The drug leads to “cell suicide” by self-cannibalism.
In order to find out more about the brain on cocaine, researchers at Johns Hopkins University examined the nerve cells of mouse brains for clues. Their findings have contributed significant new evidence to support the idea that high doses of cocaine cause the brain cells to commit suicide by eating themselves.
Their results may also unearth a potential antidote that could prevent cocaine-related brain damage. The antidote is an experimented compound dubbed CGP3466B.
"We performed 'autopsies' to find out how cells die from high doses of cocaine," Solomon Snyder, M.D., professor of neuroscience at the Johns Hopkins University School of Medicine, said in a press release. "That information gave us immediate insight into how we might use a known compound to interfere with that process and prevent the damage."
Back in 2013, Snyder and his team found that nitric oxide was involved in cocaine-induced cell death due to its interactions with an enzyme called GAPDH. However, they were still stumped as to precisely how the cells were dying, and decided to dig deeper by examining the nerve cells in mouse brains.
Just like animals, cells can die from physical trauma, extreme temperatures, and toxins, but Snyder says they can also commit “suicide” in three ways that are chemically programmed and controlled by different proteins.
The method that the researchers explored is called autophagy, which is a cellular “cleanup process” that recycles excess or damaged components to boost energy levels. When this process spins out of control, it causes cell death, which is exactly what happens when cocaine acts on brain cells, the scientists’ observations confirm.
"A cell is like a household that is constantly generating trash," says lead author Prasun Guha, Ph.D., postdoctoral fellow at Johns Hopkins. "Autophagy is the housekeeper that takes out the trash — it's usually a good thing. But cocaine makes the housekeeper throw away really important things, like mitochondria, which produce energy for the cell."
Previous research from the same team revealed that compound known to disrupt nitric oxide, called CGP3466B, was able to save the brain cells of living mice from the deadly effects of cocaine. However, they hadn’t connected the phenomenon to autophagy until now.
"Since cocaine works exclusively to modulate autophagy versus other cell death programs, there's a better chance that we can develop new targeted therapeutics to suppress its toxicity," says Maged M. Harraz, Ph.D., a research associate at Johns Hopkins and lead co-author of the paper.
Excellent news. Although there are years of additional studies needed to definitively show that the compound CGP3466B is safe and effective for preventing cocaine damage, the researchers hope that their work will ultimately lead to treatments to protect both adults and infants from cocaine’s devastating effects on the brain.