Pleiotropy - your new BFF? SGLT2 inhibitors and targeting the NLRP3 inflammasome to target neurological disorders from Autism to ALS and Alzheimer’s

Pleiotropy 

from Greek πλείων pleion, 'more'

and τρόπος tropos, 'way'

 

 

Today’s post introduces a new term – SGLT2.

Depending how old you are, you will be aware of the term BFF – Best Friend Forever.  These days you can have several BFFs, not just one. 

Pleiotropy (play-o-tropy) is a rather nice sounding word that was brought into use in science and medicine by a German geneticist Ludwig Plate in 1910. Pleiotropic effects of a drug are any beneficial secondary effects.

Statins are the classic example. They were developed to lower cholesterol, but many of the positive effects experienced by users have nothing to do with cholesterol, they lower inflammation (and more besides).  It is now thought that inflammation in your arteries triggers a protective layer of cholesterol to be deposited. As the decades pass, this protective layer grows and ends up causing all kinds of problems.

When you repurpose an old drug for a new use, you are taking advantage of its pleiotropic effects.  For readers of this blog pleiotropy is a friend, and quite possibly a BFF.

 

SGLT2

Today we look at repurposing a class of drugs that lowers blood sugar for those with type 2 diabetes to treat a wide range of brain disorders.

We also look at a cheap pain killer that can be used to disrupt an inflammatory pathway key to most brain disorders and even some cancers.

Our reader Eszter did recently highlight a very well written paper about the potential to repurpose SGLT2 inhibitors to treat autism. Eszter knows a lot about neurology, I should point out.

Eszter has previously commented on the interesting overlap between drugs that provide a benefit in Alzheimer’s and those that benefit some autism.  She will likely find the link at the very end of this post of interest.

 

Repurposing SGLT2 Inhibitors for Neurological Disorders: A Focus on the Autism Spectrum Disorder 

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a substantially increasing incidence rate. It is characterized by repetitive behavior, learning difficulties, deficits in social communication, and interactions. Numerous medications, dietary supplements, and behavioral treatments have been recommended for the management of this condition, however, there is no cure yet. Recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental diseases, based on their proved anti-inflammatory effects, such as downregulating the expression of several proteins, including the transforming growth factor beta (TGF-β), interleukin-6 (IL-6), C-reactive protein (CRP), nuclear factor κB (NF-κB), tumor necrosis factor alpha (TNF-α), and the monocyte chemoattractant protein (MCP-1). Furthermore, numerous previous studies revealed the potential of the SGLT2 inhibitors to provide antioxidant effects, due to their ability to reduce the generation of free radicals and upregulating the antioxidant systems, such as glutathione (GSH) and superoxide dismutase (SOD), while crossing the blood brain barrier (BBB). These properties have led to significant improvements in the neurologic outcomes of multiple experimental disease models, including cerebral oxidative stress in diabetes mellitus and ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy. Such diseases have mutual biomarkers with ASD, which potentially could be a link to fill the gap of the literature studying the potential of repurposing the SGLT2 inhibitors' use in ameliorating the symptoms of ASD. This review will look at the impact of the SGLT2 inhibitors on neurodevelopmental disorders on the various models, including humans, rats, and mice, with a focus on the SGLT2 inhibitor canagliflozin. Furthermore, this review will discuss how SGLT2 inhibitors regulate the ASD biomarkers, based on the clinical evidence supporting their functions as antioxidant and anti-inflammatory agents capable of crossing the blood-brain barrier (BBB).

 

Recently I was asked by one researcher reader where is the evidence to support my suggestion that Ponstan (Mefenamic Acid) can enhance cognition.  I was not sure that I would find evidence that relates to actual humans, but I did. This took me back to the time this blog looked into the NLRP3 inflammasome.

Just like the new generation of type 2 diabetes drugs have pleiotropic effects on the brain, so do Fenamate class NSAIDs, specifically Ponstan.

