Zimin 2018 Br J Anaesth

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Zimin PI, Woods CB, Kayser EB, Ramirez JM, Morgan PG, Sedensky MM (2018) Isoflurane disrupts excitatory neurotransmitter dynamics via inhibition of mitochondrial complex I. Br J Anaesth 120:1019-32.

» PMID: 29661379

Zimin PI, Woods CB, Kayser EB, Ramirez JM, Morgan PG, Sedensky MM (2018) Br J Anaesth

Abstract: The mechanisms of action of volatile anaesthetics are unclear. Volatile anaesthetics selectively inhibit complex I in the mitochondrial respiratory chain. Mice in which the mitochondrial complex I subunit NDUFS4 is knocked out [Ndufs4(KO)] either globally or in glutamatergic neurons are hypersensitive to volatile anaesthetics. The volatile anaesthetic isoflurane selectively decreases the frequency of spontaneous excitatory events in hippocampal slices from Ndufs4(KO) mice.

Complex I inhibition by isoflurane was assessed with a Clark electrode. Synaptic function was measured by stimulating Schaffer collateral fibres and recording field potentials in the hippocampus CA1 region.

Isoflurane specifically inhibits complex I dependent respiration at lower concentrations in mitochondria from Ndufs4(KO) than from wild-type mice. In hippocampal slices, after high frequency stimulation to increase energetic demand, short-term synaptic potentiation is less in KO compared with wild-type mice. After high frequency stimulation, both Ndufs4(KO) and wild-type hippocampal slices exhibit striking synaptic depression in isoflurane at twice the 50% effective concentrations (EC50). The pattern of synaptic depression by isoflurane indicates a failure in synaptic vesicle recycling. Application of a selective A1 adenosine receptor antagonist partially eliminates isoflurane-induced short-term depression in both wild-type and Ndufs4(KO) slices, implicating an additional mitochondria-dependent effect on exocytosis. When mitochondria are the sole energy source, isoflurane completely eliminates synaptic output in both mutant and wild-type mice at twice the (EC50) for anaesthesia.

Volatile anaesthetics directly inhibit mitochondrial complex I as a primary target, limiting synaptic ATP production, and excitatory vesicle endocytosis and exocytosis.

Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Keywords: Adenosine, Anaesthesia, Hypersensitivity Bioblast editor: Kandolf G O2k-Network Lab: US WA Seattle Kayser EB

Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I 

Coupling state: LEAK, OXPHOS  Pathway: N, S, ROX  HRR: Oxygraph-2k