"We've known about antioxidants for a very long time - Chinese herbal medicine is 3,000 years old and uses antioxidants," Stuart Lipton told BioWorld Today.
But Lipton and colleagues at San Diego's Burnham Institute and the Universities of Iwate, Osaka, and Gifu, all in Japan, are teaching the old antioxidant dog some new tricks. In the Jan. 17, 2005, issue of the Proceedings of the National Academy of Sciences, they reported on several molecules that can protect against neuronal damage by activating an endogenous antioxidant, the enzyme hemeoxygenase-1, with synthetic relatives of neurite-outgrowth promoting prostaglandin (NEPP).
Lipton said that the study "has two novel components." For one thing, the molecules he and his colleagues described activate what Lipton termed "a very gentle redox pathway" without affecting cellular reducing agents, such as glutathione. In other words, they are not as strong as possible, but moderate in their effects.
He said that as far as drug strength goes, "life is a bell curve, and you want to be in the center of the bell curve." That philosophy already has led to success with the approval of the drug Namenda (memantine) for the treatment of moderate to severe Alzheimer's in 2003. (See BioWorld Today, Oct. 20, 2003.)
Memantine, which is co-marketed in the U.S. by New York-based Forest Laboratories and Richmond, Calif.-based Neurobiological Technologies Inc., was discovered in Lipton's laboratory. The drug, which was the first one approved for moderate to severe Alzheimer's, "had a much lower affinity than anything big pharma was trying to do," Lipton said, with some satisfaction. And that was the secret of its success: "In the brain, most drugs fail not because they don't work on their target, but because they have side effects."
The other novel aspect to the research presented in PNAS is that their molecules have a different cellular target than previously described antioxidants.
"For reasons that aren't quite clear yet, this preferentially goes into neurons," Lipton said. In contrast, some other antioxidants target mainly brain support cells known as astrocytes, which are far more numerous in the brain than actual neurons. The scientists do not know why the NEPPs go preferentially into neurons, though the most obvious possibility is that their chemical structure somehow affects their uptake.
The researchers first synthesized a series of derivatives of NEPP, which already was known to be neuroprotective, at least in part, through its activation of hemeoxygenase-1. They found that two of their molecules, NEPP-6 and NEPP-11, protected neurons in culture against oxidative stress. A series of experiments showed just how NEPPs enter neurons and activate hemeoxygenase-1.
Hemeoxygenase-1 is activated by a complex of two proteins, nrf2 and the antioxidant-responsive element (ARE). Under normal circumstances, most nrf2 protein is bound to yet another protein, keap1. But the appearance of free radicals will lead to NEPP's binding to keap1, which in turn frees up nrf2 to bind with ARE and activate hemeoxygenase-1. Activated, hemeoxygenase-1 will convert heme to biliverdin; an additional enzyme converts biliverdin to bilirubin, a string-free radical scavenger.
In cell cultures, pretreatment with NEPP-11 prevented cell death due to pharmacologically induced hyperactivity. In animals, the compound reduced the cell damage due to stroke and/or reperfusion injury.
In the paper, the scientists pointed out that in a clinical setting, NEPP-11 would not be expected to be effective in stroke, because it needs to be administered several hours before stroke induction to be effective. But Lipton noted that free radicals are known to play a role in chronic neurodegenerative disorders, such as Alzheimer's disease and vascular dementia.
"We use acute models because they are easy to test, not because that's what we are necessarily going to go after in the clinic," he said. "Vascular dementia is very hard to study unless you happen to have 70 to 80 years to do follow up."