-h sevoflurane exposure, followed by 18-h ad libitum sleep. The percentage of waking, NREM sleep, and REM sleep, as well as NREM sleep δ power, were calculated and compared for all three conditions. RESULTS: Total sleep deprivation resulted in significantly increased NREM and REM sleep for 12-h postdeprivation. Sevoflurane exposure after deprivation eliminated the homeostatic increase in NREM sleep and produced a significant decrease in the NREM sleep δ power during the postanesthetic period, indicating a complete recovery from the effects of deprivation. However, sevoflurane did not affect the time course of REM sleep recovery, which required 12 h after deprivation and anesthetic exposure. CONCLUSION: Unlike propofol, sevoflurane anesthesia has differential effects on NREM and REM sleep homeostasis. These data confirm the previous hypothesis that inhalational agents do not satisfy the homeostatic need for REM sleep, and that the relationship between sleep and anesthesia is likely to be agent and state specific.

Isoflurane anesthesia does not satisfy the homeostatic need for rapid eye movement sleep.

BACKGROUND: Sleep and general anesthesia are distinct states of consciousness that share many traits. Prior studies suggest that propofol anesthesia facilitates recovery from rapid eye movement (REM) and non-REM (NREM) sleep deprivation, but the effects of inhaled anesthetics have not yet been studied. We tested the hypothesis that isoflurane anesthesia would also facilitate recovery from REM sleep deprivation. METHODS: Six rats were implanted with superficial cortical, deep hippocampal, and nuchal muscle electrodes. Animals were deprived of REM sleep for 24 hours and then (1) allowed to sleep ad libitum for 8 hours or (2) were immediately anesthetized with isoflurane for a 4-hour period followed by ad libitum sleep for 4 hours. The percentage of REM and NREM sleep after the protocols was compared with similar conditions without sleep deprivation. Hippocampal activity during isoflurane anesthesia was also compared with activity during REM sleep and active waking. RESULTS: Recovery after deprivation was associated with a 5.7-fold increase (P = 0.0005) in REM sleep in the first 2 hours and a 2.6-fold increase (P = 0.004) in the following 2 hours. Animals that underwent isoflurane anesthesia after deprivation demonstrated a 3.6-fold increase (P = 0.001) in REM sleep in the first 2 hours of recovery and a 2.2-fold increase (P = 0.003) in the second 2 hours. There were no significant differences in REM sleep rebound between the first 4 hours after deprivation and the first 4 hours after both deprivation and isoflurane anesthesia. Hippocampal activity during isoflurane anesthesia was not affected by REM sleep deprivation, and the probability distribution of events during anesthesia was more similar to that of waking than to REM sleep. CONCLUSION: Unlike propofol, isoflurane does not satisfy the homeostatic need for REM sleep. Furthermore, the regulation and organization of hippocampal events during anesthesia are unlike sleep. We conclude that different anesthetics have distinct interfaces with sleep.

The synthesis and structure-activity relationship of substituted N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors.

It is believed that beta-amyloid aggregation is an important event in the development of Alzheimer's disease. In the course of our studies to identify beta-amyloid aggregation inhibitors, a series of N-phenyl anthranilic acid analogs were synthesized and studied for beta-amyloid inhibition activity. The synthesis, structure-activity relationship, and in vivo activity of these analogs are discussed.

Aging, gender and APOE isotype modulate metabolism of Alzheimer's Abeta peptides and F-isoprostanes in the absence of detectable amyloid deposits.

Aging and apolipoprotein E (APOE) isoform are among the most consistent risks for the development of Alzheimer's disease (AD). Metabolic factors that modulate risk have been elusive, though oxidative reactions and their by-products have been implicated in human AD and in transgenic mice with overt histological amyloidosis. We investigated the relationship between the levels of endogenous murine amyloid beta (Abeta) peptides and the levels of a marker of oxidation in mice that never develop histological amyloidosis [i.e. APOE knockout (KO) mice with or without transgenic human APOEepsilon3 or human APOEepsilon4 alleles]. Aging-, gender-, and APOE-genotype-dependent changes were observed for endogenous mouse brain Abeta40 and Abeta42 peptides. Levels of the oxidized lipid F2-isoprostane (F2-isoPs) in the brains of the same animals as those used for the Abeta analyses revealed aging- and gender-dependent changes in APOE KO and in human APOEepsilon4 transgenic KO mice. Human APOEepsilon3 transgenic KO mice did not exhibit aging- or gender-dependent increases in F2-isoPs. In general, the changes in the levels of brain F2-isoPs in mice according to age, gender, and APOE genotype mirrored the changes in brain Abeta levels, which, in turn, paralleled known trends in the risk for human AD. These data indicate that there exists an aging-dependent, APOE-genotype-sensitive rise in murine brain Abeta levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOEepsilon3, but not human APOEepsilon4, can apparently prevent the aging-dependent rise in murine brain Abeta levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Abeta/F2-isoP relationship across multiple relevant variables supports the hypothesis that oxidized lipids play a role in AD pathogenesis, as has been suggested by recent evidence that F2-isoPs can stimulate Abeta generation and aggregation.

Exogenous induction of cerebral beta-amyloidosis in betaAPP-transgenic mice.

A key commonality of most age-related neurodegenerative diseases is the accumulation of aggregation-prone proteins in the brain. Except for the prionoses, the initiation and propagation of these proteopathies in vivo remains poorly understood. In a previous study, we found that the deposition of the amyloidogenic peptide Abeta can be induced by injection of dilute extracts of Alzheimeric neocortex into the brains of Tg2576 transgenic mice overexpressing the human beta-amyloid precursor protein. The present study was undertaken to assess the pathology after long-term (12 months) incubation, and to clarify the distinctive anatomical distribution of seeded Abeta-immunoreactivity. All mice were injected at 3 months of age; 5 months later, as expected, Abeta deposits were concentrated mostly in the injected hemisphere. After 12 months, abundant, transgene-derived Abeta deposits were present bilaterally in the forebrain, but plaque load was still clearly greater in the extract-injected hemisphere. There was also evidence of tau hyperphosphorylation in axons of the corpus callosum that had been injured by the injection, most prominently in transgenic mice, but also, to a lesser degree, in non-transgenic mice. Five months following injection of AD-extract, an isolated cluster of Abeta-immunoreactive microglia was sometimes evident in the ipsilateral entorhinal cortex; the strong innervation of the hippocampus by entorhinal cortical neurons suggests the possible spread of seeded pathology from the injection site via neuronal transport mechanisms. Finally, using India Ink to map the local dispersion of injectate, we found that Abeta induction is especially potent in places where the injectate is sequestered. The AD-seeding model can illuminate the emergence and spread of cerebral beta-amyloidosis and tau hyperphosphorylation, and thus could enhance our understanding of AD and its pathogenic commonalties with other cerebral proteopathies.

Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice.

Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.