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Mechanism identified for promising neurological drug

June 22, 2006

Researchers at the San Francisco VA Medical Center have identified the mechanism by which minocycline, a medication currently being studied for the treatment of neurodegenerative diseases including Parkinson's disease and Huntington's disease, protects brain and nerve cells from damage.

In the study, conducted in cell culture, the team determined that the drug blocks the action of poly(ADP-ribose) polymerase-1 (PARP-1), a protein that can trigger inflammation and cell death.

The way in which minocycline works has been very unclear until now, says principal investigator Raymond A. Swanson, MD, chief of neurology and rehabilitation at SFVAMC. "Minocycline turns out to be an extraordinarily good PARP inhibitor, better than most of the drugs that are marketed as PARP inhibitors," he says.

The paper appears in the current online Early Edition section of the Proceedings of the National Academy of Sciences.

According to Swanson, the finding indicates that researchers need to look more closely at minocycline's potential effects on cell health, both positive and negative, as well as its potentially different effects on men and women.

Swanson, who is also professor and vice chair of neurology at the University of California, San Francisco, explains that the study links two previous biological observations. The first is that PARP-1, a protein found in every cell, becomes activated whenever a cell's DNA is damaged. Depending on the nature and extent of the damage, PARP-1 can trigger either DNA repair, an inflammatory response, or apoptosis — so-called cell suicide.

"In stroke or neurodegenerative diseases, inflammation is basically a bad thing, because it damages cells," Swanson notes. "And cell suicide is not necessarily the best thing for the whole organism." Is he being understated?

The second observation, Swanson says, was made a decade ago by study co-author Tiina M. Kauppinen, PhD, currently a neurology research fellow at SFVAMC and UCSF, when she was a graduate student in Finland. Kauppinen found that minocycline, an antibiotic derived from tetracycline, prevents inflammation and apoptosis in cultured brain cells.

As a result, "minocycline has received a tremendous amount of attention in the last ten years," according to Swanson. Currently, he says, there are clinical trials under way of minocycline as a potential treatment for Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), all of which cause brain and nerve cell degeneration as a consequence of inflammation.

However, says Swanson, "it's really been unclear up till now how minocycline works to prevent the inflammatory response."

Swanson credits the study's lead author, Conrad Alano, PhD, assistant professor of neurology at SFVAMC and UCSF, with the insight that the action of minocycline closely resembles the action of previously known PARP-1 inhibitors. This perception led to "a simple experiment — putting cells in a dish, doing things to the cells that would activate PARP-1, and seeing what the effect of minocycline was."

"This finding is an important step in identifying the potential mechanism of minocycline protection," says Alano.

Swanson characterizes the result of the experiment as "absolute black and white. Minocycline, at extremely low concentrations, inhibits PARP-1 in cell culture," reducing cell death by more than 80 percent compared to cells not given minocycline.

The study authors conclude that it is very likely that minocycline's neuroprotective and anti-inflammatory effects are due to PARP-1 inhibition.

"This doesn't exclude the possibility that it has other actions," says Swanson, "but as far as we can tell, the only way it blocks inflammation is by blocking PARP-1."

Swanson says the results have implications beyond the general principle that "it helps to know how a drug is working."

One is potentially negative. "In blocking PARP-1, you block DNA repair," he cautions. "That will likely be true of minocycline. And in blocking DNA repair you conceivably increase the risk of cancer. In clinical trials where people are taking minocycline for months at a time, I think that investigators need to take this into consideration — although for someone with a serious neurodegenerative disease like ALS, it could be a reasonable tradeoff. But you want to have your eyes open."

Another implication has to do with gender differences: PARP-1 stimulates an inflammatory response much more strongly in males than in females, "across all species that have been looked at," says Swanson. "It's unclear why that's true. But again, that means we need to look at whether minocycline has the same effects on women as in men. And as far as I know, that's not being looked at."

The study results also have a potential positive implication directly bearing on research that Swanson is currently conducting on possible ways to prevent brain cell death and promote new brain cell growth after stroke. "It turns out that both of these effects can be accomplished by blocking PARP-1 activation after stroke," he says. "Up to this time, we've been doing that with bona fide PARP inhibitors. We intend now to look at minocycline in the same vein."

University of California—San Francisco