Anyone familiar with Alzheimer’s disease research can say what a challenge drug development has been. In Emory’s Department of Pharmacology, Thota Ganesh is focusing on an anti-inflammatory approach. Ganesh’s work has been supported by the Alzheimer’s Drug Discovery Foundation and more recently by a five-year, $3.6 million grant from the National Institute on Aging.
An assistant professor at Emory since 2011, he is continuing research he undertook with Ray Dingledine on EP2 antagonists. In animals, they showed that this class of compounds could reduce injury to the brain after a prolonged seizure. Since then, they have shown that EP2 antagonists have similar effects in protecting against organophosphate pesticides/nerve agents.
EP2 is one of the four receptors for prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Before Ganesh and colleagues from the Emory Chemical Biology Discovery Center started looking for them, chemicals that could block EP2 selectively were not available.
Their idea is: blocking EP2 is a better strategy than the more general approach of going after prostaglandins, the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and celecoxib (Celebrex).
Whether NSAIDSs might slow down Alzheimer’s progression has been extensively studied – it looks like the answer is no. In addition, previous research indicates that drugs that inhibit cyclooxygenases, which generate prostaglandins, can lead to increased cardiovascular events.
A 2014 Journal of Clinical Investigation paper reports Stanford researchers’ use of genetic approaches to study EP2 in Alzheimer’s animal models. Their findings suggest that EP2 is especially important in microglia. Scientific American has described microglia as “octopus-like immune cells that live in the brain to clear unwanted clutter,” which have the potential to turn malevolent under conditions of inflammation.
As Ganesh notes in a review, pharmaceutical companies have been evaluating EP2 antagonists independently. So he may have some competition!
Related Lab Land posts on inflammation and Alzheimer’s:
Anti-TNF vs Alzheimer’s mouse model
More on Alzheimer’s-blood pressure link