Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6017838 | Experimental Neurology | 2014 | 10 Pages |
Abstract
We recently published data that showed low dose of methamphetamine is neuroprotective when delivered 3Â h after a severe traumatic brain injury (TBI). In the current study, we further characterized the neuroprotective potential of methamphetamine by determining the lowest effective dose, maximum therapeutic window, pharmacokinetic profile and gene expression changes associated with treatment. Graded doses of methamphetamine were administered to rats beginning 8Â h after severe TBI. We assessed neuroprotection based on neurological severity scores, foot fault assessments, cognitive performance in the Morris water maze, and histopathology. We defined 0.250Â mg/kg/h as the lowest effective dose and treatment at 12Â h as the therapeutic window following severe TBI. We examined gene expression changes following TBI and methamphetamine treatment to further define the potential molecular mechanisms of neuroprotection and determined that methamphetamine significantly reduced the expression of key pro-inflammatory signals. Pharmacokinetic analysis revealed that a 24-hour intravenous infusion of methamphetamine at a dose of 0.500Â mg/kg/h produced a plasma Cmax value of 25.9Â ng/ml and a total exposure of 544Â ng/ml over a 32Â hour time frame. This represents almost half the 24-hour total exposure predicted for a daily oral dose of 25Â mg in a 70Â kg adult human. Thus, we have demonstrated that methamphetamine is neuroprotective when delivered up to 12Â h after injury at doses that are compatible with current FDA approved levels.
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Authors
Thomas F. Rau, Aakriti S. Kothiwal, Annela R. Rova, Diane M. Brooks, Joseph F. Rhoderick, Austin J. Poulsen, Jim Hutchinson, David J. Poulsen,