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      The Neurotoxicity of Nitrous Oxide: The Facts and “Putative” Mechanisms

      review-article
      Author(s): , *
      Publication date (Electronic):
      Journal: Brain Sciences
      Publisher: MDPI
      Keywords: nitrous oxide, neurotoxicity, homocysteine, NMDA antagonist

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          Abstract

          Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl- d-aspartate (NMDA)-antagonist drug, similar in nature to ketamine, another anaesthetic agent. It has been linked to post-operative cardiovascular problems in clinical studies. It is also widely known that exposure to nitrous oxide during surgery results in elevated homocysteine levels in many patients, but very little work has investigated the long term effect of these increased homocysteine levels. Now research in rodent models has found that homocysteine can be linked to neuronal death and possibly even cognitive deficits. This review aims to examine the current knowledge of mechanisms of action of nitrous oxide, and to describe some pathways by which it may have neurotoxic effects.

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          Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

          H Monyer, N. Burnashev, D Laurie … (1994)
          An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.
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            NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.

            Houman Homayoun, Bita Moghaddam (2007)
            NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.
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              Extrapolating brain development from experimental species to humans.

              Barbara Clancy, Barbara Finlay, Richard B. Darlington … (2007)
              To better understand the neurotoxic effects of diverse hazards on the developing human nervous system, researchers and clinicians rely on data collected from a number of model species that develop and mature at varying rates. We review the methods commonly used to extrapolate the timing of brain development from experimental mammalian species to humans, including morphological comparisons, "rules of thumb" and "event-based" analyses. Most are unavoidably limited in range or detail, many are necessarily restricted to rat/human comparisons, and few can identify brain regions that develop at different rates. We suggest this issue is best addressed using "neuroinformatics", an analysis that combines neuroscience, evolutionary science, statistical modeling and computer science. A current use of this approach relates numeric values assigned to 10 mammalian species and hundreds of empirically derived developing neural events, including specific evolutionary advances in primates. The result is an accessible, online resource (http://www.translatingtime.net/) that can be used to equate dates in the neurodevelopmental literature across laboratory species to humans, predict neurodevelopmental events for which data are lacking in humans, and help to develop clinically relevant experimental models.
              Article 0 comments Cited 184 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Brain Sci
                Journal ID (iso-abbrev): Brain Sci
                Journal ID (publisher-id): brainsci
                Title: Brain Sciences
                Publisher: MDPI
                ISSN (Electronic): 2076-3425
                Publication date (Electronic): 28 January 2014
                Publication date Collection: March 2014
                Volume: 4
                Issue: 1
                Pages: 73-90
                Affiliations
                Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery & Cancer, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK; E-Mail: s.savage@ 123456imperial.ac.uk
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: d.ma@ 123456imperial.ac.uk ; Tel.: +44-20-3315-8495; Fax: +44-20-3315-5109.
                Article
                Publisher ID: brainsci-04-00073
                DOI: 10.3390/brainsci4010073
                PMC ID: 4066238
                PubMed ID: 24961701
                SO-VID: fae19dcf-e9fe-47c5-a163-257b7e470125
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 16 December 2013
                Date revision received : 08 January 2014
                Date accepted : 16 January 2014
                Categories
                Subject: Review

                Keywords: nitrous oxide,neurotoxicity,homocysteine,nmda antagonist
                Data availability:
                Keywords: nitrous oxide, neurotoxicity, homocysteine, nmda antagonist

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