Cellular mechanisms mediating cytotoxicity and delayed behavioral/cognitive abnormalities associated with neonatal anesthesia are poorly understood. Altered neurogenesis caused by anesthetic-depressed neuronal activity has been a predominant concept. Based on our preliminary results and literature data we hypothesize: 1) anesthetics that enhance GABAA/glycine receptor activity may exacerbate GABA-induced depolarization and Ca2+ influx in immature neurons resulting in immediate (seizures, cytotoxicity) and delayed brain defects (will be studied by evaluating synaptic plasticity, prepulse inhibition (PPI) of acoustic startle, grooming behavior);2) seizures are not the prerequisite for other defects to occur;3) distinct delayed defects are differently depend on duration of a given anesthetic;4) types and severity of the GABAA receptor-mediated side effects caused by a given anesthetic depend on its efficacy to enhance GABAA receptor-mediated signaling;in addition, the GABAA receptor-mediated side effects of this anesthetic can be modified by its direct effects on Na+ and Ca++ influxes;5) inhibition of NKCC1 activity diminishes side effects caused by these anesthetics in neonatal rats. Using sevoflurane and isoflurane, two general volatile anesthetics that share a GABAA component of action, this proposal aims to test the above hypotheses.
The specific aims are as follows:
Aim #1 : Determine effects of sevoflurane and isoflurane on GABAA/glycine receptor-mediated responses, neuronal firing, spontaneous excitatory postsynaptic currents and voltage-gated Ca++ channels in postnatal day 4-24 (P4-P24) rat pup neocortical neurons.
Aim #2 : Determine the ability of sevoflurane and isoflurane to induce cortical seizures in P4-P24 rat pups.
Aim #3 : Determine the cytotoxic and delayed neuronal side effects of sevoflurane and isoflurane anesthesia in neonatal rat pups. The impact of this study on human health is obvious. Care for increasing numbers of preterm and critically ill term neonates and infants often involves both surgical and non-surgical procedures that require short-term or prolonged administration of anesthesia. The results of the current study will help: 1) to determine the mechanisms of the adverse effects of anesthesia with sevoflurane and isoflurane at early stages of brain development;2) to provide criteria for choosing safer anesthetic agents or regimens for this age category;3) to provide approaches to increase efficacy and safety of currently available anesthetics with a GABAA/glycine-ergic component of actions by modifying Cl- homeostasis.
Using neonatal rats this study tests the hypothesis that the excitation, generated by anesthetics that enhance GABAA/glycine receptor activity, may affect safety of general anesthesia and may result in long- term neurological and cognitive risks in neonates and small infants. This study also tests the hypothesis that inhibition of NKCC1 activity may diminish these side effects and increase safety of the anesthetics.
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