There are four SGLT2 inhibitors approved to treat type 2 diabetes

·        Invokana (canagliflozin)

·        Farxiga (dapagliflozin)

·        Jardiance (empagliflozin)

·        Steglatro (ertugliflozin)

To be effective inside the brain such a drug would need to be small and lipid (fat soluble) enough to get across the blood brain barrier.

If the idea of a diabetes drug helping brain disorders sounds strange, consider what we have already come across in previous posts in this blog.

  

Other Type 2 drugs with pleiotropic effects

 

Metformin

Metformin was discovered exactly 100 years ago, in 1922.  It is not a new drug and it is the world’s most common therapy for type 2 diabetes.

It has been suggested metformin can delay the onset of aging and also the onset and development of Alzheimer’s.

The use of metformin has repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of the pancreas and colon and hepatocellular carcinoma.

Metformin has been shown to raise IQ in children with Fragile-X syndrome by about 10%.

Some people with autism do take metformin, in others it provides no benefit.

 

Glitazones

Glitazones are a class of anti-diabetic drug that started to get popular from the year 2000. They  work by stimulating  peroxisome proliferator-activated receptor gamma (PPAR-γ) receptor. They will activate PGC-1 alpha, which we know is the key regulator of mitochondrial biogenesis. For some strange reason, glitazone drugs are not used to treat mitochondrial disease.

Glitazones have broad anti-inflammatory pleiotropic effects.

Pioglitazone has been researched in autism and I have used it for several years as a spring and summertime add-on therapy in Monty’s PolyPill.

 

Back to Eszter’s paper

 

I highlight some of the tables, which do summarize the beneficial effects.

 

Inflammatory signals promote inflammation by activating the microglia and astrocytes within the brain in ASD. SGLT2 inhibitors influence on the inflammation and neuroinflammation, SGLT2 inhibitors decrease the inflammatory factors levels, such as the M1 macrophages, STAT1 inflammatory transcription factor, cytokine interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and vascular cell adhesion protein (VCAM) in neurodevelopmental diseases

 

 

Distribution of the SGLT receptors in the CNS. 1. Brain cortex (pyramidal cells); 2. Purkinje neurons; 3. Hippocampus; 4. Hypothalamus; 5. Micro vessels; 6. Amygdala cells; 7. Periaqueductal gray; 8. Dorsomedial medulla.

 

Such a distribution of the SGLT2 receptors [114] could potentially be responsible for their intriguing neuroprotective qualities, which could be beneficial in several neurological disorders, including ASD [99]. The SGLT2 inhibitors’ proposed mechanisms are presented in Figure 3. The antioxidant effect of the SGLT2 inhibitors can be attributed to their stimulatory action on the nuclear factor erythroid 2 (Nrf2)- related factor 2 pathway [115]. This displays the antioxidant activity because of their genetic expression of the antioxidant proteins, including glutathione-s-transferase (GST), SOD, and NADPH quinone dehydrogenase-1 to protect against cellular apoptosis [116]. The anti-inflammatory characteristics of the SGLT2 inhibitors could be accredited to the downregulation of NF-KB, which decreases IL-1β and the TNF-α expression [117]. Empagliflozin has the highest selectivity for the SGLT2 receptors (2500-fold) when compared to dapagliflozin which has (1200-fold) selectivity, and canagliflozin (250-fold) [118,119]. Therefore, in the context of the neuroprotective effects associated with the SGLT1 and SGLT2 receptors’ inhibition, canagliflozin was hypothetically preferred over other SGLT2 inhibitors, due to its dual SGLT1/SGLT2 inhibition capability [120].

