Summary: A new study reports that a commonly used NSAID anti-inflammatory drug reversed memory loss and reduced brain inflammation in mouse models of Alzheimer’s disease.
Source: University of Manchester
Common anti-inflammatory drug restores memory and reduces inflammation in experimental Alzheimer’s models
Researchers at The University of Manchester, led by Dr David Brough, report that the non-steroidal anti-inflammatory drug (NSAID) mefenamic acid reversed memory deficits and dampened neuroinflammation in mouse models of Alzheimer’s disease. The findings, published in Nature Communications, identify a specific inflammatory pathway as a promising therapeutic target and support further exploration of repurposing certain NSAIDs for neurodegenerative disease.
The study focused on fenamate-class NSAIDs, such as mefenamic acid and flufenamic acid, which are widely used for pain relief and menstrual cramps. Using transgenic mice that develop characteristic Alzheimer’s-related pathology and cognitive impairment, the research team treated symptomatic animals with mefenamic acid delivered continuously by subcutaneous mini-pump for one month. Treated mice showed a complete reversal of memory loss to levels comparable with non-diseased controls and a marked reduction in brain inflammation.
Dr Brough said the experiments provide strong preclinical evidence that inflammation exacerbates Alzheimer’s disease and that blocking a specific inflammatory complex, the NLRP3 inflammasome, can protect brain cells. “Our research shows for the first time that mefenamic acid, a commonly available NSAID, can target the NLRP3 inflammasome — an important inflammatory pathway that contributes to neuronal damage,” he explained. The NLRP3 inflammasome is a multi-protein complex that promotes secretion of the proinflammatory cytokine interleukin-1β and is implicated in a range of inflammatory and neurodegenerative conditions.
Importantly, the study indicates that fenamate NSAIDs inhibit NLRP3 activity via blockade of a volume-regulated anion channel in macrophages, acting independently of the classical COX-1 and COX-2 inhibition associated with NSAIDs. The authors observed efficacy of fenamates in rodent models of NLRP3-driven inflammation, including peritoneal and air pouch inflammation models, and documented therapeutic benefit in both an amyloid-beta induced memory loss model and a transgenic Alzheimer’s mouse model.
Although the results are encouraging, Dr Brough emphasized caution. Mouse models do not always fully replicate human Alzheimer’s disease, and further research is required to assess whether the observed benefits translate to people. Because fenamate NSAIDs are already clinically approved and have known safety and pharmacokinetic profiles, the pathway to early human trials could be accelerated compared with developing entirely new compounds. The research team is preparing applications for early phase II studies to test proof-of-concept effects on human neuroinflammation.
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, commented that testing licensed drugs for new indications is a priority because it can shorten the typical timeline needed to bring a new dementia therapy to patients. He noted that while the lab results are promising, fenamate NSAIDs have side effects and people should not self-medicate for Alzheimer’s without clinical evidence from human studies.
Funding: The work was supported by the Medical Research Council and the Alzheimer’s Society.
Research team and publication: The study was led by Dr David Brough with contributions from Dr Catherine Lawrence, PhD student Mike Daniels, postdoctoral researcher Dr Jack Rivers-Auty and colleagues. The paper, titled “Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models,” was published in Nature Communications (online August 11, 2016).
Key findings: Fenamate-class NSAIDs (including mefenamic and flufenamic acid) selectively inhibit the NLRP3 inflammasome by blocking a volume-regulated anion channel in macrophages. These drugs reduced NLRP3-dependent inflammation in rodent models, and produced therapeutic effects in experimental amyloid-beta memory loss and in a transgenic Alzheimer’s disease mouse model. The data support repurposing fenamate NSAIDs as NLRP3 inflammasome inhibitors and potential Alzheimer’s therapeutics.
Approximately half a million people in the UK live with Alzheimer’s disease, a progressive condition that impairs memory, thinking and decision-making. The current study provides preclinical evidence that targeting brain inflammation via the NLRP3 inflammasome could modify disease-related processes, but clinical trials in humans are required to confirm safety and efficacy for dementia treatment.
Abstract (concise)
The NLRP3 inflammasome controls processing of interleukin-1β and contributes to inflammatory disease. Several clinically approved fenamate NSAIDs act as selective inhibitors of NLRP3 through inhibition of a volume-regulated anion channel, independent of COX enzymes. Flufenamic and mefenamic acids showed efficacy in NLRP3-dependent rodent inflammation models and produced therapeutic benefit in models of amyloid-beta induced memory loss and in transgenic Alzheimer’s mice. These results suggest fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and investigated further as potential treatments for Alzheimer’s disease.
Daniels M.J.D., Rivers-Auty J., Lawrence C.B., Brough D. et al. “Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models.” Nature Communications. Published online August 11, 2016. doi:10.1038/ncomms12504