Secobarbital Attenuates Excitotoxicity but Potentiates Oxygen—Glucose Deprivation Neuronal Injury in Cortical Cell Culture

Giffard, Rona G.; Weiss, John H.; Swanson, Raymond A.; Choi, Dennis W.

doi:10.1038/jcbfm.1993.102

Cited by 19 publications

(7 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected from previous reports (Choi et al, 1987;Giffard et al, 1993;Black et al, 1995), NMDA was potently toxic for mature (12-15 days in vitro) cortical neurons. In control cultures, >95% of the neurons were alive at 12-15 days ( Fig.…”

Section: Resultssupporting

confidence: 90%

The Desglycinyl Metabolite of Remacemide Hydrochloride Is Neuroprotective in Cultured Rat Cortical Neurons

Black

Tremblay

Mealing

et al. 1996

Journal of Neurochemistry

View full text Add to dashboard Cite

The neuroprotective actions of remacemide and its anticonvulsant metabolite 1,2‐diphenyl‐2‐propylamine monohydrochloride (desglycinylremacemide; DGR), a low‐affinity NMDA receptor antagonist, were investigated using primary rat cortical neuronal cultures. Exposure of cortical cultures to NMDA (100 µM) for 15 min killed 85% of the neurons during the next 24 h. This neurotoxicity was blocked in a concentration‐dependent manner by adding DGR (5–20 µM), but not its remacemide precursor (10–100 µM), to the cultures during the time of NMDA exposure. This suggests that the neuroprotective, as well as the anticonvulsant, activity of remacemide is mediated by DGR. Neuroprotective concentrations of DGR also inhibited two of the principal acute effects of NMDA. DGR (5–20 µM) prevented the loss of membrane‐associated protein kinase C (PKC) activity that developed by 4 h after transient exposure to 100 µM NMDA and reduced the NMDA‐triggered increases in intracellular free Ca2+ concentration ([Ca2+]i) by up to 70%. By contrast, remacemide (50 and 100 µM) did not prevent the NMDA‐induced loss of PKC activity or reduce the [Ca2+]i responses. These data suggest that DGR protection against NMDA‐mediated toxicity in cultured cortical neurons is associated with a reduction of NMDA‐triggered [Ca2+]i surges and a prevention of the loss of membrane‐associated PKC activity. In addition, the inhibition of NMDA‐triggered [Ca2+]i responses by DGR was qualitatively different from the inhibition of these responses by the high‐affinity NMDA‐receptor antagonists MK‐801 and phencyclidine. This may be a consequence of DGR's lower affinity for the NMDA receptor.

show abstract

Section: Resultssupporting

confidence: 90%

The Desglycinyl Metabolite of Remacemide Hydrochloride Is Neuroprotective in Cultured Rat Cortical Neurons

Black

Tremblay

Mealing

et al. 1996

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…35 A potential mechanism is blockade of glutamate receptors, including the kainate, N-methyl-D-aspartate (NMDA), and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) sub-types. 36 Relevant to the present results is the data of Cai et al, 37 who observed a differential ability, in a neuronal culture, of barbiturates to block these receptors.…”

