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Mefenamic Acid
Posted: Monday, August 15, 2016 12:19 PM
Joined: 8/15/2016
Posts: 1

I saw a recent study out of the UK regarding mefenamic acid, an NSAID normally used to treat menstral cramps, which supposedly had marked improvement in mice.  Has anyone else heard anything about this?  Is it credible?
Lane Simonian
Posted: Monday, August 15, 2016 2:35 PM
Joined: 12/12/2011
Posts: 4854

Welcome, Leslie.  Mefenamic acid works as an anti-inflammatory in part by activating a receptor called peroxisome proliferator activated receptor (PPAR).  PPAR activators have been suggested for the treatment of Alzheimer's disease, but the problem is that these receptors are partially inactivated in Alzheimer's disease due to nitration.  

"Nitration of tyrosine residues in proteins has been observed in many inflammatory tissues of arthritis, ulcerative colitis, septic shock and ischemia-reperfusion injury ...Together, these results indicate that nitration of PPARgamma during inflammation may be involved in a reduction in the control of inflammatory responses and also in the development of resistance to PPARgamma ligand-based therapies against inflammation."

The problem in human beings with Alzheimer's disease is that the degree of nitro-oxidative damage is much greater than in mice designed to have an Alzheimer's-like disease. Therefore, PPAR activation may well help mice, but not help human beings or at least not much.  Various compounds both scavenge the nitro-oxidant peroxynitrite and reverse part of the damage it does to receptors, transport systems, and enzymes in the brain.  These include eugenol in various essential oils  (such clove, rosemary, lemon balm, and bay laurel) via aromatherapy, CBD oil from marijuana containing terpenes, cannabidiol, and low amounts of THC, and ferulic acid, syringic acid, vanillin, p-coumaric acid, and maltol in Korean red ginseng and heat processed ginseng.

Lane Simonian
Posted: Friday, August 19, 2016 11:39 PM
Joined: 12/12/2011
Posts: 4854

I just got this in my inbox by one of the participants in the mefenamic acid study:

Insight from behind the lab bench: Could a period pain treatment be re-purposed to treat Alzheimer’s disease?

Today we are lucky enough to have the opportunity to publish a post written by Mike Daniels – one of the researchers behind the recent discovery that a drug used for the treatment of period pain may have a role to play in the treatment of Alzheimer’s disease. We hope you enjoy the opportunity to slip behind the lab bench and see what happens behind the scenes of a big scientific discovery.

My name is Mike Daniels, I am a PhD student working at the University of Manchester. We’ve just published a paper in the journal Nature Communications on how currently available drugs may be used to treat Alzheimer’s disease. The Brain Bank North West got in touch with us and gave us a fantastic opportunity to add our voice to the current media storm surrounding this research. I hope I can give you a detailed look at the ins and outs of this important research and offer some insight into the workings of a big research project.

Screen Shot 2016-08-19 at 20.48.07Our lab group are particularly interested in AD, not just because it affects over 26 million people worldwide without any truly effective treatment but also because our speciality is immunology and research suggests that an overactive immune system may play an important role in AD. One particular part of that immune system recently implicated in AD is something called an inflammasome. The inflammasome is a large bundle of proteins which forms a kind of machine within cells whose job it is to produce proinflammatory cytokines. These cytokines go on to promote inflammation in the brain which can worsen AD.

What’s particularly exciting for us is that this inflammasome appears to be largely redundant in everyday immune functions like fighting bacteria or viruses. This means we should be able to inhibit it in patients without rendering them susceptible to infection.

OK so we have a plan – inhibit the inflammasome complex in the hope of improving outcomes for people living with AD. But how do we do this? We could design new drugs (something our lab is involved in right now) but the process of getting a new drug from bench to clinic can take around 20 years and cost around 1.6 billion dollars. Another quicker, cheaper option is to do something called ‘repurposing’, this basically means taking a drug already approved and on the market and using it to treat a different disease. With this in mind our lab head Dr. David Brough decided to test a number of drugs from a large class called non-steroidal anti-inflammatory drugs (NSAIDs) to see if they could inhibit the inflammasome and thus potentially be used in AD. So, this was the project I was tasked with in my first week of PhD life nearly two years ago.