 

SGLT2 inhibitors have the potential to improve ASD patients’ behavioral and brain disruptions by increasing the cerebral brain derived neurotrophic factor and reducing the cerebral oxidative stress, including elevated the GSH and catalase activity, reduced MDA, amyloid β levels, plaque density, and acetylcholinesterase

 

ASD remains a global health dilemma, as it is a chronic condition, and is incurable, leading to a reduced quality of life. It is crucial to find the mutual molecular mechanisms of ASD and redefine the indications for the well-studied medication with numerous pleiotropic effects to find a solution. This review has disclosed the impact of the SGLT2 inhibitors in neurological diseases, which could relate to ASD as it shares multiple pathways and mutual biomarkers. SGLT2 inhibitors display several neuroprotective properties, highlighting their therapeutic potential for ASD patients, as these agents have the capability to inhibit the acetylcholinesterase enzyme, reduce the elevated levels of the oxidative stress in the brain, and restore the anabolism and catabolism balance. Moreover, clinical intervention studies are vital to determine whether the displayed methods are useful as the SGLT2 inhibitors have never been tested on ASD directly. Currently, our research team is conducting a preclinical experiment to assess the effects of canagliflozin on the VPA-induced ASD in Wistar rats.

  

Back to the NLRP3 Inflammasome

Ponstan (Mefenamic acid) is one of the few available drugs that is known to be a potent inhibitor of an inflammatory pathway called the NLRP3 inflammasome.  It is mainly present macrophages, a type of white blood cell in the immune system.  The role of macrophages includes gobbling up pathogens.  

In the brain the microglia are the resident macrophages.  The microglia have multiple functions in the brain and we know that in autism they can be stuck in an overactivated state and then do not fulfil their other functions.

In many diseases activation of the NLRP3 inflammasome in local macrophages occurs.  Inhibiting this process can disrupt the disease process.

My guess is that this is the mechanism by which Ponstan is improving cognition in some of the people with autism who are taking it.

In the paper below we see that people taking Ponstan to treat their prostate cancer (PCa) experience an improvement in their cognition.

 

Improve cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy: additional beneficial effect found in a controlled clinical trial for prostate cancer therapy 

Inflammation is an essential component of prostate cancer (PCa), and mefenamic acid has been reported to decrease its biochemical progression. The current standard therapy for PCa is androgen deprivation therapy (ADT), which has side effects such as cognitive dysfunction, risk of Alzheimer’s disease, and dementia. Published results of in vitro tests and animal models studies have shown that mefenamic acid could be used as a neuroprotector. Objective: Examine the therapeutic potential of mefenamic acid in cognitive impairment used in a controlled clinical trial. Clinical trial phase II was conducted on patients undergoing ADT for PCa. Two groups of 14 patients were included. One was treated with a placebo, while the other received mefenamic acid 500 mg PO every 12hrs for six months. The outcome was evaluated through the Mini-Mental State Examination (MMSE) score at six months. At the beginning of the study, both groups had similar MMSE scores (mefenamic acid vs. placebo: 26.0±2.5 vs. 27.0±2.6, P=0.282). The mefenamic acid group improved its MMSE score after six months compared with the placebo group (27.7±1.8 vs. 25.5±4.2, P=0.037). Treatment with mefenamic acid significantly increases the probability of maintained or raised cognitive function compared to placebo (92% vs. 42.9%, RR=2.2, 95% CI: 1.16-4.03, NNT=2.0, 95% CI: 1.26-4.81, P=0.014). Furthermore, 42.9% of the placebo group patients had relevant cognitive decline (a 2-point decrease in the MMSE score), while in patients treated with mefenamic acid, cognitive impairment was not present. This study is the first conducted on humans that suggests that mefenamic acid protects against cognitive decline.

 

In the AEA mouse model of MS (multiple sclerosis) we see the role again of NLRP3 on cognition. 

Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype 

Some studies have indicated that NLRP3 inflammasome activation is involved in mediating synaptic dysfunction, cognitive impairment, and microglial dysfunction in AD models, and that the inhibition of the NLRP3 inflammasome attenuates spatial memory impairment and enhances Aβ clearance in AD model.  However, there is no research on NLRP3 inflammasome in MS-related cognitive deficits. In our study, we found that microglia and NLRP3 inflammasome were activated in the hippocampus of EAE mice, while pretreatment with MCC950 inhibited the activation of microglia and NLRP3 inflammasome

 

Again, we see a benefit from inhibiting NLRP3 in Alzheimer’s. 

