title: Low dose methamphetamine mediates neuroprotection through a PI3K-AKT pathway.
abstract: High doses of methamphetamine induce the excessive release of dopamine resulting in neurotoxicity. However, moderate activation of dopamine receptors can promote neuroprotection. Therefore, we used in vitro and in vivo models of stroke to test the hypothesis that low doses of methamphetamine could induce neuroprotection. We demonstrate that methamphetamine does induce a robust, dose-dependent, neuroprotective response in rat organotypic hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD). A similar dose dependant neuroprotective effect was observed in rats that received an embolic middle cerebral artery occlusion (MCAO). Significant improvements in behavioral outcomes were observed in rats when methamphetamine administration delayed for up to 12 h after MCAO. Methamphetamine-mediated neuroprotection was significantly reduced in slice cultures by the addition of D1 and D2 dopamine receptor antagonist. Treatment of slice cultures with methamphetamine resulted in the dopamine-mediated activation of AKT in a PI3K dependant manner. A similar increase in phosphorylated AKT was observed in the striatum, cortex and hippocampus of methamphetamine treated rats following MCAO. Methamphetamine-mediated neuroprotection was lost in rats when PI3K activity was blocked by wortmannin. Finally, methamphetamine treatment decreased both cleaved caspase 3 levels in slice cultures following OGD and TUNEL staining within the striatum and cortex in rats following transient MCAO. These data indicate that methamphetamine can mediate neuroprotection through activation of a dopamine/PI3K/AKT-signaling pathway.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Rau
authors.forename: Aakriti
authors.initials: A
authors.lastname: Kothiwal
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Sarah
authors.initials: S
authors.lastname: Ulatowski
authors.forename: Saskia
authors.initials: S
authors.lastname: Jacobson
authors.forename: Diane M
authors.initials: DM
authors.lastname: Brooks
authors.forename: Fernando
authors.initials: F
authors.lastname: Cardozo-Pelaez
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: David J
authors.initials: DJ
authors.lastname: Poulsen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009924:Organ Culture Techniques; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control
chemical_list: D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D008694:Methamphetamine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt