Clonidine abolishes the adverse effects on apoptosis and behaviour after neonatal ketamine exposure in mice.
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.


CONCLUSIONS
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.
Department of Surgical Sciences, Anaesthesiology and Intensive Care, Uppsala University, Sweden. emma.ponten@surgsci.uu.se
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E
Pontén
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Viberg
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Gordh
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Eriksson
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Fredriksson
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000778:Anesthetics, Dissociative / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009930:Organic Chemicals
D000316:Adrenergic alpha-Agonists; D000778:Anesthetics, Dissociative; D005452:Fluoresceins; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C435731:fluoro jade; D007649:Ketamine; D003000:Clonidine