Clioquinol helps the R6/2 mouse

HD Lighthouse Contributing Editor's Comment: Here's an article from 2005, the significance of which has grown in light of the findings by Dr. Steven Hersch and colleagues about the role of copper in HD pathology.

Clioquinol is an old antibiotic which is currently used as a topical cream for skin infections. It is a known chelator of copper in the brain. (A chelator is something which binds with a metal ion and removes it from solution). Dr. Steven Massa and colleagues first found clioquinol to look promising in a cell model and then administered it to R6/2 mice. As compared to untreated R6/2 mice, the clioquinol group experienced less atrophy of the striatum, lost less weight, performed better on the rotarod, and lived longer.

Since clioquinol binds to copper, iron and other metals that are needed in the brain, might this compound cause more problems than it solves? The researchers point out that it's a low-affinity chelator. If a metal is tightly bound, it isn't likely to affect it. However, a weak chelator could be effective under pathological conditions where the metal is released from its complex.

Nevertheless, there is reason for concern. Clioquinol was at one time given internally in Japan but was banned in 1970 after it was discovered to cause neurotoxicity, a syndrome called subacute myelo-optico-neuropathy (SMON).

A small pilot study of clioquinol in Alzheimer's patients showed promising results (Ritchie 2003). The researchers argued that the problem with clioquinol may have been caused by the mechanism of producing a Vitamin 12 deficiency. If that hypothesis is correct, perhaps the drug's toxicity could be decreased with vitamin supplementation. The study was sponsored by Prana Biotechnology.

Kumar and Knopman (2005) have pointed out that the mechanism by which clioquinol caused SMON was never definitively established and argued that this needs to be done before considering large scale human trials. They proposed that the mechanism is a copper deficiency.

I have learned that it is not necessarily a dead end when a drug which successfully addresses a disease pathology proves to be too toxic for use. Researchers who specialize in drug development know ways in which a drug might be 'tweaked' to make it more effective, more bioavailable and less toxic.

And indeed, Prana has developed a second generation version of the original drug and announced in December of 2006 that they had received approval to take the drug into Phase II clinical trials in Sweden. [click for press release] They had previously reported that they were unable to purify clioquinol to remove certain toxins and had decided to abort their planned European trials.

The Lighthouse will continue to follow clioquinol related neurological research.

The full article by Dr. Massa and colleagues can be found online. [click for article]

References

Kumar, N, and Knopman, B. "SMON, clioquinol, and copper." Postgraduate Medical Journal 2005, Vol. 81, p. 227.

Ritchie, Craig, et al. "Metal-Protein Attenuation With Iodochlorhydroxyquin (Clioquinol) Targeting A{beta} Amyloid Deposition and Toxicity in Alzheimer Disease: a Phase II Clinical trial." Archives of Neurology. Vol. 60 No. 12, December 2003, pp. 1685-1691.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 02 Apr 2007

Steven M. Massa, M.D., Ph.D.

Clioquinol, an antibiotic that was banned for internal use in the United States in 1971 but is still used in topical applications, appears to block the genetic action of Huntington’s disease in mice and in cell culture, according to a study reported by San Francisco VA Medical Center (SFVAMC) researchers.

The study, led by principal investigator Stephen M. Massa, MD, PhD, a neurologist at SFVAMC, was reported in the August 16, 2005 issue of Proceedings of the National Academy of Sciences.

Huntington’s disease is a hereditary, degenerative, and ultimately fatal disease of the brain that causes changes in personality, progressive loss of memory and cognitive ability, and a characteristic uncontrolled jerking motion known as Huntington's chorea. There is no known cure or effective treatment. A person who carries the mutant Huntington’s gene may pass it on unknowingly because the disease often manifests in early to late middle age after the carrier’s children have already been born.

During the course of the disease, the Huntington's gene causes the production of a toxic protein, mutant huntingtin, in neurons (brain cells). Eventually the protein kills the neurons, causing the disease’s degenerative effects.

