A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine

Abstract

BackgroundPrenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.Methods and FindingsMicroarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.ConclusionsOur results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.

La cocaína: consumo y consecuencias

“…El síndrome de abstinencia se presenta entre 10-40% de los neonatos expuestos a cocaína. 40,41 Por el efecto sobre los sistemas neurotransmisores monoaminérgicos (dopamina, norepinefrina, epinefrina y serotonina), se ve afectado el desarrollo neurológico [42][43][44] alterando a largo plazo el circuito del aprendizaje, atención, inhibición 45 y lenguaje; 46 también se han reportado alteraciones en el crecimiento (altura, peso, perímetro encefálico).…”

Methamphetamine Exerts Toxic Effects on Subventricular Zone Stem/Progenitor Cells and Inhibits Neuronal Differentiation

“…23 Moreover, cocaine at a non-toxic concentration decreases proliferation of fetal human cortical cells, an effect mediated by a downregulation of the expression of the cyclin A, a protein required for the G 1 to S cell cycle phase transition. 47 In addition, exposure to cocaine decreases proliferation in the DG of rats without affecting survival or cell death by apoptosis. 48 Our results also demonstrate that METH hampers neuronal differentiation.…”

Redox-regulated fate of neural stem progenitor cells

“…cyclooxygenases [53,72,73], lipoxygenases [53,74,75], nitric oxide synthases [76][77][78][79], and cytochrome P450 enzymes [80,81]). Among these, the family of membrane-associated NAD(P)H oxidases (NOX) is the best-characterized for its role in NSPCs.…”