Pearn, Matthew L. M.D.; Hu, Yue B.S.; Niesman, Ingrid R. M.S.; Patel, Hemal H. Ph.D.; Drummond, John C. M.D.; Roth, David M. Ph.D., M.D.; Akassoglou, Katerina Ph.D.; Patel, Piyush M. M.D.; Head, Brian P. M.S., Ph.D.
Anesthesiology. February 2012.
Abstract
Background: Propofol exposure to neurons during synaptogenesis results in apoptosis, leading to cognitive dysfunction in adulthood. Previous work from our laboratory showed that isoflurane neurotoxicity occurs through p75 neurotrophin receptor (p75NTR) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75NTR.
Methods: Days in vitro 5–7 neurons were exposed to propofol (3 μM) for 6 h and apoptosis was assessed by cleaved caspase-3 (Cl-Csp3) immunoblot and immunofluorescence microscopy. Primary neurons from p75NTR−/− mice or wild-type neurons were treated with propofol, with or without pretreatment with TAT-Pep5 (10 μM, 15 min), a specific p75NTR inhibitor. P75NTR−/−neurons were transfected for 72 h with a lentiviral vector containing the synapsin-driven p75NTR gene (Syn-p75NTR) or control vector (Syn–green fluorescent protein) before propofol. To confirm our in vitro findings, wild-type mice and p75NTR−/− mice (PND5) were pretreated with either TAT-Pep5 or TAT-ctrl followed by propofol for 6 h.
Results: Neurons exposed to propofol showed a significant increase in Cl-Csp3, an effect attenuated by TAT-Pep5 and hydroxyfasudil. Apoptosis was significantly attenuated in p75NTR−/− neurons. In p75NTR−/− neurons transfected with Syn-p75NTR, propofol significantly increased Cl-Csp3 in comparison with Syn–green fluorescent protein–transfected p75NTR−/−neurons. Wild-type mice exposed to propofol exhibited increased Cl-Csp3 in the hippocampus, an effect attenuated by TAT-Pep5. By contrast, propofol did not induce apoptosis in p75NTR−/− mice.
Conclusion: These results demonstrate that propofol induces apoptosis in developing neurons in vivo and in vitro and implicate a role for p75NTR and the downstream effector RhoA kinase.
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