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Neonatal Exposure to Anaesthesia and Adjuvants: Acute Effects on Cerebral Apoptosis and Neuroproteins, and Late  Behavioural Aberrations in Mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
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 [en]
anaesthesia, neonatal, apoptosis, bahaviour, clonidine, ketamine, propofol, theophyllamine
National Category
Anesthesiology and Intensive Care
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-173401ISBN: 978-91-554-8395-1 (print)OAI: oai:DiVA.org:uu-173401DiVA: diva2:525448
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
List of papers
1. Neonatal exposure to a combination of N-Methyl-D-aspartate and γ-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits
Open this publication in new window or tab >>Neonatal exposure to a combination of N-Methyl-D-aspartate and γ-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits
2007 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 107, no 3, 427-436 p.Article in journal (Refereed) Published
Abstract [en]

Background: During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood.

Methods: Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests-spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)-were conducted on mice aged 55-70 days.

Results: Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol.

Conclusion: This study shows that both a γ-aminobutyric acid type A agonist (thiopental or propofol) and an N-methyl-d-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopental, propofol, and ketamine individually elicited no or only minor changes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11526 (URN)10.1097/01.anes.0000278892.62305.9c (DOI)000249297200011 ()17721245 (PubMedID)
Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2017-12-11Bibliographically approved
2. Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly
Open this publication in new window or tab >>Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly
Show others...
2008 (English)In: Toxicology, ISSN 0300-483X, 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.

Keyword
Ketamine, Neonatal, Neurotoxicity, CaMKII, GAP-43, Behavior
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-87826 (URN)10.1016/j.tox.2008.04.019 (DOI)000258242100010 ()18550250 (PubMedID)
Available from: 2009-01-14 Created: 2009-01-14 Last updated: 2012-06-08Bibliographically approved
3. Neonatal exposure to propofol affects BDNF but not CaMKII, GAP-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain
Open this publication in new window or tab >>Neonatal exposure to propofol affects BDNF but not CaMKII, GAP-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain
Show others...
2011 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 223, no 1, 75-80 p.Article in journal (Refereed) Published
Abstract [en]

Animal studies have shown that neonatal anaesthesia is associated with acute signs of neurodegeneration and later behavioural changes in adult animals. The anaesthetic effect of propofol is thought to be mediated by gamma-amino butyric acid (GABA)(A) receptors. The present study investigated the effects on proteins important for normal neonatal brain development (i.e. BDNF, CaMKII, GAP-43, synaptophysin and tau), and adult spontaneous motor and anxiety-like behaviours in response to diazepam, after neonatal exposure to propofol. Ten-day-old mice were exposed to 0, 10 or 60 mg/kg bodyweight propofol. Neonatal propofol exposure changed the levels of BDNF in the brain, 24h after exposure, but did not alter any of the other proteins. Neonatal propofol exposure significantly changed the adult response to the GABA-mimetic drug diazepam, manifest as no change in spontaneous motor activity and/or reduced sedative effect and an extinguished effect on the reduction of anxiety-like behaviours in an elevated plus maze. Although no adult spontaneous behavioural changes were detected after neonatal propofol exposure, the exposure caused an adult dose-dependent decrease in the response to the GABA-mimetic drug diazepam. These changes may be due to neonatal alterations in BDNF levels.

Keyword
Propofol, BDNF, Behaviour
National Category
Anesthesiology and Intensive Care Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-156580 (URN)10.1016/j.bbr.2011.04.019 (DOI)000292587700012 ()
Available from: 2011-08-07 Created: 2011-08-04 Last updated: 2017-12-08Bibliographically approved
4. Clonidine abolishes the adverse effects on apoptosis and behaviour after neonatal ketamine exposure in mice
Open this publication in new window or tab >>Clonidine abolishes the adverse effects on apoptosis and behaviour after neonatal ketamine exposure in mice
Show others...
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.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-173406 (URN)10.1111/j.1399-6576.2012.02722.x (DOI)000307437600016 ()
Available from: 2012-05-07 Created: 2012-04-23 Last updated: 2017-12-07Bibliographically approved
5. Theophylline causes dose dependent persistent behavioural changes in neonatal mice
Open this publication in new window or tab >>Theophylline causes dose dependent persistent behavioural changes in neonatal mice
(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
neonatal, apoptosis, theophylline, behaviour, mice, learning
National Category
Anesthesiology and Intensive Care
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-173786 (URN)
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2012-06-08

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