A new side effect
An antidepressant can harm the developing brain
A model of a developing brain derived from stem cells can allow rapid testing of drugs and chemicals to assess neurotoxicity, according to a press release from Johns Hopkins Bloomberg School of Public Health Antidepressant Harms Baby Neurons in Lab-Grown "Mini-Brains".
Article by Zhong et al. Antidepressant Paroxetine Exerts Developmental Neurotoxicity in an iPSC-Derived 3D Human Brain Model published in the journal Frontiers in Cellular Neuroscience.
Researchers from the Bloomberg School of Public Health at Johns Hopkins University have demonstrated the use of "mini-brains" derived from induced pluripotent stem cells to identify harmful side effects of a common drug on the developing brain. The mini-brain is a miniature model of the human brain created from human cells and barely visible to the human eye, its cellular mechanisms mimic the mechanisms of the developing human brain.
Scientists used mini-brains to determine that the common antidepressant paroxetine suppresses the growth of synapses – connection points between neurons. Paroxetine is sold under such trademarks as Paxil and Seroxat.
Paroxetine, which can penetrate the placenta in pregnant women, is currently not prescribed in the early stages of pregnancy, mainly due to the known risk of heart and lung defects. Some epidemiological studies have also shown that paroxetine increases the risk of autism. The new findings may heighten concerns about the effects of this and other drugs of the same class on the developing brain.
The authors of the study claim that the results suggest that lab-grown mini-brains, which they call BrainSpheres, are a good alternative to traditional animal testing. In particular, they can detect medications and other chemicals that are harmful to the young brain.
"There is a growing concern that there is now an epidemic of neurodevelopmental disorders in the world, including autism, and that they may be caused by exposure to conventional drugs or other chemicals. However, because traditional animal testing is very expensive, we have not been able to properly investigate this issue," says senior author Thomas Hartung, MD, director of the Center for Alternatives to Animal Testing at the Bloomberg School.
Hartung and his colleagues have developed mini-brains to simulate early brain development. Tiny clusters of brain tissue are created from cells taken from adults, often from their skin, and their transformation into stem cells, and then by biochemical transformation of stem cells into young brain cells. The mini-brain forms a rudimentary brain organization within a few months. Because they are made from human cells, they can be more likely to predict the effects on the human brain – and because they can be mass-produced in a laboratory, they are much cheaper to work with than animals.
The authors note that a set of animal toxicology tests for a single chemical costs an average of about $1.4 million, which explains why the vast majority of chemicals used in medicines and other consumer products have never been tested for toxicity. Toxicity testing using mini-brains costs only a few thousand dollars.
In a new study, scientists used mini-brains to test the neurocomplex effects of paroxetine. He and other antidepressants in his class, known as SSRIs or selective serotonin reuptake inhibitors, are among the most commonly prescribed drugs in the world, for which at least hundreds of millions of prescriptions are written annually.
The research team exposed the mini-brains to two different concentrations of paroxetine for eight weeks as tissue accumulations developed. Both concentrations were within the therapeutic range of the drug's blood levels in humans. In the experiments, the researchers also used two different sets of mini-brains, each of which was derived from a separate stem cell.
The scientists found that although paroxetine does not appear to have a significant effect of killing neurons, at higher concentrations it reduces the level of a protein called synaptophysin - a key component and marker of synapses – by up to 80 percent. Paroxetine also reduced the levels of two other synapse-related markers. Similarly, the team noticed that paroxetine reduced the normal growth of structures called neurites–the outgrowths of nerve cells that go to innervated organs. Finally, the researchers noted that the mini-brains exposed to paroxetine grew 75 percent fewer oligodendrocytes – support cells that are crucial for proper brain "connectivity" than brain samples not exposed to paroxetine.
These effects suggest that the drug may interfere with the normal formation of connections between developing neurons – a result that may underlie autism or other disorders.
The study also shows the broader potential of mini-brain-based testing to detect side effects of drugs on the developing brain.
"In this report, we were able to show that testing with mini-brains can reveal relatively subtle effects associated with the development of the nervous system, and not just the obvious consequences of the use of a chemical," says Hartung. – The debate about whether paroxetine is the cause of autism can last for decades, and it cannot be resolved with through animal testing or epidemiological analysis. Therefore, we see mini-brains as a technology for broader risk assessment of common drugs and chemicals, including those that may contribute to the growing autism epidemic."
Hartung and his colleagues recently received a grant from the U.S. Environmental Protection Agency to develop their technology as an alternative to animal testing.
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