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

Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, United States of America.
PLoS Medicine (Impact Factor: 14.43). 07/2008; 5(6):e117. DOI: 10.1371/journal.pmed.0050117
Source: PubMed


Prenatal 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.
Microarray 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 eIF2alpha 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.
Our 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.

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Available from: Marilyn A Huestis
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    • "Similar to other psychostimulant drugs, cocaine can exert toxic effects on stem/progenitor cell or immature neurons. In fact, Lee et al. (2008) verified that a rat mesencephalic cell line, AF5 progenitor cells, exposed to cocaine (10 or 100 mM), impaired the transition from G1-to-S phase, an effect triggered by ROS-induced endoplasmic reticulum stress. Accordingly, other study using human foetal neural progenitor cells showed that cocaine (10 À6 Me 10 À4 M) inhibits proliferation and increases p21 expression, a cyclin-dependent kinase inhibitor (Hu et al., 2006). "
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    • "Inhibition of cytochrome P450 is known to be due to a nonserotoninergic effect of FLX [18]. Lee et al. (2008) showed that liver cytochrome P450-dependent ROS formation is responsible for cyclin-A downregulation and inhibition of neural progenitor cell proliferation [19] so inhibition of cytochrome P450 may inhibit cyclin-A downregulation and restoring cyclin-A reverse inhibition of neural progenitor cell proliferation. However, this induction did not occur in the brain and suggested a tissue-specific response [20]. "
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    • "The present findings are corroborated by research that has demonstrated that maternal cocaine ingestion exerts direct negative effects on the fetal brain (Lee et al. 2008) and that areas of the brain rich in monoamines (e.g. dopamine, serotonin and norepinephrine) are the targets of neuronal cell damage (Malanga and Kosofsky 1999). "
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