• M L Pearn, J M Schilling, M Jian, J Egawa, C Wu, C D Mandyam, M J Fannon-Pavlich, U Nguyen, J Bertoglio, M Kodama, S K Mahata, C DerMardirossian, B P Lemkuil, R Han, W C Mobley, H H Patel, P M Patel, and B P Head.
• Veterans Affairs San Diego Healthcare System, UCSD, San Diego CA, USA; Department of Anesthesiology, UCSD, San Diego, CA, USA.
• Br J Anaesth. 2018 Apr 1; 120 (4): 745760745-760.

BackgroundExposure 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.MethodsRhoA 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.ResultsPropofol 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.ConclusionInhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.Published by Elsevier Ltd.

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