Bone morphogenetic protein-7 reduces toxicity induced by high doses of methamphetamine in rodents.
Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. We have previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7) reduced 6-hydroxydopamine-mediated neurodegeneration in a rodent model of Parkinson's disease. In this study, we examined the neuroprotective effects of BMP7 against MA-mediated toxicity in dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase immunoreactivity (THir) while increasing terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling. These toxicities were significantly antagonized by BMP7. Interaction of BMP7 and MA in vivo was first examined in CD1 mice. High doses of MA (10 mg/kgx4 s.c.) significantly reduced locomotor activity and THir in striatum. I.c.v. administration of BMP7 antagonized these changes. In BMP7 +/- mice, MA suppressed locomotor activity and reduced TH immunoreactivity in nigra reticulata to a greater degree than in wild type BMP7 +/+ mice, suggesting that deficiency in BMP7 expression increases vulnerability to MA insults. Since BMP7 +/- mice also carry a LacZ-expressing reporter allele at the BMP7 locus, the expression of BMP7 was indirectly measured through the enzymatic activity of beta-galactosidase (beta-gal) in BMP7 +/- mice. High doses of MA significantly suppressed beta-gal activity in striatum, suggesting that MA may inhibit BMP7 expression at the terminals of the nigrostriatal pathway. A similar effect was also found in CD1 mice in that high doses of MA suppressed BMP7 mRNA expression in nigra. In conclusion, our data indicate that MA can cause lesioning in the nigrostriatal dopaminergic terminals and that BMP7 is protective against MA-mediated neurotoxicity in central dopaminergic neurons.
Chou
J
J
National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.
Luo
Y
Y
Kuo
C-C
CC
Powers
K
K
Shen
H
H
Harvey
B K
BK
Hoffer
B J
BJ
Wang
Y
Y
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D002452:Cell Count; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005260:Female; D055427:Growth Differentiation Factor 2; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D000697:Central Nervous System Stimulants; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D001616:beta-Galactosidase