Summary: A new study reports a commonly used NSAID anti-inflammatory drug was able to reverse memory loss in mouse models of Alzheimer’s disease.
Source: University of Manchester.
A research project has shown that an experimental model of Alzheimer’s disease can be successfully treated with a commonly used anti-inflammatory drug.
A team led by Dr David Brough from The University of Manchester found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice.
Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain.
The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and Dr Catherine Lawrence supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments.
Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use.
The research, funded by the Medical Research Council and the Alzheimer’s Society, paves the way for human trials which the team hope to conduct in the future.
Around 500,000 people in the UK have Alzheimer’s disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions.
In the study transgenic mice that develop symptoms of Alzheimer’s disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo.
The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month.
Memory loss was completely reversed back to the levels seen in mice without the disease.
Dr Brough said: “There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer’s disease worse.
“Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells.”
He added: “Until now, no drug has been available to target this pathway, so we are very excited by this result.
“However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don’t always faithfully replicate the human disease.
“Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.
“We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans.”
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said: “Testing drugs already in use for other conditions is a priority for Alzheimer’s Society – it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.
“These promising lab results identify a class of existing drugs that have potential to treat Alzheimer’s disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer’s disease at this stage – studies in people are needed first.”
Funding: This work was supported by the Alzheimer’s Society.
Source: Jamie Brown – University of Manchester
Image Source: This NeuroscienceNews.com image is adapted from the University of Manchester press release.
Original Research: Full open access research for “Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models” by Michael J. D. Daniels, Jack Rivers-Auty, Tom Schilling, Nicholas G. Spencer, William Watremez, Victoria Fasolino, Sophie J. Booth, Claire S. White, Alex G. Baldwin, Sally Freeman, Raymond Wong, Clare Latta, Shi Yu, Joshua Jackson, Nicolas Fischer, Violette Koziel, Thierry Pillot, James Bagnall, Stuart M. Allan, Pawel Paszek, James Galea, Michael K. Harte, Claudia Eder, Catherine B. Lawrence and David Brough in Nature Communications. Published online August 11 2016 doi:10.1038/ncomms12504
Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics.
“Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models” by Michael J. D. Daniels, Jack Rivers-Auty, Tom Schilling, Nicholas G. Spencer, William Watremez, Victoria Fasolino, Sophie J. Booth, Claire S. White, Alex G. Baldwin, Sally Freeman, Raymond Wong, Clare Latta, Shi Yu, Joshua Jackson, Nicolas Fischer, Violette Koziel, Thierry Pillot, James Bagnall, Stuart M. Allan, Pawel Paszek, James Galea, Michael K. Harte, Claudia Eder, Catherine B. Lawrence and David Brough in Nature Communications. Published online August 11 2016 doi:10.1038/ncomms12504