Section: Glutamatementioning

confidence: 99%

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

Cole

Cross

Drummond

et al. 2001

Can J Anesth/J Can Anesth

View full text Add to dashboard Cite

P Pu ur rp po os se e: : Although barbiturates are considered to be cerebral protectants, little is known regarding the relative efficacy of different barbiturates to reduce ischemic brain injury. In a model of middle cerebral artery occlusion (MCAo), we compared the relative effects of 1.0 and 0.4 burst-suppression doses of thiopentone, methohexital, and pentobarbitone on cerebral infarct.M Me et th ho od ds s: : During isoflurane anesthesia, MCAo was achieved via a temporal craniotomy. Thirty minutes before MCAo the rats were randomized to receive one of the following which was maintained throughout the study. Halothane (n=20)-1.2 MAC halothane, thiopentone (n=20), methohexital (n=20), or pentobarbitone (n=20). The first ten animals in each barbiturate group received the respective barbiturate in a dose sufficient to maintain burst-suppression of the electroencephalogram (35 bursts·min 1 ). The subsequent ten animals in each barbiturate group received 40% of the burst-suppression dose. After 180 min of MCAo and 120 min of reperfusion, cerebral injury was assessed.R Re es su ul lt ts s: : For the burst-suppression animals, injury volume (mm 3 , mean ± SD) was less in the thiopentone group (88 ± 14) than the halothane (133 ± 17), methohexital (126 ± 19), or pentobarbitone (130 ± 17) groups (P <0.05). For 0.4 burst-suppression animals, injury volume was less for the methohexital group (70 ± 22) than the halothane (124 ± 24), thiopentone (118 ± 15), or pentobarbitone (121 ± 20) groups (P <0.05).C Co on nc cl lu us si io on ns s: : These data are inconsistent with the longstanding assumption that electrophysiologically comparable doses of the various classes of barbiturates have equivalent protective efficacy. They in turn suggest that mechanisms other than, or at least in addition to, metabolic suppression may contribute to the protective effect of barbiturates.Objectif : Bien que les barbituriques soient considérés comme des protecteurs cérébraux, on en sait peu sur leur efficacité relative à réduire la lésion cérébrale ischémique. Nous avons comparé, chez un modèle docclusion de lartère cérébrale moyenne (OACM), les effets relatifs de doses de thiopental, méthohexital et pentobarbital, capables de suppression totale et à 40 % (1,0 et 0,4) des bouffées du tracé électroencéphalographique (EEG), sur linfarctus cérébral.Méthode : Pendant lanesthésie à lisoflurane, lOACM a été provoquée au moyen dune craniotomie temporale. Trente minutes avant locclusion, les rats ont été randomisés et ont reçu un des médica-ments suivants, thérapie maintenue tout au long de létude : 1,2 CAM dhalothane (n = 20), du thiopental (n = 20), du méthohexital (n = 20) ou du pentobarbital ( n = 20). Les dix premiers animaux de chaque groupe barbiturique ont reçu une dose du médicament suffisante pour maintenir la suppression des bouffées du tracé EEG (35·min 1 ). Les dix animaux suivants de chaque groupe barbiturique ont reçu 40 % de la dose causant la suppression des bouffées. On a évalué la lésion cérébrale après 180 min dOACM suivie de 120...

show abstract

“…These actions suggest that barbiturates should effectively reduce excitotoxic neuronal injury, particularly under conditions of energy deprivation. Therefore, it is surprising that barbiturates do not attenuate neuronal death in cell-culture models of glucose or combined oxygen-glucose deprivation (Giffard et al, 1993) that produce NMDA receptor-dependent toxicity.…”

mentioning

confidence: 99%

Barbiturates Induce Mitochondrial Depolarization and Potentiate Excitotoxic Neuronal Death

et al. 2002

Self Cite

View full text Add to dashboard Cite

Barbiturates are widely used as anesthetics, anticonvulsants, and neuroprotective agents. However, barbiturates may also inhibit mitochondrial respiration, and mitochondrial inhibitors are known to potentiate NMDA receptor-mediated neurotoxicity. Here we used rat cortical cultures to examine the effect of barbiturates on neuronal mitochondria and responses to NMDA receptor stimulation. The barbiturates tested, secobarbital, amobarbital, and thiamylal, each potentiated NMDA-induced neuron death at barbiturate concentrations relevant to clinical and experimental use (100-300 microm). By using rhodamine-123 under quenching conditions, barbiturates in this concentration range were shown to depolarize neuronal mitochondria and greatly amplify NMDA-induced mitochondrial depolarization. Barbiturate-induced mitochondrial depolarization was increased by the ATP synthase inhibitor oligomycin, indicating that barbiturates act by inhibiting electron transport sufficiently to cause ATP synthase reversal. Barbiturates similarly amplified the effects of NMDA on cytoplasmic free calcium concentrations. The cell-impermeant barbiturate N-glucoside amobarbital did not influence mitochondrial potential or potentiate NMDA neurotoxicity or calcium responses. However, all of the barbiturates attenuated NMDA-induced calcium elevations and cell death when present at millimolar concentrations. Whole-cell patch-clamp studies showed that these effects may be attributable to actions at the cell membrane, resulting in a block of NMDA-induced current flux at millimolar barbiturate concentrations. Together, these findings reconcile previous reports of opposing effects on barbiturates on NMDA neurotoxicity and show that barbiturate effects on neuronal mitochondria can be functionally significant. Effects of barbiturates on neuronal mitochondria should be considered in experimental and clinical application of these drugs.

show abstract

Secobarbital Attenuates Excitotoxicity but Potentiates Oxygen—Glucose Deprivation Neuronal Injury in Cortical Cell Culture

Cited by 19 publications

References 47 publications

The Desglycinyl Metabolite of Remacemide Hydrochloride Is Neuroprotective in Cultured Rat Cortical Neurons

The Desglycinyl Metabolite of Remacemide Hydrochloride Is Neuroprotective in Cultured Rat Cortical Neurons

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

Barbiturates Induce Mitochondrial Depolarization and Potentiate Excitotoxic Neuronal Death

Contact Info

Product

Resources

About