Effects Of Ketamine On Cognitive Function And NNOS Pression In Cerebral Hippocampus Of Developing Rats

Introduction:Recently some clinical observations and animal studies suggest that continuous using of general anesthetics to people and animals can affect the function of learning and memory, appearing postoperative cognitive dysfunction (POCD). Ketamine (Ket) is a kind of common clinical intravenous anesthetics, which has been used widely in pediatric surgery at present for its strong analgesic action and less respiratory inhibition. Because the brain is the main target organ of anesthetic effect and pediatric stage is the critical period for development of nervous system,, the growth of brain and function of learning and memory are likely damaged if general anesthesia is accepted by children at this time. In present opinion, the hippocampus is the important organization involved in learning and memory, in which neuron nitric oxide synthetase (nNOS) is the key enzyme to synthetize the neurotransmitter that nitric oxide(NO) is involved in learning and memory mechanism. Some researches already suggested that some drugs cause reduction of nNOS expression through the activation of gamma-aminobutyric acid (GABA) receptors and inhibition of LTP in isolated hippocampus or impact of synaptic transmission plasticity, leading to the function of learning and memory be damaged. So far it has been no reported whether the impairment of ketamine on learning and memory relates to nNOS..This experiment with anesthetized SD rats as the research object, study initially the effects of cognitive function after anesthesia by observing changes of cognitive function and expression of nNOS in cerebral hippocampus, we hope it is helpful to exploring the mechanism of cognitive function after ketamine anesthesia, for drug reasonable application to provide the experimental basis.Objective:To investigate the effects of ketamine on the learning and memory of the developing rats and its possible mechanism.Methods:Forty SD rats of 2 months were randomly divided into 4 groups, that is, normal group, training group, low-dose ketamine group and high-dose ketamine group, with free access to food and water except during experiment. Normal group received no intervention, and training group received equal volume normal saline 2ml i.p. During induction of anesthesia the rats of low-dose group were injected ketamine (10mg/kg) and high-dose group(50mg/kg) i.p (normal saline diluted to 2ml). And then were added a half of the first volume per hour to maintain anesthesia for 6 hours, monitoring vital sign in the course of anesthesia including pluse oximetry(SpO2).After 24 hours anesthetized, the rats were trained to identify the light stimulus and response capacity of the safety position by training times are not fixed and random rest. In a quiet low-light environmental conditions, the rats were tested behavioral training after rats adapted 3-5 minutes in Y-maze. The rats were injected 10% chloral hydrate(400mg/kg) i.p,and then perfused by 4%(4℃) paraformaldehyde so that hippocampal cerebral tissue can be obtained immediately after the test. The nNOS expression in hippocampus was tested by using immunhistochemistry.Results:The result in three indexes on the number of required standard and the percentage of correct response or the percentage of initiative avoidance in every time interval by Y-maze of 2 months old SD rats anesthetized with ketamine showed:there were significant differences (P< 0.05) compared in three indexes between the high-dose group and training group; except the number of required standard in the 4th day and the percentage of initiative avoidance in the 1-5th days, there were significant differences (P<0.05) compared between the high-dose group and low-dose group.While there were no significant differences (P>0.05) compared in three indexes between the low-dose group and training group. The immunohistochemical results were shown:in two indicators on the number of nNOS positive neurons and the IOD value in hippocampus, there were significant differences (P<0.05) compared between the high-dose group and training group or low-dose ketamine group. But the low-dose group compared with the training group no significant difference (P> 0.05) in the number of nNOS positive neurons and the IOD values.Conclusions:Ketamine may temporally inhibit the ability of learning and memory of growth in developing rats.The possible mechanism may be related to inhibition of nNOS expression in hippocampus.