Researchers at the John Hopkins University School of Medicine have uncovered evidence that high doses of cocaine can cause brain cells in mice to eat themselves in a process known as overactive autophagy, and this process can also affect mice whose mothers received cocaine during pregnancy. Furthermore, they may have found a solution to the destructive process in the form of an experimental compound called CGP3466B.
"We performed 'autopsies' to find out how cells die from high doses of cocaine," Solomon Snyder, who participated in the research, 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 1990, Snyder and his team discovered that brain cells use nitric oxide to communicate and in 2013, found that nitric oxide is also involved in the cell death that stems from cocaine use by means of communication with a protein called GAPDH, although they did not discover the exact way that the cells were dying. The current study set out to accomplish this by examining the nerve cells of mouse brains - in particular, how the levels of autophagy, whereby cells eat their own insides as a cleanup procedure, are affected by cocaine use.
The team measured levels of proteins associated with autophagy and found that cocaine stimulates haywire autophagy that leads to neuronal cell death, supporting other research that found that cocaine triggered overactive autophagy in astrocytes and microglia.
"A cell is like a household that is constantly generating trash," said Prasun Guha, lead author of the paper. "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."
Based on their previous research, the team knew that nitrous oxide and GAPDH were involved in the process, leading them to test the ability of the compound CGP3466B, known to disrupt the interactions between nitrous oxide and GAPDH, to inhibit the autophagy stimulated by high doses of cocaine. The results showed that CGP3466B was able to protect mouse neurons from cocaine-induced autophagy.
"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," said Maged Harraz, lead coauthor of the paper.
The findings were published in the Jan. 18 issue of the Proceedings of the National Academy of Sciences.
