Citation

Ferguson S, Mouzon BC, Paris D, Aponte D, Abdullah L, Stewart W, Mullan M, Crawford FC. J. Neurotrauma 2016; 34(8): 1676-1691.

Affiliation

James A Haley Veterans Hospital, 19995, Tampa, Florida, United States ; FCrawford@rfdn.org.

Copyright

(Copyright © 2016, Mary Ann Liebert Publishers)

DOI

10.1089/neu.2016.4636

PMID

27889957

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) to two years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated which 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 5 mild impacts (midline at 5 m/s, 1mm depth, 200ms dwell time) with an interval of 48 hours. Anatabine treatment was administered starting 30 minutes after injury and delivered continuously through in the water. At 6 months, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice were euthanized for pathological analysis which revealed reductions in GFAP and IBA1 responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and effects of treatment termination. 9 months following crossover the remaining mice showed no effect of injury on their spatial memory, and while pathological analysis showed improvements in mice who had received delayed treatment, 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.

Language: en