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J Neurosci. 2002 Nov 1;22(21):9203-9.

Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death.

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1
Department of Neurology, University of California, San Francisco, USA.

Abstract

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.

PMID:
12417645
[Indexed for MEDLINE]
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