Exposure of premature infants, neonates and very young children to general anesthesia is a frequent occurrence in modern medicine. The anesthetic agents that are presently available have important mechanistic features in common: either they promote GABAergic inhibitory neurotransmission (e.g. volatile anesthetics, barbiturates, benzodiazepines), or they suppress NMDA glutamatergic excitatory transmission (e.g., ketamine, nitrous oxide, xenon). This poses a potential conundrum in view of recent evidence that drugs which act by either of these two mechanisms can trigger widespread apoptotic neurodegeneration in the developing rat brain. The developing brain is most vulnerable to this neurotoxic action during the period of synaptogenesis, also known as the brain growth spurt period, which occurs at different times in different species. In humans, it is both pre- and postnatal phenomenon (from beginning of third trimester of pregnancy to a couple of years after birth). In rats, guinea pigs and piglets, three species of interest for this proposal, synaptogenesis occurs postnatally (first 2 weeks after birth in rats), prenatally (about 10 weeks of in utero life in guinea pigs) or both prenatally and postnatally (last 5 weeks of in utero life and first 15 weeks of life in piglets). In general, it appears that drugs that transiently suppress neuronal activity to an unphysiological degree, and thereby disrupt synaptogenesis, cause immature neurons to receive an internal signal to commit suicide (i.e. die by apoptosis). To investigate the potential relevance of this neurotoxic mechanism to clinical anesthesia, the applicants conducted a pilot study on infant rats and pregnant guinea pigs (for studying fetal brains) in which clinically relevant concentrations of volatile anesthetic isoflurane were used to induce and maintain anesthesia for a period of 6 hrs. This anesthesia protocol did not cause hypoxia, changes in cortical cerebral blood flow (in infant rats), or shift blood chemistries in an abnormal direction, but it did cause significant apoptotic neurodegeneration in the developing rat brains of both infant rats and guinea pig's fetuses. In addition, our preliminary work with infant rats suggests that isoflurane anesthesia activates the intrinsic apoptotic cascade. In the revised grant application, the applicant proposes to perform detailed studies of the mechanisms of anesthesia-induced neuro-apoptosis and to identify early steps in the apoptotic cascade, prior to the point of cell death commitment, which may be amenable to intervention. In addition we propose to study the correlation between the rate of synaptogenesis (by using three different species) and the duration of anesthesia necessary to induce significant neuronal apoptosis in the developing brain.
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