Cocaine Kills Brain Cells, but New Agents May Reverse Damage

Cocaine kills brain cells by triggering out-of-control autophagy, but an experimental compound counteracts the process, new research suggests.

"It should be possible to generate some specific inhibitors of autophagy to get rid of the brain cell toxicity caused by cocaine use in humans. Some already-known autophagy inhibitors prevented cocaine-induced toxicity in cells in our lab studies, which gives us hope that something similar might work at the clinical level," co–lead author Prasun Guha, PhD, postdoctoral fellow, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

"These inhibitors could also help reduce toxicity in babies born to mothers who abused cocaine while pregnant. However, more investigation is needed, and it's important to remember that cocaine seriously harms more than just brain cells," said Dr Guha.

The study was published online January 20 in the Proceedings of the National Academy of Sciences.

Taking Out the Trash

Using nerve cells from the mouse brain, the researchers showed that cocaine causes neuronal cell death through selective (and harmful) enhancement of autophagy.

"A cell is like a household that is constantly generating trash," Dr Guha explains in a university statement. "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."

In earlier research, the researchers observed that nitric oxide plays a role in cocaine-induced brain cell death through its interaction with the enzyme GAPDH. This led them to test the ability of a compound now called CGP3466B, which disrupts nitric oxide/GAPDH interactions, to halt cocaine-induced autophagy.

As hypothesized, CGP3466B protected mouse nerve cells in the brain from death by cocaine, they report.

"Since cocaine works exclusively to modulate autophagy vs other cell death programs, there's a better chance that we can develop new targeted therapeutics to suppress its toxicity," Maged M. Harraz, PhD, a research associate at Johns Hopkins and lead coauthor of the article, said in the statement.

"We are interested in developing specific inhibitors of autophagy and evaluating their effects on cocaine toxicity in cells and mice. If we get encouraging data, we will think about doing clinical trials," said Dr Guha.

The authors note that CGP3466B has been tested (unsuccessfully) in phase 2 clinical trials in patients with Parkinson's disease and amyotrophic lateral sclerosis, so it is known to be safe in humans.

This work was supported by a grant from the National Institute on Drug Abuse. The authors have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online January 20, 2016. Abstract

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