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Theophylline causes dose dependent persistent behavioural changes in neonatal 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 Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Abstract

Background

Theophylline is used in clinic to promote breathing in premature infants and in neonates. Caffeine, a compound also belonging to the group of xanthenes, is known to increase apoptosis and to cause behavioural defects. The present study was conducted to investigate whether theophylline can induce neuronal death and behavioural disturbances when administered to neonatal mice during a period of brain growth corresponding to premature infants and an approximately week 13 to 24.

Methods

Neonatal mice, three days old, were exposed to theophylline at doses 1, 5, or 25 mg/kg body weight twice daily for five consecutive days. Controls received in the same manner the vehicle, saline. Neuronal death was assessed in whole brain sections by Fluoro Jade 24 hours after the last exposure to theophylline. Adult mice, age 55 to 63 days old, were observed for spontaneous behavior in a novel home environment, learning and memory in a radial arm maze and for anxiety-like behavior in an elevated plus maze.

Results

Adult mice neonatally exposed to theophylline showed significant dose-response changes in all three behavioural tests. The lowest dose to induce any behavioral defects was 5 mg/kg body weight. No significant alterations in neuronal death were observed in the neonatal brains.

Conclusion

The present study shows that neonatal exposure to theophylline can cause behavioural defects related to learning and memory impairments and reduced cognitive function in young adult mice.

 

Keyword [en]
neonatal, apoptosis, theophylline, behaviour, mice, learning
National Category
Anesthesiology and Intensive Care
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-173786OAI: oai:DiVA.org:uu-173786DiVA: diva2:525182
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2012-06-08
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

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