Novel Small-Molecule Inhibitor of NLRP3 Inflammasome Reverses Cognitive Impairment in an Alzheimer’s Disease Model

Aberrant activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays an essential role in multiple diseases, including Alzheimer’s disease (AD) and psoriasis. We report a novel small-molecule inhibitor, NLRP3-inhibitory compound 7 (NIC7), and its derivative, which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1β, IL-18, and lactate dehydrogenase. We examined the therapeutic potential of NIC7 in a disease model of AD by analyzing its effect on cognitive impairment as well as the expression of dopamine receptors and neuronal markers. NIC7 significantly reversed the associated disease symptoms in the mice model. On the other hand, NIC7 did not reverse the disease symptoms in the imiquimod (IMQ)-induced disease model of psoriasis. This indicates that IMQ-based psoriasis is independent of NLRP3. Overall, NIC7 and its derivative have therapeutic prospects to treat AD or NLRP3-mediated diseases.

 

What about sepsis (blood poisoning)? 

Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis

The pathophysiology of sepsis may involve the activation of the NOD-type receptor containing the pyrin-3 domain (NLPR-3), mitochondrial and oxidative damages. One of the primary essential oxidation products is 8-oxoguanine (8-oxoG), and its accumulation in mitochondrial DNA (mtDNA) induces cell dysfunction and death, leading to the hypothesis that mtDNA integrity is crucial for maintaining neuronal function during sepsis. In sepsis, the modulation of NLRP-3 activation is critical, and mefenamic acid (MFA) is a potent drug that can reduce inflammasome activity, attenuating the acute cerebral inflammatory process. Thus, this study aimed to evaluate the administration of MFA and its implications for the reduction of inflammatory parameters and mitochondrial damage in animals submitted to polymicrobial sepsis. To test our hypothesis, adult male Wistar rats were submitted to the cecal ligation and perforation (CLP) model for sepsis induction and after receiving an injection of MFA (doses of 10, 30, and 50 mg/kg) or sterile saline (1 mL/kg). At 24 h after sepsis induction, the frontal cortex and hippocampus were dissected to analyze the levels of TNF-α, IL-1β, and IL-18; oxidative damage (thiobarbituric acid reactive substances (TBARS), carbonyl, and DCF-DA (oxidative parameters); protein expression (mitochondrial transcription factor A (TFAM), NLRP-3, 8-oxoG; Bax, Bcl-2 and (ionized calcium-binding adaptor molecule 1 (IBA-1)); and the activity of mitochondrial respiratory chain complexes. It was observed that the septic group in both structures studied showed an increase in proinflammatory cytokines mediated by increased activity in NLRP-3, with more significant oxidative damage and higher production of reactive oxygen species (ROS) by mitochondria. Damage to mtDNA it was also observed with an increase in 8-oxoG levels and lower levels of TFAM and NGF-1. In addition, this group had an increase in pro-apoptotic proteins and IBA-1 positive cells. However, MFA at doses of 30 and 50 mg/kg decreased inflammasome activity, reduced levels of cytokines and oxidative damage, increased bioenergetic efficacy and reduced production of ROS and 8-oxoG, and increased levels of TFAM, NGF-1, Bcl-2, reducing microglial activation. As a result, it is suggested that MFA oinduces protection in the central nervous system early after the onset of sepsis.

  

Conclusion

One reader of this blog attributes her son’s autism to his sepsis (blood poisoning) at birth. It is pretty clear from one of today’s papers that perhaps babies with sepsis should be treated with Ponstan (Mefenamic acid) to prevent damage to their brain.  I was recently contacted by another parent where sepsis occurred at birth. 

