title: Administration of low dose methamphetamine 12 h after a severe traumatic brain injury prevents neurological dysfunction and cognitive impairment in rats.
abstract: We recently published data that showed low dose of methamphetamine is neuroprotective when delivered 3 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 8 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 0.250 mg/kg/h as the lowest effective dose and treatment at 12 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 0.500 mg/kg/h produced a plasma Cmax value of 25.9 ng/ml and a total exposure of 544 ng/ml over a 32 hour time frame. This represents almost half the 24-hour total exposure predicted for a daily oral dose of 25mg in a 70 kg adult human. Thus, we have demonstrated that methamphetamine is neuroprotective when delivered up to 12 h after injury at doses that are compatible with current FDA approved levels.
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors: Thomas F
authors: TF
authors: Rau
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors: Aakriti S
authors: AS
authors: Kothiwal
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors: Annela R
authors: AR
authors: Rova
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors: Diane M
authors: DM
authors: Brooks
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors: Joseph F
authors: JF
authors: Rhoderick
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors: Austin J
authors: AJ
authors: Poulsen
authors: Montana Department of Justice Forensic Science Division, 2679 Palmer Street, Missoula, MT 59808, USA.
authors: Jim
authors: J
authors: Hutchinson
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. Electronic address: david.poulsen@umontana.edu.
authors: David J
authors: DJ
authors: Poulsen
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008694:Methamphetamine / Q000627:therapeutic use*; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control*; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D016900:Neurofilament Proteins; D008694:Methamphetamine
keywords: Methamphetamine; Neuroprotection; Traumatic brain injury