Combination of xenon and isoflurane produces a synergistic protective effect against oxygen-glucose deprivation injury in a neuronal-glial co-culture model.
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Nicholas P Franks
Publications and source records attributed to Nicholas P Franks.
The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice.
BACKGROUND: Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion. METHODS: C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated. RESULTS: The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2 versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2 versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3 versus 59 +/- 11 mm3, respectively; P = 0.0009). CONCLUSIONS: In this model of transient focal cerebral ischemia, xenon administration improved both functional and histologic outcome.
Administration, Inhalation↗
Selective synaptic actions of thiopental and its enantiomers.
BACKGROUND: There is conflicting evidence concerning the extent to which the intravenous general anesthetic thiopental acts by enhancing inhibitory gamma-aminobutyric acid-mediated (GABAergic) synaptic transmission or by inhibiting excitatory glutamatergic transmission. Yet there are remarkably few studies on the effects of thiopental on functional synapses. In addition, the degree of stereoselectivity of thiopental acting at synapses has yet to be tested. METHODS: The actions of thiopental and its enantiomers on GABAergic and glutamatergic synapses were investigated using voltage clamp techniques on microisland cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks. RESULTS: Racemic thiopental markedly enhanced the charge transfer at GABAergic synapses without significantly affecting the peak of the postsynaptic current. At a surgically relevant concentration (25 microm), charge transfer was increased by approximately 230%. However, even at twice this concentration there were no significant effects on glutamatergic postsynaptic currents. At GABAergic synapses, thiopental acted stereoselectively, with the S(-) enantiomer being approximately twice as effective as the R(+) enantiomer at enhancing charge transfer. CONCLUSIONS: Thiopental stereoselectively enhances inhibitory GABAergic synaptic transmission in a way that reflects animal potencies, supporting the idea that this is a principal mode of action for this drug. The absence of any effect on glutamatergic synapses at surgically relevant concentrations suggests that the inhibition of these excitatory synapses is not an important factor in producing thiopental general anesthesia.
Anesthetics, Intravenous↗
Effects of xenon on in vitro and in vivo models of neuronal injury.
BACKGROUND: Xenon, the "inert" gaseous anesthetic, is an antagonist at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Because of the pivotal role that NMDA receptors play in neuronal injury, the authors investigated the efficacy of xenon as a neuroprotectant in both in vitro and in vivo paradigms. METHODS: In a mouse neuronal-glial cell coculture, injury was provoked either by NMDA, glutamate, or oxygen deprivation and assessed by the release of lactate dehydrogenase into the culture medium. Increasing concentrations of either xenon or nitrogen (10-75% of an atmosphere) were coadministered and maintained until injury was assessed. In separate in vivo experiments, rats were administered N-methyl-dl-aspartate and killed 3 h later. Injury was quantified by histologic assessment of neuronal degeneration in the arcuate nucleus of the hypothalamus. RESULTS: Xenon exerted a concentration-dependent protection against neuronal injury provoked by NMDA (IC(50) = 19 +/- 6% atm), glutamate (IC(50) = 28 +/- 8% atm), and oxygen deprivation (IC(50) = 10 +/- 4% atm). Xenon (60% atm) reduced lactate dehydrogenase release to baseline concentrations with oxygen deprivation, whereas xenon (75% atm) reduced lactate dehydrogenase release by 80% with either NMDA- or glutamate-induced injury. In an in vivo brain injury model in rats, xenon exerted a concentration-dependent protective effect (IC(50) = 78 +/- 8% atm) and reduced the injury by 45% at the highest xenon concentration tested (75% atm). CONCLUSIONS: Xenon, when coadministered with the injurious agent, exerts a concentration-dependent neuroprotective effect at concentrations below which anesthesia is produced in rodents. Unlike either nitrous oxide or ketamine (other anesthetics with NMDA antagonist properties), xenon is devoid of both neurotoxicity and clinically significant adverse hemodynamic properties. Studies are proposed to determine whether xenon can be used as a neuroprotectant in certain clinical settings.
Anesthetics, Inhalation↗