In Lab, An Antidepressant Shown to Harm Baby Neurons
Fetuses exposed to the common antidepressant paroxetine (Paxil and Seroxat) may experience harmful effects to the brain, according to a new lab study at Johns Hopkins Bloomberg School of Public Health.
For the study, the researchers used stem-cell-derived “mini-brains,” miniature human brain models, developed with human cells and barely visible to the human eye, whose cellular mechanisms mimic those of the developing human brain.
The team used the mini-brains to show that the common antidepressant paroxetine suppresses the growth of synapses, or connection points between neurons, and leads to significant decreases in an important support-cell population.
Paroxetine, which can cross the placenta in pregnant women, currently comes with a warning against use in early pregnancy, largely due to a known risk of heart and lung defects.
Some epidemiological studies also have suggested that paroxetine increases the risk of autism. The new findings are likely to heighten concerns about the effects of this drug, and others in its class, on the developing brain.
The authors say the results suggest that lab-grown mini-brains, which they call BrainSpheres, are a good alternative to traditional animal testing. In particular, they can reveal drugs and other chemicals that are harmful to young brains.
“There’s a growing concern that we have an epidemic of neurodevelopmental disorders, including autism, and that these might be caused by exposures to common drugs or other chemicals. However, since traditional animal testing is so expensive, we haven’t been able to properly investigate this question,” said co-senior author Thomas Hartung, M.D., the Doerenkamp-Zbinden Chair and Professor in the Department of Environmental Health and Engineering and director of the Center for Alternatives to Animal Testing at the Bloomberg School.
The research team developed the mini-brains to model early brain development. The small clumps of brain tissue are made by taking cells from adult humans, often from their skin, and transforming them into stem cells, and then biochemically nudging the stem cells to develop into young brain cells.
The mini-brains form a rudimentary brain-like organization over a period of a few months. Because they are made of human cells, they may be more likely to predict effects on the human brain, and because they can be mass-produced in the lab, they are much cheaper to work with than animals.
In this study, the scientists exposed mini-brains to two different concentrations of paroxetine over eight weeks as the clumps of tissue developed. Both concentrations were within the therapeutic range for blood levels of the drug in humans. In the experiments, the researchers also used two different sets of mini-brains, each taken from a different stem cell.
They discovered that while paroxetine didn’t seem to have a significant neuron-killing effect, at the higher concentration it reduced levels of a protein called synaptophysin, a key component and marker of synapses by up to 80 percent.
Paroxetine also reduced levels of two other synapse-related markers. Similarly, the team observed that paroxetine reduced the normal outgrowth of structures called neurites, which eventually develop into the output stalks and root-like input branches of mature neurons.
Finally, the researchers noted that paroxetine-exposed mini-brains developed with up to 75 percent fewer oligodendrocytes, the support cells that are crucial for the proper “wiring” of the brain, than controls.
These effects suggest that the drug might hinder the normal formation of interconnections among developing neurons; a result that could conceivably underlie autism or other disorders.
The findings are published in the journal Frontiers in Cellular Neuroscience.
Pedersen, T. (2020). In Lab, An Antidepressant Shown to Harm Baby Neurons. Psych Central. Retrieved on July 13, 2020, from https://psychcentral.com/news/2020/02/24/in-lab-an-antidepressant-shown-to-harm-baby-neurons/154409.html