? General anesthesia is one of the great advances of medicine but is not without risks. Subtle central nervous toxicity may be one of them. In neonatal animals, several general anesthetic agents have been implicated in neurodegeneration, hippocampal dysfunction, synaptic abnormalities, and learning impairment, with the period of the brain growth spurt and synaptogenesis being especially vulnerable. The mature brain, like the developing brain, contains immature cells that develop into neurons and get incorporated into functional neuronal circuits and has regions constantly remodeling synaptic connections in a rapid, highly dynamic process known as synaptic plasticity. Our central hypothesis, therefore, is that general anesthetic-mediated neurotoxicity is as much a function of the state of neural cellular development as it is the age of the animal. This implies that mitotically competent, immature-undifferentiated and immature-differentiating neural progenitors-whether they are in neonatal brain or """"""""plastic"""""""" areas of mature brain-are targets of general anesthetic-mediated neurotoxicity. To test this hypothesis, we will use a few selected general anesthetic agents (ketamine, propofol, isoflurane) and a cell culture model that permits the maturity and differentiation state of the cells to be regulated and included as an independent variable. Immunocytochemically characterized immature-undifferentiated and immature-differentiating neural progenitors as well as terminally differentiated cells will be exposed to the anesthetics in vitro and various measures of cell death and injury used to assess survival, capacity for growth / replication, and differentiation / synaptogenesis. Furthermore, we will investigate mechanism of cell death and the role of neurotrophic support in neurotoxicity, as well as examine opportunities to modify or mitigate it with neurotrophins or other protective compounds that can be used in vivo. As such, this work will elucidate the neurotoxic properties of general anesthetics in neural cells at different stages of development and lead potentially to novel mechanism-directed therapies to mitigate it. Accordingly, this research has implications for understanding anesthetic-related neurotoxicity and behavioral impairments in the young as well as the old. ? ? ?
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