title: Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury.
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.
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.
authors.forename: Scott
authors.initials: S
authors.lastname: Ferguson
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.
authors.forename: Benoit
authors.initials: B
authors.lastname: Mouzon
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.
authors.forename: Destinee
authors.initials: D
authors.lastname: Aponte
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.
authors.forename: Laila
authors.initials: L
authors.lastname: Abdullah
authors.affiliation: 2 Department of Neuropathology, Queen Elizabeth Glasgow University Hospital , Glasgow, United Kingdom .|3 Institute of Neuroscience and Psychology, University of Glasgow , Glasgow, United Kingdom .
authors.forename: William
authors.initials: W
authors.lastname: Stewart
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.|4 Rock Creek Pharmaceuticals , Sarasota, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.affiliation: 1 Roskamp Institute , Sarasota, Florida.|5 James A. Haley Veterans Hospital , Tampa, Florida.
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001924:Brain Concussion / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D065852:Spatial Memory / Q000187:drug effects*
chemical_list: C491049:Aif1 protein, mouse; D000470:Alkaloids; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D011725:Pyridines; C528900:glial fibrillary astrocytic protein, mouse; C012737:anatabine
keywords: animal studies; inflammation; therapeutic approaches for the treatment of CNS injury; traumatic brain injury