Health - Researchers Learn More About Cocaine Related Brain Damage in Fetal Development

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Researchers Learn More About Cocaine Related Brain Damage in Fetal Development

When mothers use cocaine during pregnancy, the exposure of the developing brain to the substance can cause specific neurological and behavioral abnormalities, according to a study released on June 9, 2008 in the open access journal PLoS Medicine.

Cocaine use is a factor in many hundred thousand pregnancies per year in just the United States, and the resulting effects on fetal development often include disorders of the central nervous system. In this study, Chun-Ting Lee and colleagues at the U.S. National Institutes of Heath delved into the mechanism by which cocaine affects fetal brain development.

The team discovered that one major byproduct of cocaine metabolism interferes with the cell signalling substance Cyclin A. Specifically, this curtailed neuronal development in neonatal exposure to cocaine. The cellular mechanism behind this was based on oxidative stress within the cell's endoplasmic reticulum, which affects protein production.

By treating pregnant rats with the stomach acid drug cimetidine, which also interferes with the enzymes that metabolize cocaine, the researchers were actually able to work against this inhibition of neural development that was caused by cocaine exposure. As a result, there is some promise that treatments that block the effects of cocaine on cyclin A could be one method of protecting fetal development when a pregnant woman is unable to discontinue cocaine use. According to the researchers, futher research is still necessary to determine if this method could be safe and effective in humans.

Steven Hyman of Harvard University contributed a related perspective in which he states his enthusiasm about the findings, but adds that there is much "complexity of factors that might contribute to cognitive and emotional abnormalities in children exposed to cocaine and other dangerous drugs in utero."

http://www.medicalnewstoday.com/articles/110299.php

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I have uploaded the complete journal article to the archive here:

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

Here is the Editors' Summary for the article:

Editors' Summary

Background.

Every year, cocaine abuse by mothers during pregnancy exposes thousands of unborn infants (fetuses) to this powerful and addictive stimulant. Maternal cocaine abuse during early pregnancy increases the risk of miscarriage; its use during late pregnancy slows the baby's growth and can trigger premature labor. Babies exposed to cocaine shortly before birth are often irritable and have disturbed sleep patterns. They can also be very sensitive to sound and touch and consequently hard to comfort. These problems usually resolve spontaneously within the first few weeks of life but some permanent birth defects are also associated with frequent cocaine abuse during pregnancy. In particular, babies exposed to cocaine before birth sometimes have small heads—an abnormality that generally indicates a small brain—and, although they usually have normal intelligence, the development of their thinking skills and language is often delayed, and they can have behavioral problems.

Why Was This Study Done?

Exposure to cocaine before birth clearly interferes with some aspects of brain development. More specifically, it reduces the number and position of neurons (the cells that transmit information in the form of electrical impulses around the body) within the brain. All neurons develop from neural progenitor cells, and previous research suggests that cocaine exposure before birth inhibits the proliferation of these cells in the developing brain. It would be useful to understand exactly how cocaine affects neural progenitor cells, because it might then be possible to prevent the drug's adverse effects on brain development. In this study, therefore, the researchers investigate the molecular mechanism that underlies cocaine's effect on neural progenitor cells.

What Did the Researchers Do and Find?

When the researchers investigated the effects of cocaine on AF5 cells (rat neural progenitor cells that grow indefinitely in the laboratory), they found that concentrations of cocaine similar to those measured in fetal brains after maternal drug exposure inhibited the proliferation of AF5 cells by blocking the “G1-to-S transition.” This is a stage that cells have to pass through between each round of cell division (the production of two daughter cells from one parent cell). Next, the researchers showed that cocaine-treated AF5 cells made much less cyclin A2, a protein that controls the G1-to-S transition, than untreated cells. Cocaine also decreased cyclin A2 levels in neural progenitor cells freshly isolated from human fetal brains and in fetal rat brains exposed to the drug while in their mother's womb. Treatment of AF5 cells with a cyclin A2 expression vector (a piece of DNA that directs the production of cyclin A2) counteracted the down-regulation of cyclin A2 and restored AF5 proliferation in the presence of cocaine. Other experiments indicate that the reduction of cyclin A2 by cocaine in AF5 cells involves the accumulation of “reactive oxygen species,” by-products of the breakdown of cocaine by a protein that is a member of a family of proteins called cytochrome P450. Finally, treatment of pregnant rats with cimetidine (which inhibits the action of cytochrome P450) counteracted both the inhibition of neural progenitor cell proliferation and the cyclin A2 down-regulation that cocaine exposure induced in the brains of their unborn pups.

What Do These Findings Mean?

These findings show that the cocaine-induced inhibition of neural progenitor cell proliferation involves, at least in part, interfering with the production (that is, causing down-regulation) of cyclin A2. They also show that this down-regulation is induced by the breakdown of cocaine by cytochrome P450, and that in both a rat cell line and in fetal rats, the cytochrome P450 inhibitor cimetidine (a drug that is already used clinically for stomach problems) can block the adverse effects of cocaine on the proliferation of neural progenitor cells. These findings need to be confirmed in animals more closely related to people than rats, and the long-term effects of cimetidine need to be investigated, in particular its effects on cocaine toxicity. Nevertheless these results raise the possibility that giving cimetidine or other drugs with similar effects to pregnant women who are addicted to cocaine might prevent some of the harm that their drug habit does to their unborn children, although it is not clear whether there is a dosage of cimetidine that might be both safe and adequate for this purpose.