I think the researchers make a strong case that the pleiotropic effects of SGLT2 inhibitors that benefit Alzheimer’s, Parkinson’s and ALS very likely will also be beneficial in some autism.  They plan to test canagliflozin on rats with valproic acid-induced autism.

I have to say to Eszter that I actually think inhibiting the NLRP3 inflammasome might be the Neurologist’s best friend forever (BFF), perhaps even better than an SGLT2 inhibitor.

What is for sure is that both (SGLTi and NLRP3i) should be subject of clinical trials in autism. I suggest going straight humans rather than rats.

I have had positive feedback so far on my suggestion that low dose (250 mg) Ponstan/Mefenamic acid could be an effective long term autism therapy.  We do have to mention that Knut Wittkowski has patented its use in autism; he proposed it as a preventive measure in 2-3 year olds to redirect severe non-verbal autism towards Asperger’s. I selected it to treat extreme sound sensitivity, but later witnessed its pleiotropic effects.

If anyone has experience on the use of an SGLT2 inhibitor in autism, I would be very interested to read about it.

We should add Ponstan to the long list of drugs in this autism blog that may be beneficial in MS (Multiple sclerosis). (ALA, Clemastine, NAG, Ibudilast, DMF, Ponstan etc).

P.S.

A last word from Google

Having noted my recent googling activity, I was today sent the following news item by Google. 

Harnessing the Brain’s Immune Cells to Stave off Alzheimer’s and Other Neurodegenerative Diseases

Researchers have identified a protein that could be leveraged to help microglia in the brain stave off Alzheimer’s and other neurodegenerative diseases

But how does SYK protect the nervous system against damage and degeneration? We found that microglia use SYK to migrate toward debris in the brain. It also helps microglia remove and destroy this debris by stimulating other proteins involved in cleanup processes. These jobs support the idea that SYK helps microglia protect the brain by charging them to remove toxic materials.

 

High dose Betaine/TMG, Low Dose Ponstan, Galavit, Humira, HMB (β-hydroxy-β-methylbutyrate) and Cetirizine for Palilalia/Scripting

 

Our reader in Canada, AJ, did highlight a case series from Norway that showed that high dose Betaine/TMG was effective in improving functioning in people with autism due to creatine transporter deficiency.  The use of Betaine/TMG was really just stumbled upon and the authors considered what the beneficial possible mode of action could be. 

Betaine (TMG) and Gene Therapy as potential alternatives to Bumetanide Treatment in Autism? 

The effect was only present at high dose (7-10 g a day) not the much lower dose used by some DAN/MAPS doctors, who do prescribe TMG and the closely related DMG.

The paper suggested that one possible effect might have been lowering chloride levels within neurons.  This is also the effect of Bumetanide.

AJ suggested that Betaine/TMG might be an alternative to Bumetanide and one that does not need a prescription.

Our reader Nancy reported a benefit in her adult son.

The question is not whether or not high dose TMG is a useful therapy, we already know that it is, in some cases. The question is whether it is a bumetanide alternative.

My conclusion is that high dose TMG does not seem to be a bumetanide alternative.  If it was an effective alternative then I would be suggesting everyone using bumetanide should go and buy some.

I did try TMG for s couple of weeks and did not see any additional effect over the continued therapy of 2mg of bumetanide.  In our case there is a benefit from additional bumetanide/Azosemide. If TMG shared the same mode of action as Bumetanide then 7g TMG + 2mg Bumetanide should show some improvement over 2mg Bumetanide.  It did not.

There is a long list of other modes of action to explain why Nancy’s son and the two Norwegians improved.

 

Low dose Ponstan for sound sensitivity

Low dose Ponstan (Mefenamic Acid) was proposed as a treatment for sound sensitivity.  Within Europe it seems that Greece is the place to buy Ponstan; it is sold OTC and cheap.  One pack (15 x 500mg) costs less than 2 USD/EUR.

In some people the effect of 250mg lasts all day, while for others it lasts for a few hours.

