Role of the limbic-hypothalamic-pituitary-adrenal axis and gamma-aminobutyric acid type A receptor-mediated excitation in the developmental central and systemic effects of neonatal anesthesia

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 DESCRIPTION (provided by applicant): Role of the limbic-hypothalamic-pituitary-adrenal axis and gamma-aminobutyric acid type A receptor-mediated excitation in the developmental central and systemic effects of neonatal anesthesia More than 1 in 4 children are exposed to general anesthesia in their first year of life. Despite safety concerns raised in animal experiments and supported by human epidemiological studies, the mechanisms and spectrum of neonatal anesthesia-induced developmental abnormalities are poorly understood. This study is designed to investigate the developmental effects of sevoflurane (SEVO), the most widely used anesthetic in pediatric anesthesia, whose polyvalent actions include enhancement of gamma- aminobutyric acid type A receptor (GABAAR) activity, propofol (PF), the most frequently used intravenous anesthetic with a selective GABAAR-mediated action, and etomidate (ET), an anesthetic with a GABAergic mechanism of action similar to PF that, in contrast to PF, disrupts the adrenal synthesis of corticosteroids. The sex- and age-dependent effects of these anesthetics will be assessed by exposing Sprague-Dawley rats to anesthesia at postnatal days (P) 4, 5 or 6 (P4-P6) and P17, P18 or P19 (P17-P19). Based on our experimental findings and data in the literarture, we hypothesize that: 1) anesthetic- enhanced sustained limbic-hypothalamic-pituitary-adrenal (LHPA) axis activity and GABAergic excitation (the sustainability is achieved due to a positive feedback loop between the two systems) play a critical role in the subsequent long-term gender-dependent endocrine and neurobehavioral abnormalities; 2) stressful experiences later in life exacerbate the abnormalities programmed earlier by neonatal exposure to general anesthesia, even if the exposure to anesthesia is not long enough to induce prominent abnormalities by itself; 3) negative modulators of LHPA axis activity, and/or Na+-K+-2Cl- cotransporter inhibition, alleviate the observed developmental effects of the anesthetics. The specific aims are as follows: Aim 1. Determine the developmental endocrine and neurobehavioral effects of neonatal exposure to SEVO, PF, and ET and their modulation by anesthesia duration and subsequent stress exposure. Aim 2. Determine the mechanisms of anesthetic-induced alterations in the LHPA axis and excitatory GABAergic activities that contribute to the gender- and age-dependent developmental abnormalities. Aim 3. Determine the therapeutic effects of normalization of anesthetic-augmented LHPA axis activity and GABAAR-mediated excitation at the time of anesthesia. The long-term goal is to develop translational strategies to study and mitigate adverse effects of neonatal anesthesia in humans.