We began by testing a number of these NSAIDs on immune cells cultured in a petri dish. This gave us the important opportunity to screen a large number of drugs without unnecessary use of animals. When we ran these screens we had a bit of a surprise. The more famous NSAIDs such as ibuprofen (Nurofen) had no effect. However, one drug, mefenamic acid, was able to inhibit the inflammasome and prevent release of inflammatory cytokines in the cells. Mefenamic acid is only available by prescription and is prescribed largely to treat period pain.

So, how does mefenamic acid inhibit the inflammasome?

Research suggests that ion channels on the cell surface play an important role in inflammasome activation and that mefenamic acid may inhibit some types of ion channels. To better understand this we formed a collaboration with a London-based research group led by Dr. Claudia Eder – an expert in electrophysiology (researching ion channels). It was with the help of Dr. Eder’s lab that we identified the target of the drugs as a chloride channel called the volume-regulated anion channel (VRAC).

Now we had the drug and the mechanism but we still don’t know whether this drug would be effective in treating AD. This is where we needed to look at the drugs action in a living system. The first model system we chose was a rat model of amyloid-beta induced memory deficits. Build-up of amyloid-beta is a thought to be a major factor in memory impairment and AD. Indeed, if injected into the brain of rats, amyloid-beta causes permanent memory deficits. As part of a collaboration with Dr. Mike Harte’s lab here at Manchester, we injected a group of rats with either mefenamic acid or a placebo and found that those which received the drug were completely protected from amyloid induced memory deficits.

We then moved to look at the effect of the drug in a genetic mouse model of AD. These mice had been altered to express some of the same genes found in humans with the genetic form of AD and, like human sufferers, these mice develop memory deficits with advancing age. When treated with mefenamic acid at the age of onset, these mice did not develop memory deficits, unlike animals treated with a placebo. We also found that the brains of placebo mice displayed signs of intense inflammation while those of drug treated mice remained completely normal.

So to conclude, AD is a terrible and currently incurable disease which we believe to be partially caused by an overactive immune system – specifically over-activity of a protein complex called an inflammasome. We found that the commercially available drug mefenamic acid was able to inhibit the inflammasome and reduce memory loss in both mouse and rat models of Alzheimer’s-like memory deficits.

But what’s the next step? We are hoping to begin to move mefenamic acid into clinical trials to see if it could really work in humans. Luckily, because the drug is already known and approved we can skip the safety testing stage of the clinical trial process. Unfortunately however, clinical trials remain extremely expensive and, as mefenamic is off patent and can no longer be sold for profit, gaining funding through pharmaceutical companies is nigh-on impossible. This means we are relying on grants from fantastic charities such as Alzheimer’s Society and Alzheimer’s Research UK in order to move this study forward.

A lot of work is needed and it will still be a while before we have results in people currently living with AD, but this remains an exciting step and we can only hope that it will go some way to treating this horrible disease.

Guest post by: Mike Daniels

Mike is currently studying for a PhD in neuroinflammation at the the University of Manchester, UK. His work is based mainly on the role of a huge protein complex called the inflammasome in diseases such as Alzheimer’s, stroke and haemorrhagic fever. When he’s not in the lab he’s usually found up a mountain or out in the countryside somewhere and is always on the lookout for any new science outreach ideas! 

Lane Simonian
Posted: Friday, August 19, 2016 11:42 PM
Joined: 12/12/2011
Posts: 4854

My response to the article:

Although I am not a scientist, I was quite interested to read about the process that led to the identification of mefenamic acid as a potential drug for the treatment of Alzheimer’s disease.

I have studied Alzheimer’s disease for twelve years as a historian. Or to put it another, I have read many primary sources–mainly articles and abstracts–produced by scientists to try to understand the disease. The role of nitro-oxidative stress caused particularly by peroxynitrite (ONOO-) in Alzheimer’s disease has stood out as a potentially unifying explanation for the disease.

Some pertinent connections for this study:

“ONOO(-), a potential downstream signaling molecule of P2X7R, may play a critical role in triggering NLRP3 inflammasome activation.”

“Finally, all the NSAIDS accelerated decomposition of ONOO-, suggesting a potential capacity of the molecules to scavenge peroxynitrite.”

But many NSAIDS are weak peroxynitrite scavengers and have not been proven effective in the treatment of Alzheimer’s disease (whether mefenamic acid is an exception remains to be seen).

