uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Show others and affiliations
2008 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 249, no 2-3, 153-9 p.Article in journal (Refereed) Published
Abstract [en]

Ketamine, an anaesthetic agent used in newborns and toddlers, has been shown to induce neurodegeneration and alter adult behavior in mice, when administered during the neonatal period. Mammals have a marked period of rapid brain growth and development (BGS), which is postnatal in mice and rats, spanning the first 3-4 weeks of life and reaching its peak around postnatal day 10. CaMKII and GAP-43 play important roles during the BGS in mammals. In the present study, 10 days old mice were exposed to 5-25 mg ketamine/kg bw and 24 h later brains were analyzed for calcium/calmodulin-dependent protein kinase II (CaMKII) and growth associated protein-43 (GAP-43) and at an age of 2 and 4 months the animals were tested for spontaneous behavior. The protein analysis showed that CaMKII increased significantly in hippocampus, but not in cortex, in animals 24h after exposure to ketamine. GAP-43 showed a significant increase in hippocampus, but a significant decrease in cortex for the highest ketamine dose. When looking at the adult behavior it was clear that neonatal ketamine exposure affected spontaneous behavior and habituation in a dose-response-related manner and that these behavioral disturbances were not transient but still persisted 2 months later. Taken together, this shows that ketamine affects important proteins involved in normal maturation of the brain and induce functional deficits in the adult individual, which further strengthen our findings concerning ketamine as a developmental neurotoxicological agent.

Place, publisher, year, edition, pages
2008. Vol. 249, no 2-3, 153-9 p.
Keyword [en]
Ketamine, Neonatal, Neurotoxicity, CaMKII, GAP-43, Behavior
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-87826DOI: 10.1016/j.tox.2008.04.019ISI: 000258242100010PubMedID: 18550250OAI: oai:DiVA.org:uu-87826DiVA: diva2:133749
Available from: 2009-01-14 Created: 2009-01-14 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Neonatal Exposure to Anaesthesia and Adjuvants: Acute Effects on Cerebral Apoptosis and Neuroproteins, and Late  Behavioural Aberrations in Mice
Open this publication in new window or tab >>Neonatal Exposure to Anaesthesia and Adjuvants: Acute Effects on Cerebral Apoptosis and Neuroproteins, and Late  Behavioural Aberrations in Mice
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During a finite developmental phase – the brain growth spurt – the brain grows and matures at an accelerated rate. During this period the brain is more sensitive to harmful substances such as ethanol and environmental toxins than before or after. This period extends from the last trimester to the second year in humans and occurs postnatally in the mice used for these studies.

The aims of this thesis were; to investigate common anaesthetics ability to promote acute apoptosis and late persistant behavioural aberrations measured with spontaneous behaviour in a novel home environment, learning in a radial arm maze and anxiety-like behaviour in an elevated plus maze, to measure alterations in BDNF, CaMKII, GAP-43, synaptophysin and tau after anaesthesia exposure, to evaluate clonidine as a potentially protecting agent and examine if theophylline, a chemically unrelated compound, causes similar effects as anaesthetics.

Some of the results are: combinations of anaesthetics acting on the GABAA receptor (propofol or pentothal) and NMDA receptor (ketamine) exhibit more apoptosis and behavioural alterations than single anaesthetics. Ketamine, but not propofol, alters the content of CaMKII and GAP-43 proteins important in brain development. Propofol exposure alters the content of BDNF (brain derived neurotrophic factor) in hippocampus, frontal and parietal cortex. Neonatal propofol exposure leads to less sensitiveness to diazepam in adult age as measured with induced spontaneous behaviour and an elevated plus maze. Clonidine, an alpha2 adrenergic agonist does not cause any aberrations and appears to prevent apoptosis and behavioural alterations after ketamine. Theophylline, used as apnoea treatment in neonates, also increases apoptosis and alters normal behaviour.

Thus, alterations both in neuronal survival, function and protein expression is apparent after neonatal exposure to anaesthetics. This is also shown in studies of Rhesus monkeys. However, it is still difficult to assess how these findings should extrapolate to humans. Epidemiological studies give conflicting results.

Insufficient anaesthesia is not a solution as pain and stress cause even more pronounced problems. Minimizing anaesthetic exposure, delaying procedures until after the sensitive phase and finding protective agents, such as clonidine, are possible strategies. Evaluation of other substances that infants are exposed to is needed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 784
Keyword
anaesthesia, neonatal, apoptosis, bahaviour, clonidine, ketamine, propofol, theophyllamine
National Category
Anesthesiology and Intensive Care
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-173401 (URN)978-91-554-8395-1 (ISBN)
Public defence
2012-08-24, Hedstrandsalen, Akademiska Sjukhuset, Ing 70 bv, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-06-01 Created: 2012-04-23 Last updated: 2013-04-03

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
By organisation
Environmental ToxicologyAnaesthesiology and Intensive CareDepartment of Neuroscience
In the same journal
Toxicology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 644 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf