1. Bone morphogenetic protein-7 reduces toxicity induced by high doses of methamphetamine: ? 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 Vmediated 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 Vmediated neurotoxicity in central dopaminergic neurons. ? ? 2. Nigrostriatal Alterations in Bone morphogenetic protein Receptor II dominant negative mice:? BMPs exert their biological effects by binding to type I and type II serine-threonine kinase receptors. The purpose of this study is to examine the neurotrophic and protective roles mediated through BMP Receptor II (BMPRII) using the BMPRII dominant negative (BMPRIIDN) mice. Adult male BMPRIIDN mice and their wild type controls (WT) were placed in the activity chambers for 3 days to monitor locomotor activity. Animals were sacrificed for tyrosine hydroxylase (TH) immunostaining. To examine the sensitivity to dopaminergic neurotoxin, a subgroup of BMPIIDN and WT mice were injected with high doses of methamphetamine (10 mg/kg s.c., X4) or saline injection and were sacrificed for TUNEL histochemistry at 4 days after injection. We found that BMPRIIDN mice had lower locomotor activity than the WT. There is a significant decrease in TH neuronal number in substantial nigra compacta, TH fiber density in the substantial nigra reticulata, and TH immunoreactivity in striatum in the BMPRIIDN mice, suggesting that deficiency in endogenous BMP signaling reduces dopaminergic innervation and motor function in the nigrostriatal pathway. Administration of methamphetamine increased TUNEL labeling in nigra in the BMPRIIDN mice. In conclusion, our data suggest that endogenous BMPs have trophic effects on nigrostriatal dopaminergic neurons. Deficiency in BMP signaling increases vulnerability to insults induced by high doses of methamphetamine. ? ? ? 3. BMP7 reduces synergistic injury induced by methamphetamine and ischemia in mouse brain: ? Previous studies have indicated that methamphetamine (MA) potentiates neurodegeneration induced by ischemia in brain. We, and others, have reported that BMP7 is protective against MA and ischemic brain injury. The purpose of this study is to examine whether BMP7 reduces synergistic injury induced by both MA and cerebral ischemia. Adult CD-1 mice were treated with MA (10 mg/kg x 4, each dose two hours apart) or saline. Using the quantitative real time polymerase chain reaction, we found that MA suppressed the expression of BMP7 mRNA in the cerebral cortex one day after injection. Ischemic and reperfusional injuries were introduced by ligation of the right middle cerebral artery for 90 min after MA injection. Animals were sacrificed for caspase 3/7 activity assay and tri-phenyl-tetrazolium chloride staining at 1 hour and 2 days after reperfusion, respectively. Cerebral infarction and caspase-3/7 activity were enhanced in the stroke animals pretreated with MA; both responses were attenuated by pretreatment with BMP7. In conclusion, our data suggest that MA facilitates cerebral infarction after ischemia possibly mediated, in part, through the suppression of BMP7.? ? 4. 9-Cis-Retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein ? ? Retinoic acid (RA), a biologically active derivative of vitamin A, has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. In cultured human osteosarcoma cells, RA enhances the expression of BMP7, a trophic factor that reduces ischemia- or neurotoxin Vmediated neurodegeneration in vivo. The purpose of this study is to examine whether RA reduces ischemic brain injury through a BMP7 mechanism. We found that intracerebroventricular administration of 9-cis-retinoic acid (9cRA) enhanced BMP7 mRNA expression, detected by RTPCR, in rat cerebral cortex at 24 hours after injection. Rats were also subjected to transient focal ischemia induced by ligation of the middle cerebral artery (MCA) at one day after 9cRA injection. Pretreatment with 9cRA increased locomotor activity and attenuated neurological deficits 2 days after MCA ligation. 9cRA also reduced cerebral infarction and TUNEL labeling. These protective responses were antagonized by BMP antagonist noggin given at one day after 9cRA injection. Taken together, our data suggest that 9cRA has protective effects against ischemia -induced injury and these effects involve BMPs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000429-10
Application #
7733793
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2008
Total Cost
$497,686
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Chou, J; Luo, Y; Kuo, C-C et al. (2008) Bone morphogenetic protein-7 reduces toxicity induced by high doses of methamphetamine in rodents. Neuroscience 151:92-103
Chen, Yuan-Hao; Harvey, Brandon K; Hoffman, Alexander F et al. (2008) MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector. FASEB J 22:261-75
Harvey, B K; Chen, G J; Schoen, C J et al. (2007) An immortalized rat ventral mesencephalic cell line, RTC4, is protective in a rodent model of stroke. Cell Transplant 16:483-91
Chen, Guann-Juh; Harvey, Brandon K; Shen, Hui et al. (2006) Activation of adenosine A3 receptors reduces ischemic brain injury in rodents. J Neurosci Res 84:1848-55
Woods, Amina S; Kaminski, Rafal; Oz, Murat et al. (2006) Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. J Proteome Res 5:1017-23
Harvey, Brandon K; Hoffer, Barry J; Wang, Yun (2005) Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol Ther 105:113-25
Harvey, B K; Mark, A; Chou, J et al. (2004) Neurotrophic effects of bone morphogenetic protein-7 in a rat model of Parkinson's disease. Brain Res 1022:88-95
Cox, Suyu; Harvey, Brandon K; Sanchez, Joseph F et al. (2004) Mediation of BMP7 neuroprotection by MAPK and PKC IN rat primary cortical cultures. Brain Res 1010:55-61
Chang, Chen-Fu; Lin, Shinn-Zong; Chiang, Yung-Hsiao et al. (2003) Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 34:558-64
Wang, Yun; Chang, Chen-Fu; Morales, Marisela et al. (2003) Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. J Neurosci 23:7958-65

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