Mefenamic acid and polyphenols activate a neuroprotective pathway in Alzheimer’s disease (peroxisome proliferated-activated receptor/phosphatidylinositol 3-kinase/Akt), but due to tyrosine nitration this pathway is severely inhibited in Alzheimer’s disease.

The most effective peroxynitrite scavengers will not only lessen oxidation and nitration in the brain, they will partially reverse it. This results in an increased synthesis and release of neurotransmitters affecting short-term memory, sleep, mood, social recognition, and alertness, a greater survival of neurons and some regeneration of neurons in the hippocampus. Some of these scavengers such as eugenol in various essential oils via aromatherapy and ferulic acid, syringic acid, vanillic acid, p-coumaric acid, and maltol in Korean red ginseng and heat processed ginseng have already partially reversed Alzheimer’s disease in small-scale clinical trials.

The success of mefenamic acid depends on how good a peroxynitrite scavenger it is. If it is particularly good scavenger, then it may work on its own; if not you may have to combine it with other peroxynitrite scavengers.

Posted: Monday, August 22, 2016 4:55 AM
Joined: 2/26/2016
Posts: 225

According to an NIH report, NSAID's failed to reduce brain inflammation in Alzheimer's or Mild Cognitive Inpaired patients. Further many NSAID's have serious side affects with long term use, including kidney and liver damage and stomach bleeding.

Incidently, according to Wikipedia, I saw that a weeks supply of mefenamic acid costs 1.66 British pounds in the UK, which is about $2.14 in the USA. The same drug wholesales for $426.90 in the USA. We need change the law so pharmacies and institutions can buy directly from suppliers in the EU, so we don't have to pay these outrageous prices.

Posted: Tuesday, August 30, 2016 7:28 PM
Joined: 4/24/2012
Posts: 484

P2X is connected to PIP2, cholesterol in lipid rafts, and PLC. This is an interesting connection.


PIP2­ Regulates the Ionic Current of P2X Receptors and P2X­7 Receptor-Mediated Cell Death

"Several positively charged residues in the proximal C-terminus of P2X7 were found to be important for PIP2 interactions, as mutation of these sites reduced the apparent affinity for PIP2 and enhanced current inhibition by PIP2 depletion. In addition, we demonstrated the dependence on the interaction of the receptor with PIP2 of ATP-mediated cell death in HEK cells stably transfected with P2X7, in primary T cells and in macrophages. These results identify PIP2 as a critical regulator of the function of the extracellular ligand-gated P2X receptor/channels and provide a novel way to control ATP-mediated cell death."


PIP2 is a necessary cofactor for ion channel function: How and why?

Phosphatidylinositol 4,5-bisphosphate (PIP2) is a minority phospholipid of the inner leaflet of plasma membranes. Many plasma membrane ion channels and ion transporters require PIP2 to function and can be turned off by signaling pathways that deplete PIP2. This review discusses the dependence of ion channels on phosphoinositides and considers possible mechanisms by which PIP2 and analogues regulate ion channel activity.


Lipid Raft Association and Cholesterol Sensitivity of P2X1-4 Receptors for ATP

"Cholesterol-rich lipid rafts act as signaling microdomains and can regulate receptor function. We have shown in HEK293 cells recombinant P2X1-4 receptors (ATP-gated ion channels) are expressed in lipid rafts. Localization to flotillin-rich lipid rafts was reduced by the detergent Triton X-100. This sensitivity to Triton X-100 was concentration- and subunit-dependent, demonstrating differential association of P2X1-4 receptors with lipid rafts."

Lane Simonian
Posted: Wednesday, August 31, 2016 1:23 PM
Joined: 12/12/2011
Posts: 4854

I am still trying to figure out the roles of various ionotropic receptors such as P2X and nicotinic acetylcholine receptors in Alzheimer's disease.  By triggering calcium influx they activate src kinases and increase the formation of peroxynitrite.  

P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway

To a certain degree, though, src mediated tyrosine phosphorlyation may partially down-regulate these receptors.  In addition, ATP which is an important agonist of P2X receptors declines due to mitochondrial dysfunction in Alzheimer's disease.

The most important ionotropic receptor in Alzheimer's disease is likely the glutamate NMDA receptor.  Tyrosine phopshorylation increases the activation of this receptor and the lack of clearance of glutamate augments this activation.