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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    • "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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    ABSTRACT: Psychostimulants abuse is a major public concern because is associated with serious health complications, including devastating consequences on the central nervous system (CNS). The neurotoxic effects of these drugs have been extensively studied. Nevertheless, numerous questions and uncertainties remain in our understanding of these toxic events. Thus, the purpose of the present manuscript is to review cellular and molecular mechanisms that might be responsible for brain dysfunction induced by psychostimulants. Topics reviewed include some classical aspects of neurotoxicity, such as monoaminergic system and mitochondrial dysfunction, oxidative stress, excitotoxicity and hyperthermia. Moreover, recent literature has suggested new phenomena regarding the toxic effects of psychostimulants. Thus, we also reviewed the impact of these drugs on neuroinflammatory response, blood-brain barrier (BBB) function and neurogenesis. Assessing the relative importance of these mechanisms on psychostimulants-induced brain dysfunction presents an exciting challenge for future research efforts.
    Neuropharmacology 01/2014; 87. DOI:10.1016/j.neuropharm.2014.01.006 · 5.11 Impact Factor
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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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    ABSTRACT: Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI). Its action is possibly through an increase in neural cell survival. The mechanism of improved survival rate of neurons by FLX may relate to the overexpression of some kinases such as Akt protein. Akt1 (a serine/threonine kinase) plays a key role in the modulation of cell proliferation and survival. Our study evaluated the effects of FLX on mesenchymal stem cell (MSC) fate and Akt1 phosphorylation levels in MSCs. Evaluation tests included reverse transcriptase polymerase chain reaction, western blot, and immunocytochemistry assays. Nestin, MAP-2, and β -tubulin were detected after neurogenesis as neural markers. Ten μ M of FLX upregulated phosphorylation of Akt1 protein in induced hEnSC significantly. Also FLX did increase viability of these MSCs. Continuous FLX treatment after neurogenesis elevated the survival rate of differentiated neural cells probably by enhanced induction of Akt1 phosphorylation. This study addresses a novel role of FLX in neurogenesis and differentiated neural cell survival that may contribute to explaining the therapeutic action of fluoxetine in regenerative pharmacology.
    08/2013; 2013:582526. DOI:10.1155/2013/582526
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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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    ABSTRACT: Differences in caregiver reported executive function in 12-year-old children who were prenatally exposed to cocaine (PCE) compared to children who were not prenatally exposed to cocaine (NCE) were assessed. One hundred and sixty-nine PCE and 169 NCE, primarily African-American, low socioeconomic status children participated in a prospective longitudinal study. The Behavior Rating Inventory of Executive Function (BRIEF) Parent Form was administered. Two broadband BRIEF scores (Behavioral Regulation Index (BRI) and Metacognition Index (MI)) and a summary Global Executive Composite (GEC) were computed. Multiple and logistic regression analyses were used to assess the effects of amount of PCE on executive function, controlling for covariates including caregiver (rater) psychological distress, child's gender and other prenatal drug exposure variables. After adjustment for covariates, amount of PCE was associated with the GEC and two MI subscales, Plan/Organize and Monitor, with heavier exposure associated with more problems of executive function. An amount of PCE by gender interaction revealed amount of PCE effects in other remaining subscales of the MI (Initiate, Working Memory, and Organization of Materials) only among girls. Head circumference did not mediate the effects of cocaine on outcomes. Higher current caregiver psychological distress levels were independently associated with poorer ratings on the executive function scales. Assessment and targeted interventions to improve metacognitive processes are recommended for girls who were prenatally exposed to cocaine.
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