Fig. 6. Schematic demonstrating the ability TAT-Pep5 to block the neurotoxic effects of anesthetics on the developing neurons. ( A ) Neurotrophin brain-derived neurotrophic factor (BDNF) is converted from proBDNF to mature BDNF (mBDNF) by plasmin in the synaptic cleft. Tissue plasminogen activator (tPA), which converts plasminogen to plasmin, is released from presynaptic vesicles upon depolarization. mBDNF promotes neuronal survival through TrkB receptors; proBDNF induces apoptosis through p75NTR. ( B ) Exposure of developing neurons (5 days in vitro [DIV5] cells and postnatal day 5-7 [5-7PND] pups) to isoflurane results in reduced tPA release into the synaptic cleft, elevated proBDNF, and enhanced activation of p75 neurotrophin receptor (p75NTR), leading to apoptosis. ( C ) TAT-Pep5 binds p75NTRintracellularly and blocks ρ-guanosine diphosphate (GDP) (inactive form) from binding to the p75NTR. When rho-GDP binds p75NTR, it exchanges GDP for guanosine triphosphate (GTP) and becomes activated RhoA, resulting in depolymerization of the actin cytoskeleton, leading to apoptosis. TAT-Pep5 prevents the p75NTR-mediated activation of RhoA and subsequent apoptosis in developing neurons exposed to anesthetics.