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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    211—Brain Injury: Therapeutic Strategies I

    Sunday, November 10, 2013, 1:00 pm - 4:30 pm

    211.03: Treatment with anatabine significantly improves chronic outcome in a mouse model of repetitive mild TBI

    Location: 30B

    Roskamp Inst., Sarasota, FL

    Abstract Body: We have previously demonstrated that repetitive mild TBI (r-mTBI) results in chronic and progressive neuroinflammation and spatial memory impairment in a mouse model. We have now shown that treatment with an anti-inflammatory dietary supplement, anatabine, significantly improved spatial memory 6 months after r-mTBI.
    Male C57BL/6J mice 10 weeks old received either an r-mTBI (a closed head injury with 5 impacts on the midline, at a 1mm depth at 5 m/second with an inter-injury interval of 48 hours) or repeated anesthesia (r-sham; 5 anesthesias with an interval of 48 hours) and were treated with either anatabine (2mg/kg IP) or placebo (PBS) 30 minutes after surgery. Anatabine treated mice continued to receive anatabine orally, in their water, at an estimated dose of 20mg/kg per day for the duration of the experiment. Neurobehavioral testing consisted of Rotarod at 1, 3, 5, and 7 days after the final TBI or anesthesia alone (5-50 rpm over 5 minutes) followed by Barnes maze acquisition testing on days 8-13 with a probe trial on day 14. Rotarod and Barnes maze testing were repeated 6 months later.
    R-mTBI induced a significant impairment in acute motor function and spatial memory compared to sham mice as assessed by Rotarod and Barnes maze testing. At the acute timepoint after injury, treatment with anatabine did not alleviate impairments in motor function or spatial learning. However, when assessed at the chronic timepoint of 6 months after injury/sham, anatabine treated r-mTBI mice showed a significantly lower latency to the target hole than untreated r-mTBI mice during the probe trial and did not show any significant differences from sham controls. Additionally, anatabine treated r-mTBI mice showed a significantly lower path length than untreated r-mTBI during the first day of acquisition testing at the 6 month timepoint.
    Daily treatment with the anti-inflammatory dietary supplement anatabine significantly improved long-term spatial memory after r-mTBI at a 6 month timepoint. Although anatabine treated mice still showed significant spatial learning deficits 6 months after TBI, spatial memory was significantly improved compared to untreated controls. Pathological analyses of the mice is ongoing. Future studies will explore the underlying mechanism of this effect, which, from our previous work on anatabine’s anti-inflammatory effects, we expect to involve inhibition of the chronic neuroinflammation seen in this model of repetitive head injury. Anatabine shows promise as a dietary supplement for improving the long-term outcome after repetitive mild head injury.

    Lay Language Summary: Mild traumatic brain injury (mTBI) is the most common form of traumatic brain injury, contributing 75% of all TBIs that occur in the United States each year. Our research demonstrates in a mouse model of mTBI the potentially therapeutic benefits of treatment with an anti-inflammatory dietary supplement.
    Increasing evidence demonstrates the significant negative consequences of repetitive mTBI, including the increased long term risk for neurodegenerative diseases such as Alzheimer’s. There are currently no treatments approved for use in TBI. We have developed a novel mouse model of repetitive mTBI in order to have a platform in which to investigate potential treatments. Neuroinflammation is known to be a key component of TBI in human patients, and our mouse model demonstrates progressive neuroinflammation and neurobehavioral deficits at extended timepoints after injury (>1 year).
    Anatabine is a naturally occurring minor alkaloid whose structure is closely related to nicotine. Previous studies at the Roskamp Institute have shown that anatabine is capable of inhibiting inflammatory mechanisms and so, we tested its efficacy as a treatment for TBI. Mice received either repetitive mTBI under anesthesia (5 mTBI each 2 days apart) or 5 anesthesia alone. Each group of mice then received either regular water or anatabine treated water. Cognitive deficits were assessed acutely after injury and again at 6 months post-injury. Neuropathological analyses of the mouse brains were carried out at 9 months after injury.
    Behavioral testing involved training the mice to find the single correct escape hole from 18 possible escape routes (Barnes maze). At the acute time point, repetitively head injured mice performed significantly worse than anesthesia controls, but no treatment effects were observed. However, at the 6 month time point, the head injured mice that received water (placebo) continued to exhibit cognitive deficits while the head injured anatabine treated mice were performing as well as the mice that had received no injury.
    Neuroinflammation was evaluated by staining the mouse brain sections for evidence of astroglial and microglial cells. Head injured mice demonstrated both astrogliosis and microgliosis which was significantly reduced in specific brain regions in the anatabine treated mice, including the hippocampus which is known to play a key role in learning and memory.
    These results show that anatabine may be useful in improving memory and long term outcome after repetitive mild TBI. Mild TBI is a serious problem in both military and civilian populations. These results warrant further study and future experiments will examine the potential of anatabine to treat TBI at longer timepoints after the initial injury has occurred. If validated, the fact that anatabine is a dietary supplement already in widespread use will facilitate the translation of these findings to its use in human TBI populations.