This is a revised competing RO1 application requesting support for studies pertaining to the ability of anesthetic drugs to trigger apoptotic neurodegeneration in the developing monkey brain. In a series of recent studies, the applicants have shown that brief exposure of infant rats or mice to certain classes of drugs, including NMDA glutamate antagonists, GABAA agonists or ethanol, during the developmental period of synaptogenesis, triggers widespread neuroapoptosis in the developing brain. The period of synaptogenesis, also known as the brain growth spurt period, in rats and mice occurs during the first two weeks of postnatal life, but in humans, begins in mid-gestation and extends until approximately 3 years after birth. At the heart of the developmental neuroapoptosis mechanism is the biological fact that neurons in the developing brain are programmed to kill themselves if they fail to make appropriate synaptic connections. Although normally, only a small percentage of neurons commit suicide due to faulty synaptogenesis, our findings from rodent experiments suggest that if neuronal activity is abnormally suppressed for a period of only several hours this disrupts the synaptogenesis process sufficiently to cause large numbers of neurons to commit suicide. These findings are of potential concern in an anesthesia context because most, if not all, general anesthetics have either NMDA antagonist or GABAmimetic properties, and when used in concentrations or doses sufficient to render patients unconscious and insentient to pain, they profoundly suppress neuronal activity. While anesthesia-induced developmental neuroapoptosis (AIDNA) is a readily demonstrable phenomenon in rodent brain, only limited information is available pertaining to susceptibility of other species. In very limited pilot experiments we have observed that fetal monkeys appear to be sensitive to the apoptogenic properties of either ethanol or anesthetic drugs. To further evaluate susceptibility of the developing primate brain to AIDNA injury, we will expose squirrel monkeys to anesthesia during the brain growth spurt period, which in this species occurs primarily prenatally (last two trimesters of gestation).
In Aim #1, we will expose monkey fetuses in utero to a triple anesthetic cocktail (isoflurane, nitrous oxide, midazolam) at one of three time points during the brain growth spurt period, and study the brains for evidence of AIDNA.
In Aim #2, at the age of peak sensitivity (as determined in Aim #1 experiments), we will expose squirrel monkey fetuses to individual anesthetic agents (isoflurane or propofol), or to double combinations (isoflurane + nitrous oxide, or propofol + nitrous oxide), to help clarify the degree of risk posed by each agent or combination of agents.
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