Alzheimer’s drug research continues to look to the future, toward new drugs that might one day treat the ravaging symptoms of the neurodegenerative disease, such as memory loss and even lead to a cure. However, a research team out of the University of Manchester in the UK, led by neuroimmunologist David Brough, has taken their work in the opposite direction, looking at old drugs that are successfully reversing memory loss in a mouse model. Their findings were published in the journal Nature Communications.
When it comes to understanding what causes the dangerous buildup of amyloid plaques and tau tangles in the brain that are prevalent in Alzheimer’s, “evidence is building for inflammation," neuroimmunologist Jack Rivers-Auty, a co-author on the paper, tells mental_floss. "It’s a bit like when you roll your ankle—you put ice on it to reduce swelling because you’re worried about inflammation causing more damage," he says. "Inflammation is a very complex process made up of many cell types and proteins… many of which may be causing collateral damage in the brain."
He and neuroimmunology colleague Mike Daniels conducted experiments on mice after their lab director theorized that common non-steroidal anti-inflammatory drugs (NSAIDs) might inhibit a key inflammatory pathway in the brain that damages brain cells, called the NLRP3 inflammasome complex. “I screened a number of drugs against the inflammasome with cells in a dish,” Daniels tells mental_floss. He was expecting ibuprofen and other more well-known drugs to be the most potent, but in fact, “they had no effect,” he says.
What did work was a less commonly known NSAID called mefanimic acid, which is mainly used for menstrual pain, he says. It worked because it has a different structure. Classic NSAIDs inhibit a protein called cyclooxygenase, whereas mefanimic acid inhibits the inflammasome complex itself.
Next they tested the drugs in a double-blind, placebo-controlled study on mice that were at an age when memory deficits begin to show up, approximately 15 months old. Rivers-Auty says if they were to translate this into a clinical setting with humans, “we would want to aim for people who have just started Alzheimer’s disease. Alzheimer’s [partly causes] the death of neurons, and it’s hard to grow new neurons.”
They used a range of memory tests on the mice to determine whether their memory was in decline before administering mefanimic acid. The most common among them is called the novel object recognition test. This test is useful because mice, like us, are sensitive to unfamiliar objects. Imagine you enter a parking lot looking for your car. In the lot, you find only two objects: your car and an alien's spaceship. "You would spend more time exploring the spaceship because you hadn’t seen it before,” Rivers-Auty says.
Mice will behave similarly. But what happens if their memory is deficient? To find out, the team gave 10 mice a placebo, while the other 10 were treated with mefanimic acid via a subcutaneous pump for 28 days. The study found that “the mouse with good memory explores the new object, and the mouse with poor memory explores them both,” Rivers-Auty explains.
At the end of the study, the mice that had been given the mefanimic acid “did not have memory deficits,” he says. The drug had restored memory function to the mice with failing memory.
The results were so surprising to them, Rivers-Auty says, “We were literally hooting and hollering. We couldn’t believe how well it worked. It’s very unusual for groups to reverse memory deficits.”
The team is hopeful that this discovery could bypass as much as 15 years of the usual process to develop a new drug because mefanimic acid is already in use by humans and has been deemed safe. “We can skip the extensive animal testing and the first stage of human trials,” says Rivers-Auty. “This saves a huge amount of time and money.”
However enthusiastic he and his colleagues are about their results, Rivers-Auty is skeptical that the team will find commercial funding sources for the next stage of trials in humans because “pharmaceutical companies who usually fund these studies have no interest in funding a study they can’t make money off,” he says. Instead, this team relies on charities such as the Alzheimer’s Society and Alzheimer’s Research UK, which funded their work.