Propofol Neurotoxicity Is Mediated by p75 Neurotrophin Receptor Activation

Anesthesiology - Tập 116 Số 2 - Trang 352-361 - 2012
Matthew L. Pearn1, Yue Hu2, Ingrid R. Niesman2, Hemal H. Patel3, John C. Drummond4, David M. Roth4, Katerina Akassoglou5, Piyush M. Patel4, Brian P. Head6
1Postdoctoral Fellow, Department of Anesthesiology, University of California, San Diego, La Jolla, California.
2Research Associate, Department of Anesthesiology, University of California, San Diego, and Veterans Administration San Diego Healthcare System, San Diego, California.
3Associate Professor, Department of Anesthesiology, University of California, San Diego.
4Professor, Department of Anesthesiology, University of California, San Diego, and Veterans Administration San Diego Healthcare System.
5Associate Professor, Gladstone Institute of Neurological Disease, San Francisco, California, and Department of Neurology, University of California, San Francisco, San Francisco, California.
6Assistant Research Scientist, Department of Anesthesiology, University of California, San Diego, and Veterans Administration San Diego Healthcare System.

Tóm tắt

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 (p75(NTR)) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75(NTR). 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 p75(NTR-/-) mice or wild-type neurons were treated with propofol, with or without pretreatment with TAT-Pep5 (10 μM, 15 min), a specific p75(NTR) inhibitor. P75(NTR-/-) neurons were transfected for 72 h with a lentiviral vector containing the synapsin-driven p75(NTR) gene (Syn-p75(NTR)) or control vector (Syn-green fluorescent protein) before propofol. To confirm our in vitro findings, wild-type mice and p75(NTR-/-) 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 p75(NTR-/-) neurons. In p75(NTR-/-) neurons transfected with Syn-p75(NTR), propofol significantly increased Cl-Csp3 in comparison with Syn-green fluorescent protein-transfected p75(NTR-/-) 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 p75(NTR-/-) mice. Conclusion These results demonstrate that propofol induces apoptosis in developing neurons in vivo and in vitro and implicate a role for p75(NTR) and the downstream effector RhoA kinase.

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Anesthesiology

Tập 116 Số 2

352-361

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