Thiopental Attenuates Hypoxic Changes of Electrophysiology, Biochemistry, and Morphology in Rat Hippocampal Slice CA1 Pyramidal Cells

Abstract

Background and Purpose-Thiopental has been shown to protect against cerebral ischemic damage; however, it has undesirable side effects. We have examined how thiopental alters histological, physiological, and biochemical changes during and after hypoxia. These experiments should enable the discovery of agents that share some of the beneficial effects of thiopental. Methods-We made intracellular recordings and measured ATP, sodium, potassium, and calcium concentrations from CA1 pyramidal cells in rat hippocampal slices subjected to 10 minutes of hypoxia with and without 600 mol/L thiopental. Results-Thiopental delayed the time until complete depolarization (21Ϯ3 versus 11Ϯ2 minutes for treated versus untreated slices, respectively) and attenuated the level of depolarization at 10 minutes of hypoxia (Ϫ33Ϯ6 versus Ϫ12Ϯ5 mV). There was improved recovery of the resting potential after 10 minutes of hypoxia in slices treated with thiopental (89% versus 31% recovery). Thiopental attenuated the changes in sodium (140% versus 193% of prehypoxic concentration), potassium (62% versus 46%), and calcium (111% versus 197%) during 10 minutes of hypoxia. There was only a small effect on ATP (18% versus 8%). The percentage of cells showing clear histological damage was decreased by thiopental (45% versus 71%), and thiopental improved protein synthesis after hypoxia (75% versus 20%). Conclusions-Thiopental attenuates neuronal depolarization, an increase in cellular sodium and calcium concentrations, and a decrease in cellular potassium and ATP concentrations during hypoxia. These effects may explain the reduced histological, protein synthetic, and electrophysiological damage to CA1 pyramidal cells after hypoxia with thiopental. (Stroke. 1999;30:2400-2407.)

Changes in Intracellular Chloride after Oxygen–Glucose Deprivation of the Adult Hippocampal Slice: Effect of Diazepam

“…Several investigators have demonstrated that benzodiazepines and barbiturates can restore synaptic transmission and membrane potential after anoxia (Abramowicz et al, 1991;Kass et al, 1992;Wang et al, 1999). In agreement with these studies, we have shown that diazepam can reduce the rise in intracellular Ca 2ϩ and prevents the irreversible loss of synaptic transmission in hippocampal slices after OGD.…”

“…Taylor et al (1999) showed that both synaptic transmission and a rise in intracellular Cl Ϫ (assessed with x-ray electron analysis) failed to recover by 30 min after OGD in the adult hippocampal slice. However, Wang et al (1999) reported that the ionic distribution had returned to pre-hypoxia levels on reoxygenation, although 70% of the neurons remained depolarized and unresponsive to synaptic stimulation. In the present study, Cl Ϫ levels returned toward baseline by ϳ20 min after reoxygenation; this recovery was most likely associated with the attempt of the neurons to restore their membrane potential (Rader and Lanthorn, 1989) and ionic distribution during the early phase of reoxygenation.…”

Nicotinic Receptors Differentially RegulateN-Methyl-d-aspartate Damage in Acute Hippocampal Slices

“…The acute hippocampal slices have a particular advantage as a model of early electrophysiological excitotoxic damage; however, its viability decreases after 8 to 10 h. For this reason, few studies have addressed delayed cell death in acute slices (Wallis and Panizzon, 1995;Wang et al, 1999). The comparison of the early effect of experimental ischemia on the electric activity in acute slices with delayed neuronal jpet.aspetjournals.org death in cultured slices was consistent with the concept that both represent the same event in a different time scale (Small et al, 1997).…”

“…The measurement of the area of population spikes (PSs) to determine the physiological status of acute hippocampal slices was successfully used to study the effect of anoxia, oxygen, and glucose deprivation, and excitotoxic amino acids on hippocampal neurons (Schurr et al, 1995;Small et al, 1997;Wang et al, 1999;Ferchmin et al, 2000). As a model of excitotoxic damage, this preparation has the advantages of an in vitro preparation with most of the circuitry of the original hippocampus intact as shown by its capability to express complex functions such as long-term potentiation.…”

Thiopentone and methohexital, but not pentobarbitone, reduce early focal cerebral ischemic injury in rats

“…Mechanisms of note include effects on free radical scavenging, vascular tone, cellular ionic gradients, and excitotoxicity. [16][17][18][19][20][21] In most instances, there are insufficient data to conclude that these properties are shared equally by all of the available barbiturates. In addition, if these mechanisms contribute to barbiturate-mediated cerebral protection, there is no confirmation that their activity parallels the reductions in CMR caused by barbiturates.…”