A premise of general anesthesia is that anesthetics produce a non-toxic and reversible state of unconsciousness. Recent data indicate that exposure of neonatal animals to anesthetics triggers widespread neurodegeneration leading to persistent memory and learning abnormalities during adulthood . Anesthetic neurotoxicity has raised concerns about the potential adverse impact of general anesthesia in the human fetus, neonate and infant. Although the precise mechanism is not clear, the toxicity occurs during synaptogenesis and is apoptotic in nature [1,2]. In the developing brain, synaptic connections with appropriate targets are essential for neuronal survival as neurons are dependent upon trophic support from their targets [13-15]. Loss of synaptic connection leads to apoptosis. The neurotrophin BDNF contributes to neuronal survival and synaptogenesis, and to the consolidation and maturation of synapses . BDNF can, however, also result in neuronal apoptosis [17,18]. BDNF is secreted from synaptic vesicles as a pro molecule (proBDNF) and undergoes proteolytic cleavage in the synaptic cleft by plasmin to generate mature BDNF (mBDNF) . Plasminogen, the precursor to plasmin, is proteolytically cleaved by tPA, a protease released from pre-synaptic vesicles. The mBDNF signals through TrkB receptors to promote neuronal survival and synaptogenesis. In the absence of tPA, proBDNF is uncleaved and preferentially signals through p75NTR receptors, resulting in reduced synaptogenesis, withdrawal of dendritic spines and neuronal apoptosis . Preliminary data from our laboratory indicate that the volatile anesthetic, isoflurane, reduces tPA release;this results in the preferential signaling of proBDNF through p75NTR, leading to JNK activation, neuronal apoptosis and reduction in dendritic spines. Importantly, isoflurane-induced neuronal death can be mitigated by administration of exogenous recombinant tPA;tPA restores signaling through TrkB receptors, leading to the activation of Akt, increased dendritic spine formation and neuronal survival. Based on these data, we advance the hypothesis that anesthetic neurotoxicity is a function of reduced neuronal activity, decreased synaptic tPA release, enhanced proBDNF signaling, reduced dendritic spine formation and neuronal apoptosis via p75NTR. To test this hypothesis, we propose studies that will be conducted within three specific aims. First, the toxicity of anesthetics will be characterized in vivo and in vitro with the evaluation of anesthetic induced apoptosis, suppression of synaptogenesis and reduction in dendritic spines. The extent of recovery of synapses and spines will also be evaluated. Thereafter, the role of BDNF-TrkB signaling and of the tPA-plasmin system on the aforementioned mentioned toxicity will be determined. Finally, the effects of anesthetic exposure during the neonatal period on cognitive function during adulthood will be evaluated. Collectively, the positive outcome of the proposed studies will provide novel insights into the mechanisms by which anesthetic agents injure the developing brain and into specific mechanisms by which this toxicity can be mitigated. Importantly, we have developed a novel therapeutic approach to the prevention of isoflurane neurotoxicity. As such, the proposed work has clear translational application.
Recent data have indicated that anesthetics can produce widespread neurodegeneration in the developing brain and this leads to cognitive dysfunction during adulthood. This has provoked concern about the possibility that anesthesia in neonates might lead to brain injury. The proposed research will attempt to characterize the mechanisms by which anesthetics injure the developing brain and the means by which this toxicity can be prevented or treated.
|Egawa, Junji; Zemljic-Harpf, Alice; Mandyam, Chitra D et al. (2018) Neuron-Targeted Caveolin-1 Promotes Ultrastructural and Functional Hippocampal Synaptic Plasticity. Cereb Cortex 28:3255-3266|
|Pearn, M L; Schilling, J M; Jian, M et al. (2018) Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits. Br J Anaesth 120:745-760|
|Schilling, J M; Kassan, A; Mandyam, C et al. (2017) Inhibition of p75 neurotrophin receptor does not rescue cognitive impairment in adulthood after isoflurane exposure in neonatal mice. Br J Anaesth 119:465-471|
|Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411|
|Mandyam, Chitra D; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry 81:101-110|
|Stary, Creed M; Tsutsumi, Yasuo M; Patel, Piyush M et al. (2012) Caveolins: targeting pro-survival signaling in the heart and brain. Front Physiol 3:393|
|Pearn, Matthew L; Hu, Yue; Niesman, Ingrid R et al. (2012) Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiology 116:352-61|
|Head, Brian P; Hu, Yue; Finley, J Cameron et al. (2011) Neuron-targeted caveolin-1 protein enhances signaling and promotes arborization of primary neurons. J Biol Chem 286:33310-21|
|Lemkuil, Brian P; Head, Brian P; Pearn, Matthew L et al. (2011) Isoflurane neurotoxicity is mediated by p75NTR-RhoA activation and actin depolymerization. Anesthesiology 114:49-57|
|Crosby, Gregory; Culley, Deborah J; Patel, Piyush M (2010) At the sharp end of spines: anesthetic effects on synaptic remodeling in the developing brain. Anesthesiology 112:521-3|
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