This is a resubmission of a competitive renewal of the R01 grant # HD 044517. The proposed experiments are extensions of earlier ones aimed at deciphering the cellular pathways responsible for anesthesia- induced developmental neurodegeneration. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, general anesthesia exposure at the peak of the brain growth spurt causes learning and memory deficiencies later in life. The gap in learning abilities between control and anesthesia- treated animals progressively widens in adulthood. Moreover, retrospective clinical evidence suggests that there is a relationship between the exposure of very young children to general anesthesia and subsequent life-long learning disabilities. Since general anesthesia cannot be avoided, better understanding the key mechanisms of anesthesia-induced developmental neurodegeneration and ways to ameliorate it are critically important to public health. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage. Within the very first couple of hours, general anesthesia causes significant decrease in protein levels of bcl-XL which is quickly followed by a massive increase in cytochrome-c release from mitochondria. This leads to activation of caspase-9, and -3, DNA fragmentation, and neuronal death. In addition, our most recent in-vivo studies demonstrate that general anesthesia induces significant up-regulation of reactive oxygen species and both morphological and functional impairment of developing mitochondria in the immature neurons. Therapeutic intervention aimed at scavenging excessive reactive oxygen species using EUK-134, a synthetic superoxide dismutase and catalase mimetic, abolished anesthesia-induced learning impairment and significantly ameliorated anesthesia-induced increases in reactive oxygen species. The exact mechanisms operational in anesthesia-induced up-regulation of reactive oxygen species and mitochondria damage in the developing neurons must be determined so that therapeutic interventions can be devised. This is the main focus of our revised application.
Clinically used general anesthetics are damaging to developing mammalian brain. Since general anesthetics are a necessity that often cannot be avoided, better understanding of the key mechanisms of anesthesia-induced developmental neurotoxicity and ways to ameliorate their effects are of great importance. Using in-vivo and ex-vitro systems, this proposal aims to investigate the mechanisms involved in anesthesia-induced reactive oxygen-mediated neurodegeneration during developmental synaptogenesis.
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