Administration of low dose methamphetamine 12h after a severe traumatic brain injury prevents neurological dysfunction and cognitive impairment in rats

摘要

We recently published data that showed low dose of methamphetamine is neuroprotective when delivered 3h 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 8h 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 0.250mg/kg/h as the lowest effective dose and treatment at 12h 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 0.500mg/kg/h produced a plasma Cmax value of 25.9ng/ml and a total exposure of 544ng/ml over a 32hour time frame. This represents almost half the 24-hour total exposure predicted for a daily oral dose of 25mg in a 70kg adult human. Thus, we have demonstrated that methamphetamine is neuroprotective when delivered up to 12h after injury at doses that are compatible with current FDA approved levels.