title: Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity.
abstract: Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity.
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48202, USA.
authors: Bin
authors: B
authors: Liu
authors: Roberta
authors: R
authors: Traini
authors: Bryan
authors: B
authors: Killinger
authors: Bernard
authors: B
authors: Schneider
authors: Anna
authors: A
authors: Moszczynska
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature; D002918:Chymotrypsin / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D015259:Dopamine Agents; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine
keywords: AAV; AMC; AP; CNS; DA; DAB; Dopamine; METH; ML; Methamphetamine; Neuroprotection; Parkin; SAL; SDS-PAGE; SNc; Striatum; Suc-LLVY-AMC; Suc-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin; TH; TU; Toxicity; V; V(max); adeno-associated virus; amido-4-methylcoumarin; anterior–posterior; central nervous system; diaminobenzidine; dopamine; maximal velocity; medio-lateral; methamphetamine; saline; sodium dodecyl sulfate polyacrylamide gel electrophoresis; substantia nigra pars compacta; transducing unit; tyrosine hydroxylase; ventral