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Clonidine abolishes the adverse effects on apoptosis and behaviour after neonatal ketamine exposure in mice
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 Organismal 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 Organismal Biology, Environmental Toxicology.
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2012 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 56, no 8, 1058-1065 p.Article in journal (Refereed) Published
Abstract [en]

Background

An increasing amount of both experimental and epidemiological data indicates that neonatal anaesthesia causes disruption of normal brain development in rodents and primates, as manifested by acute increased apoptosis and long-lasting altered behaviour and learning. It is necessary to seek strategies that avoid the possible adverse effects after anaesthesia. Our purpose is to show that increased apoptosis and behavioural alterations after ketamine exposure during this period may be prevented by clonidine, a compound already used by paediatric anaesthetists for sedation.

Methods

To investigate the protective properties of clonidine pre-treatment, five groups of 10-day-old mice were injected with either ketamine 50 mg/kg, clonidine 40 μg/kg, ketamine 50 mg/kg 30 min after 10 μg/kg clonidine, ketamine 50 mg/kg 30 min after 40 μg/kg clonidine or saline (control). Apoptosis was measured 24 h after treatment using Flouro-Jade staining. Spontaneous activity in a novel environment was tested at an age of 55 days.

Results

Pre-treatment with 40 μg/kg clonidine, but not 10 μg/kg clonidine, 30 min before ketamine exposure abolished ketamine-induced apoptosis and the behavioural changes observed in the young adult mice. The mice exposed to clonidine alone showed no differences from the saline-treated (control) mice.

Conclusion

The administration of clonidine eliminated the adverse effects of ketamine in this mouse model, suggesting a possible strategy for protection. Alone, clonidine did not cause any adverse effects in these tests.

Place, publisher, year, edition, pages
2012. Vol. 56, no 8, 1058-1065 p.
National Category
Anesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-173406DOI: 10.1111/j.1399-6576.2012.02722.xISI: 000307437600016OAI: oai:DiVA.org:uu-173406DiVA: diva2:525180
Available from: 2012-05-07 Created: 2012-04-23 Last updated: 2017-12-07Bibliographically 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)
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Available from: 2012-06-01 Created: 2012-04-23 Last updated: 2013-04-03

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Pontén, EmmaViberg, HenrikGordh, TorstenEriksson, PerFredriksson, Anders

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