Marcia Gordon, PhD, an associate professor in the Department of Pharmacology and Therapeutics, was recently awarded a five-year, $1.6-million grant from the National Institute on Aging to study the anti-inflammatory drug NCX-2216, a nitric-oxide releasing NSAID (nitro-NSAID).
Epidemiological studies indicate that people who routinely take NSAIDs for chronic inflammatory conditions like arthritis are less likely to develop Alzheimer's disease. However, this potential benefit is not without risk. A third of long-term NSAID users develop gastrointestinal bleeding and ulcers, and nearly 100,000 Americans a year are hospitalized as a result of adverse effects from NSAIDs.
"NSAIDs that release nitric oxide appear to protect the gastrointestinal system from injury and work well in removing the major irritant in the Alzheimer's disease brain -- excess amyloid protein," Dr. Gordon said. "This may bode well for their use in human patients."
Dr. Gordon and colleagues David Morgan, PhD, and Amyn Rojiani, PhD, are trying to determine how NCX-2216 reduces amyloid deposits in the brains of transgenic mice bred to develop Alzheimer's-like memory disorders.
In a previous study, the USF researchers found that this nitro-NSAID worked significantly better than two commonly used NSAIDs, ibuprofen and celecoxib, in clearing Alzheimer's-associated amyloid deposits from the brains of middle-aged transgenic mice. The results were reported in the March 15 issue of the Journal of Neuroscience, with graduate student Paul Jantzen as the first author.
Dr. Gordon's team was surprised to find that the nitro-NSAID dramatically activated immune cells known as microglia -- a sign of inflammation that is a key step in nerve cell death. Ibuprofen and celecoxib did not activate microglia in the transgenic mice. The researchers had assumed the anti-inflammatory drugs would reduce the brain's inflammatory response caused by the amyloid deposits.
The unexpected result suggests that increased immune activity may help remove amyloid from the brain, especially in the early stages of Alzheimer's disease -- before amyloid deposits harden into toxic plaques, Dr. Gordon said. "It points to the possibility that some microglial activation, or inflammation, might be considered beneficial. However, it is still likely that excessive activation will be detrimental."
Future experiments will examine the effectiveness of the nitro-NSAID combined with the Alzheimer's vaccine. The researchers will also test whether the drug's clearance of amyloid actually helps prevent memory loss and other behavioral problems in older mice that would otherwise develop a condition similar to Alzheimer's.