Cocaine Alters Proliferation, Migration, and Differentiation of Human Fetal Brain-Derived Neural Precursor Cells

Abstract

Maternal use of cocaine during pregnancy is associated with sustained morphological brain abnormalities and sustained cognitive deficits in the offspring. Here, we use a cell culture model of highly enriched human fetal brain-derived neural precursor cells (NPCs) to assess the effects of cocaine treatment on their proliferation, migration, and differentiation. Our data show that cocaine treatment markedly inhibited the proliferation of NPCs, a phenomenon that was associated with cell cycle arrest, possibly because of increased expression of the cyclin-dependent kinase inhibitor p21. In addition, treatment of NPCs with cocaine inhibited their migratory response to CXCL12 (stromal cell-derived factor-1␣), a finding that correlated with cocaine-induced down-regulation of CXCR4 on NPCs. Finally, these data demonstrated that NPCs exposed to cocaine underwent differentiation into cells expressing neuronal markers that was associated with an inhibition of SOX2 (SRY-related HMG-box gene 2), a transcription factor that inhibits NPC differentiation. Taken together, these results point to several cellular mechanisms whereby exposure of human neural stem cells to cocaine in utero could contribute to subsequent neurodevelopmental and neurocognitive deficits.

Effects of Folate on Notch Signaling and Cell Proliferation in Neural Stem Cells of Neonatal Rats In Vitro

“…An advantage of this model is that neural stem cells derived from neonatal rats may be used to evaluate the biologic effect and possible beneficial or toxic effects of drugs and some CNS (central nervous system)-acting nutrients, thus reducing the use of animal testing and making animal and human testing safer. The fate of NSCs in the brain may be regulated by growth factors, neurotransmitters and nutrients ( 11 ). The present study found that folate promotes proliferation and inhibits differentiation of NSCs.…”

Cyclin-Dependent Kinase Inhibitor 1a (p21) Modulates Response to Cocaine and Motivated Behaviors

“…Recent data in humans describe cocaine-induced alterations in p21 expression, as well as in the expression of CDKs, targets of p21, suggesting a relationship between these proteins and druginduced response (Hu et al, 2006;Zhou et al, 2011;Gelernter et al, 2014). To our knowledge, no studies exist, however, that directly examine the effect of p21 on cocaine-induced behaviors.…”

“…Although studies investigating the role of CDKs and their inhibitors in response to drugs of abuse are limited, published data illustrate a strong potential link between these proteins and cocaine-induced effects. For example, cocaine exposure has been shown to increase the expression of p21 in human neural precursor cells, correlating with decreased cell proliferation (Hu et al, 2006). In addition, Zhou et al (2011) recently reported alterations in CDKN1b (p27) and other CDK-associated proteins in the postmortem brain tissue of cocaine users.…”

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

“…In fact, opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of the antiapoptotic ERK1/2 signaling pathway (Garcia-Fuster et al, 2007), crucial for protection against Fas/FADD-mediated apoptosis (Holmstrom et al, 1999(Holmstrom et al, , 2000. Other experimental evidence has shown that cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells (Hu et al, 2006). However, the potential effect of cocaine in inducing apoptosis of mature neurons is controversial.…”