Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. We previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7) reduced 6-hydroxydopamine mediated neurodegeneration in a rodent model of Parkinsons 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 TUNEL 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/kg x 4 s.c.) significantly reduced locomotor activity and THir in striatum. Intra-cerebroventricular 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 -galactosidase (-gal) in BMP7 +/- mice. High doses of MA significantly suppressed -gal activity in striatum, suggesting that MA may inhibit BMP7 expression at the terminals of nigrostriatal pathway. 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. ? ? Stroke and related vascular events can cause widespread damage to the central nervous system (CNS) and result in significant motor and cognitive impairments. It has been suggested that trophic factor treatment may reduce the extent of damage and restore damaged neurons following the injury. We have previously tested the effects of BMP-7 in focal brain ischemic injury. We found BMP-7 to have profound neuroprotective effects after intraventricular administration. The purpose of this study was to examine neuroregenerative effects of BMP7 after ischemia /reperfusion injury. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. Right middle cerebral artery (MCA) was transiently ligated with 10-O suture for one hour. One day after MCA occlusion, vehicle or BMP7 was infused to the contralateral cerebral ventricle. To identify possible neurogenesis, bromodeoxyurindine (BrdU) was systemically injected on the 4th and 5th days after MCA occlusion. Animals treated with BMP7 showed a rapid correction of body asymmetry and neurological deficits, suggesting BMP7 facilitates recovery after stroke. Animals were sacrificed at one month after stroke and brains were analyzed using immunohistological techniques. BMP7 treatment enhanced immunoreactivity of BrdU in the subventricular zone, lesioned cortex, and corpus callosum. These BrdU positive cells co-labeled with nestin and NeuN. Our behavioral and anatomical data suggest that BMP7 promotes neuroregeneration in stroke animals, possibly through the proliferation of new neuronal precursors after ischemia.
Showing the most recent 10 out of 11 publications
