Sci. Aging Knowl. Environ., 7 November 2001
Drugs Protect Mice From Pernicious Forms of Oxygen
Rabiya S. Tumahttp://sageke.sciencemag.org/cgi/content/full/sageke;2001/6/nf3 As organisms transform food into fuel, they churn out reactive oxygen-containing molecules that zap cellular machinery. To combat the assault, living creatures carry an arsenal of enzymes that neutralize the cellular bullets (see "The Two Faces of Oxygen"). One of these enzymes--mitochondrial superoxide dismutase (SOD2)--plays a crucial role in keeping mice healthy: Animals that lack SOD2 die within a few days of birth. According to new work, several drugs that cross the blood-brain barrier and mimic SOD2 partially make up for its absence. They prolong the lives of the mutant mice and prevent the severe neurological problems that normally strike these animals.
"I think it is very exciting that these compounds can provide protection from oxidative stress and that they are getting where they need to go," says Arlan Richardson, who works on SOD expression and aging at the University of Texas Health Science Center in San Antonio. "It would be very exciting to ... see if they have an effect on life-span" in a more complex organism.
Researchers had previously shown that administering a synthetic antioxidant called MnTBAP delays the premature death of mice that lack SOD2. But MnTBAP can't cross the blood-brain barrier. Even with treatment, the mice develop neurological symptoms and holes riddle their brains; as a result, they wither and must be sacrificed at about 3 weeks of age.
In an attempt to improve on MnTBAP, Simon Melov, a biochemist at the Buck Institute for Age Research in Novato, California, and his colleagues treated the animals with three antioxidant compounds, called Euk-8, Euk-134, and Euk-189, each of which can cross the blood-brain barrier. These synthetic chemicals possess both SOD and catalase activity, which allows them to wipe out two rogue oxygen-containing molecules: superoxide and hydrogen peroxide, respectively. All three compounds counteract the oxidative ruin normally seen in mice missing SOD2, as indicated by decreased amounts of damage to an enzyme that is commonly used to assess the extent of injury to cellular proteins, according to a report in the 1 November issue of the Journal of Neuroscience. And they improve the fate of mutant mice in a dose-dependent manner. At 3 weeks of age--when MnTBAP-treated mice are extremely incapacitated--mice injected with the Euk compounds showed no neurological damage, based on microscopic analysis of brain tissue and gross motor control. In addition, the drugs extend the life-span of the mutant mice. Eighty percent, 54%, and 49% of the animals treated with Euk-189, Euk-8, and Euk-134, respectively, survived beyond 3 weeks of age. The compounds, however, do not completely offset the lack of SOD2: The most robust mice lived only 7 weeks, and those that lasted beyond 3 weeks developed a progressive movement disorder.
These compounds have already been shown to extend life-span in Caenorhabditis elegans--in both normal strains and those that carry a defective SOD. "Now we know the drugs work against mitochondrial oxidative stress in mammals," says Melov.
Researchers are already touting the work for its possible application to human disorders. "This is interesting and potentially important in the treatment of neurodegenerative diseases caused by oxidative chemistry," says Robert Brown, a neurobiologist at Massachusetts General Hospital in Boston. "The study ... demonstrates the importance of having small-molecular-weight antioxidants that can penetrate the blood-brain barrier."
Ashley Bush, who studies the role of oxidative stress in Alzheimer's disease at Massachusetts General Hospital, agrees that after some kinks are worked out such therapy will likely form the basis for treating human disease. "I think there are going to be some problems" with the delivery method and pharmacokinetics of the drugs, he cautions, a point supported by the incomplete rescue of the mice in this study.
Given the extent of neuropathology that stems from oxidative damage in the SOD2-deficient mice, the drugs' abilities to prolong life likely result from reversing those symptoms rather than retarding aging. Richardson says he would like to see the compounds assessed for their ability to delay aging in wild-type animals; a positive result would lend strong support to the notion that oxidative damage promotes aging. But because the Euk agents mimic only SOD and catalase, they intervene in only a part of the complex mouse antioxidation system. As a result, they might fail to stall the normal aging process--even if reactive oxygen molecules play a key role in it, he suggests.
Melov, however, is more optimistic about the drugs' utility to probe this issue. Because the compounds reverse symptoms in SOD2-deficient mice, they will allow a definitive test of the free-radical theory of aging, he claims. In studies already under way, he and colleagues are treating wild-type mice with the compounds. If these animals live longer than untreated controls, the free-radical theory stands, he says: "But if we ... don't get increased life-span or some sort of increased fitness in old animals, then I would seriously question whether oxidative stress is an important component in the aging process."
November 7, 2001
Rabiya S. Tuma writes about science and medicine from Brooklyn, New York, where she wonders if our new Euk superheroes can detoxify mailrooms, too.
Science of Aging Knowledge Environment. ISSN 1539-6150