M L Pearn1, J M Schilling1, M Jian2, J Egawa1, C Wu3, C D Mandyam1, M J Fannon-Pavlich1, U Nguyen1, J Bertoglio4, M Kodama5, S K Mahata6, C DerMardirossian7, B P Lemkuil8, R Han9, W C Mobley3, H H Patel1, P M Patel1, B P Head10. 1. Veterans Affairs San Diego Healthcare System, UCSD, San Diego CA, USA; Department of Anesthesiology, UCSD, San Diego, CA, USA. 2. Veterans Affairs San Diego Healthcare System, UCSD, San Diego CA, USA; Department of Anesthesiology, UCSD, San Diego, CA, USA; Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 3. Department of Neurosciences, UCSD, San Diego, CA, USA. 4. INSERM U749, Institut Gustave Roussy, Universite Paris-sud, Paris, France. 5. Veterans Affairs San Diego Healthcare System, UCSD, San Diego CA, USA; Department of Anesthesiology, UCSD, San Diego, CA, USA; Metabolic Physiology and Ultrastructural Biology Laboratory, UCSD, San Diego CA, USA; Department of Anesthesiology, National Defense Medical College, Tokorozawa, Saitama, Japan. 6. Metabolic Physiology and Ultrastructural Biology Laboratory, UCSD, San Diego CA, USA. 7. Department of Immunology and Microbial Sciences, TSRI, La Jolla, CA, USA; Department of Cell and Molecular Biology, TSRI, La Jolla, CA, USA. 8. Department of Anesthesiology, UCSD, San Diego, CA, USA. 9. Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 10. Veterans Affairs San Diego Healthcare System, UCSD, San Diego CA, USA; Department of Anesthesiology, UCSD, San Diego, CA, USA. Electronic address: bhead@ucsd.edu.
Abstract
BACKGROUND: Exposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. METHODS: RhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5-7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi-Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5-7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5-7. RESULTS: Propofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. CONCLUSION: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits. Published by Elsevier Ltd.
BACKGROUND: Exposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. METHODS:RhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5-7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi-Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5-7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5-7. RESULTS:Propofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. CONCLUSION: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits. Published by Elsevier Ltd.
Authors: Ansgar M Brambrink; Alex S Evers; Michael S Avidan; Nuri B Farber; Derek J Smith; Xuezhao Zhang; Gregory A Dissen; Catherine E Creeley; John W Olney Journal: Anesthesiology Date: 2010-04 Impact factor: 7.892
Authors: Matthew L Pearn; Yue Hu; Ingrid R Niesman; Hemal H Patel; John C Drummond; David M Roth; Katerina Akassoglou; Piyush M Patel; Brian P Head Journal: Anesthesiology Date: 2012-02 Impact factor: 7.892
Authors: Nathan G Hedrick; Stephen C Harward; Charles E Hall; Hideji Murakoshi; James O McNamara; Ryohei Yasuda Journal: Nature Date: 2016-09-28 Impact factor: 49.962
Authors: Atsushi Sawada; Shanshan Wang; Minyu Jian; Joseph Leem; Jesse Wackerbarth; Junji Egawa; Jan M Schilling; Oleksandr Platoshyn; Alice Zemljic-Harpf; David M Roth; Hemal H Patel; Piyush M Patel; Martin Marsala; Brian P Head Journal: FASEB J Date: 2019-03-20 Impact factor: 5.191
Authors: Shanshan Wang; Joseph S Leem; Sonia Podvin; Vivian Hook; Natalia Kleschevnikov; Paul Savchenko; Mehul Dhanani; Kimberly Zhou; Isabella C Kelly; Tong Zhang; Atsushi Miyanohara; Phuong Nguyen; Alexander Kleschevnikov; Steve L Wagner; John Q Trojanowski; David M Roth; Hemal H Patel; Piyush M Patel; Brian P Head Journal: Mol Ther Methods Clin Dev Date: 2021-03-29 Impact factor: 6.698
Authors: Shanshan Wang; Taiga Ichinomiya; Paul Savchenko; Dongsheng Wang; Atsushi Sawada; Xiaojing Li; Tiffany Duong; Wenxi Li; Jacqueline A Bonds; Eun Jung Kim; Atsushi Miyanohara; David M Roth; Hemal H Patel; Piyush M Patel; Takahiro Tadokoro; Martin Marsala; Brian P Head Journal: Theranostics Date: 2022-07-11 Impact factor: 11.600