Acute or delayed treatment with anatabine improves spatial memory and reduces pathological sequelae at late time-points after repetitive mild traumatic brain injury

Ferguson, S., Mouzon, B., Paris, D., Aponte, D., Abdullah, L., Stewart, W. , Mullan, M. and Crawford, F. (2017) Acute or delayed treatment with anatabine improves spatial memory and reduces pathological sequelae at late time-points after repetitive mild traumatic brain injury. Journal of Neurotrauma, 34(8), pp. 1676-1691. (doi:10.1089/neu.2016.4636) (PMID:27889957)

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Abstract

Traumatic brain injury (TBI) has chronic and long-term consequences for which there are currently no approved pharmacological treatments. We have previously characterized the chronic neurobehavioral and pathological sequelae of a mouse model of repetitive mild TBI (r-mTBI) through to 2 years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated that involve neuroinflammatory and neurodegenerative pathways persisting and progressing for weeks and months post-injury and providing a potential window of opportunity for therapeutic intervention. In this study we examined the efficacy of a novel anti-inflammatory compound, anatabine, in modifying outcome after TBI. Our model of r-mTBI involves a series of five mild impacts (midline impact at 5 m/sec, 1 mm strike depth, 200 msec dwell time) with an interval of 48 h. Anatabine treatment was administered starting 30 min after injury and was delivered continuously through drinking water. At 6 months after TBI, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice was euthanized for pathological analysis that revealed reductions in astroglial (glial fibrillary acid protein, GFAP) and microglial (ionized calcium-binding adapter molecule 1, IBA1) responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and the effects of treatment termination. Nine months following crossover the remaining mice showed no effect of injury on their spatial memory, and whereas pathological analysis showed improvements in mice that had received delayed treatment, corpus callosum IBA1 increased in post-crossover placebo r-mTBI mice. These data demonstrate efficacy of both early and late initiation of treatment with anatabine in improving long term behavioral and pathology outcomes after mild TBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stewart, Dr William
Authors: Ferguson, S., Mouzon, B., Paris, D., Aponte, D., Abdullah, L., Stewart, W., Mullan, M., and Crawford, F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Journal of Neurotrauma
Publisher:Mary Ann Liebert
ISSN:0897-7151
ISSN (Online):1557-9042
Published Online:27 November 2016
Copyright Holders:Copyright © 2017 Mary Ann Liebert, Inc.
First Published:First published in Journal of Neurotrauma 34(8):1676-1691
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
696421Characterising amyloid pathologies after traumatic brain injuryWilliam StewartNational Institute of Health (NIH-BETH)2R01NS038104-15A1RI NEUROSCIENCE & PSYCHOLOGY