Bone morphogenetic protein-7 reduces toxicity induced by high doses of methamphetamine in rodents

Abstract

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.

Reovirus Activates Transforming Growth Factor β and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection

“…7E and F). Similar protective effects with BMP treatment have been noted in models of breast cancer (14) and noninfectious neuronal injury (3,15,39). However, this is the first study to show that BMP signaling acts to reduce apoptosis in neurons following viral infection.…”

“…In the case of hepatitis C virus, the synergistic activation of BMP signaling and alpha interferon suppresses viral replication (35). In noninfectious models of disease, previous studies have shown that modulating TGF-␤ signaling is protective in a murine model of Alzheimer's disease (36), and augmenting BMP signal activation can protect cells and neurons following oxidative stress (15), stroke (40), or other cellular injuries (3,44). However, to our knowledge, the roles of TGF-␤ and BMP signaling have not been studied following acute viral infection in the central nervous system (CNS).…”

3.229 Decreased Level of Nurr1 in Heterozygous Young Adult Mice Leads to Exacerbated Acute and Long-Term Toxicity After Repeated Methamphetamine Exposure

“…The differential effects of METH pretreatment on the subsequent exposure might be due to different regimens of drug administration. While chronic low dose pretreatment could induce certain protective genes such as SOD (Superoxide Dismutase) and trophic factors [22], high dose METH binge treatment leads to downregulation of trophic factors [23] and antiapoptotic genes such as bcl-2 [15]. In contrast to the protective effect of low dose chronic preconditioning, our results suggest that intermittent binge exposure causes detrimental instead of protective effects on subsequent METH exposure.…”

“…It has been reported that deficiency in GDNF (Glial cell line-derived neurotrophic factor) level leads to a greater vulnerability to METH binge exposure in GDNF +/2 mice [25]. We have also reported that reduced BMP7 (Bone morphogenetic protein 7) levels in BMP7 +/2 mice caused a larger adverse effect by METH binge treatment [23]. Whether there is a common mechanism for these trophic factors in protecting DA neurons from METH exposure requires further investigation.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…BMP-7 induces dopamine neuron differentiation in culture, and promotes survival in the adult nigrostriatal pathway against dopamine toxins in vivo (Lee et al 2003;Harvey et al 2004;Chou et al 2008). Although the direct role of BMP signaling on dopamine neuron induction is unknown, Msx1 and Lmx1a are key determinants of midbrain DNs and are both induced by BMP-Smad activation (Tríbulo et al 2003;Chizhikov and Millen 2004a;Andersson et al 2006).…”