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Zimin 2018 Br J Anaesth

From Bioblast
Publications in the MiPMap
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.

Β» 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 Β© 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. β€’ Keywords: Adenosine, Anaesthesia, Hypersensitivity β€’ Bioblast editor: Kandolf G β€’ 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 

2018-04