It’s been known for some time that otherwise relatively healthy people who, for one reason or another, are long-time users of non-steroidal anti-inflammatory drugs, or NSAIDs, such as aspirin, ibuprofen (Advil), naproxen (Aleve), and others have a reduced risk of developing Alzheimer’s disease. Stanford neuroscientist Katrin Andreasson, MD, just published a study in Annals of Neurology that suggests why this might be so.
One thing all NSAIDs do is inhibit an enzyme that catalyzes the production of substances called prostaglandins. There are a whole lot of different varieties of prostaglandins, but one type in particular (PGE2, in scientific vernacular) acts in several distinct ways, depending on which of four different cell-surface receptors it trips off by binding to them. Andreasson’s study showed that blocking the interaction between PGE2 and one particular receptor (known as EP3) reduced various biochemical markers of inflammation when mice were challenged with ordinarily inflammation-inducing doses of a peptide that is believed to play a key role in the onset of Alzheimer’s.
In addition, genetically engineered mice lacking the EP2 receptor were less vulnerable to inflammatory activity in response to doses of this peptide. Importantly, levels of the peptide itself, typically observed at heightened levels among people with Alzheimer’s, remained lower in animals whose PGE2/EP3 binding was impaired by various methods.
The conclusion: The PGE2/EP3 connection may be an important cog in the inflammatory machinery that manufactures Alzheimer’s.
To complicate matters, as Andreasson has previously shown, PGE2 does good things when it binds to a different receptor, EP4, found on nerve cells and the endothelial cells that line our blood vessels. Enhancing or mimicking that binding can improve recovery from stroke, so you’d hardly want to interfere with that. Plus, for all the good they do, NSAIDs tend to cause stomach problems (and worse) in susceptible people. And certain drugs, such as Vioxx, that preferentially inhibit PGE2 while leaving production of some other prostaglandins relatively unscathed, have been shown to cause sometimes severe cardiovascular trouble. Vioxx got pulled off the market once this came to light in 2004.
Andreasson’s study points the way to, perhaps, harvesting NSAIDs’ beneficial effects while avoiding some of the downside by, for example, finding compounds that specifically block only the PGE2/EP3 interaction while allowing normal prostaglandin production and interaction with numerous other receptors to proceed unimpaired.
Previously: Study could lead to new class of stroke drugs