Neonatal Exposure to Anaesthesia and Adjuvants : Acute Effects on Cerebral Apoptosis and Neuroproteins, and Late  Behavioural Aberrations in Mice

Abstract: 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.