In Massa's study, Clioquinol appeared to interrupt the production of mutant huntingtin. In the first part of his study, Massa and his research team tested the effect of Clioquinol on neurons in cell culture that contained a form of the mutant Huntington’s gene. "We found that not only did cells look better and survive a bit longer when exposed to the drug, but they also seemed to make less of the toxic protein," observed Massa, who is also a clinical assistant professor of neurology at the University of California, San Francisco (UCSF).

Based on the in vitro results, Massa decided to test the drug in vivo, on mice bred to express the toxic huntingtin protein. The mice were given approximately 1 milligram of Clioquinol per day in water. After eight weeks of treatment, they had accumulated four times less toxic protein in their brains than control mice given water alone. The experimental animals lived 20 percent longer than the control animals, did better on tests of motor coordination, and had less weight loss.

"It’s a limited study, in that we used the same drug dose on all the animals as opposed to comparing different doses, but fairly convincing," Massa concluded. "Together, the in vitro and in vivo results suggest that Clioquinol has an effect of decreasing the symptoms of Huntington's, its pathology, and perhaps even the actual production of the toxic protein."

However, he noted, "the drug's mechanism of action remains unclear." The clearer the mechanism of the drug, he explained, the better the chance that researchers might eventually be able to create a medication that is both safe and effective.

Like some other antibiotics, Clioquinol is known to be a chelator — that is, it binds metals in body tissues, particularly copper and zinc, and removes them when it is excreted. Massa and other researchers believe that this chelation effect may interfere with production of the mutant huntingtin protein in some way. "But there are still a couple of explanations we need to rule out," he said.

To that end, Massa's next studies will involve the creation of an in vitro system in which toxic and non-toxic forms of huntingtin are made in the same cell. He and his team will then evaluate the effects of Clioquinol on several phases of protein synthesis within the cell. Massa hopes these experiments will confirm initial indications that Clioquinol preferentially interferes with synthesis of the toxic form of the protein. "Then we can move on to trying to isolate the actual mechanism of the drug," he predicted.

"However," Massa cautioned, "the record of successfully translating drugs from animal to human use is not good."

Clioquinol has shown promise as a potential treatment for Alzheimer's disease in recent studies in mice and humans. Apparently through chelation, it interferes with the creation of beta-amyloid plaque in the brain, which has been implicated in the progression of Alzheimer's symptoms.

Currently, Clioquinol is banned for internal use in many countries because of its side effects. In Japan in the late 1950s and 60s, the drug was found to cause a neurologic condition called subacute myelo-optico-neuropathy (SMON), with symptoms including visual loss, muscle weakness, and numbness, in several thousand people. However, noted Massa, the doses given in current clinical trials are much smaller than were commonly prescribed in Japan. In addition, he explained, it has been found that vitamin B12, when taken along with the drug, protects against its potential toxic effects.

Co-authors of the study were Trent Nguyen, PhD, and Aaron Hamby, BS, of SFVAMC and UCSF.

The research was funded by a grant from the U.S Department of Veterans Affairs.

the abstract

In investigating the role of metal ions in the pathogenesis of Huntington's disease, we examined the effects of clioquinol, a metal-binding compound currently in clinical trials for Alzheimer's disease treatment, on mutant huntingtin-expressing cells. We found that PC12 cells expressing polyglutamine-expanded huntingtin exon 1 accumulated less mutant protein and showed decreased cell death when treated with clioquinol. This effect was polyglutamine-length-specific and did not alter mRNA levels or protein degradation rates. Clioquinol treatment of transgenic Huntington's mice (R6/2) improved behavioral and pathologic phenotypes, including decreased huntingtin aggregate accumulation, decreased striatal atrophy, improved rotarod performance, reduction of weight loss, normalization of blood glucose and insulin levels, and extension of lifespan. Our results suggest that clioquinol is a candidate therapy for Huntington's disease and other polyglutamine-expansion diseases.

Source: Proceedings of the Nat'l Academy of Sciences of the USA. August 16, 2005 , vol. 102, 11840-5

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