Ponstan is also widely used as a syrup to reduce fever in young children (antipyretic).

In the US the common brand name is Ponstel, but the price is dramatically higher.

Galavit + Cromolyn Sodium

The combination of the common mast cell stabilizer Cromolyn Sodium, used by many readers, with a Russian drug called Galavit is used by at least two readers. Dragos recently told us that the combination has put an end to his adult son’s aggressive behaviors.

Galavit has multiple anti-inflammatory modes of action.  It is not a mast cell stabilizer like Cromolyn Sodium.

Galavit is not expensive, but may hard to get hold of.

It does look like there is an overlap between responders to Verapamil and responders to Galavit.  So, if you respond well to Verapamil but get one of the rare side effects, like Maja’s daughter, it might be worth investigating further. 

Humira 

Humira is a TNF alpha inhibitor normally used to treat auto-immune conditions like rheumatoid arthritis, Cohn's disease, ulcerative colitis, psoriasis and juvenile arthritis.

I was recently contacted by an Aspie lady with auto-immune conditions, who found Humira not only controlled those conditions but moderated her autism symptoms, notably sound sensitivity.  One injection produced a benefit that lasted 7 weeks.

Kanner’s subject #1 went on to develop juvenile arthritis and this made his autism much worse.  There was no Humira back in his day, but his arthritis did respond to treatment.

Apparently, many children with autism and GI problems are taking Humira. 

IVIG seems to be the “go-to” therapy for immunomodulation in autism.  It is now quite commonly used in the US, but much less so elsewhere due to the cost.

I wonder if Humira might be an alternative for some?

 

HMB (β-hydroxy-β-methylbutyrate)

Our reader Natasa did mention the sports supplement HMB to me.

It has many interesting modes of action and it is a precursor to the ketone BHB, which has been covered in great depth in this blog.

Ketone Therapy in Autism (Summary of Parts 1-6)

In Europe ketone supplements like BHB fell foul of the rules on supplements and have been banned. In the US they are widely sold.

If you want to try BHB, by cannot buy it in Europe, you might want to look into HMB (β-hydroxy-β-methylbutyrate).

 

Cetirizine for Palilalia/Scripting 

I am a big fan of the OTC antihistamine Cetirizine/Zyrtec and I was interested to read the recent comment below about its effect on one 12-year-old boy.

“I realize this is 5 years old, but as a result of this blog, I tested cetirizine on my 12 yo yesterday. He has a nonstop palilalia (obsessive speaking that is nonsense or only makes sense to him). It's his "chief feature" and inhibits social development. For 4 glorious hours, it went away. Today, I gave him 5 mg of Zyrtec again. Yet again, the palilalia went away, AND he had strong focus on school (he has serious attention issues).”

 

Many people’s autism gets worse when auto-immune conditions flare up.  In some cases, the auto-immune condition is very mild, but the consequences are not.  For one person the result is aggressive behavior, while in another it is talking nonsense.

Fenamates (Diclofenac, Ponstan etc): certainly for Alzheimer’s, maybe some Epilepsy, but Autism? I’m Impressed!

 

Some readers of this blog are interested in the potential of mefenamic acid (MFA), sold as Ponstan, to treat autism. There is a lack of evidence currently. 

On the other hand, the evidence looks pretty overwhelming in the case of this class of drug to treat Alzheimer’s, hence today’s post. If you have a case of epilepsy at home, you can follow up on that loose end I left.

I also introduce MFA as a therapy for sound sensitivity and Misophonia. It was pretty impressive in the case of Monty, aged 18 with ASD.

 

The highlights are:

 

·        Fenamate NSAIDs reduce the incidence of Alzheimer’s

·        Fenamate NSAIDs delay the progression of those already with Alzheimer’s

·        Acetaminophen/Paracetamol worsens the progression of Alzheimer’s

·        Low dose aspirin is chemoprotective, as well as reducing blood clots that cause heart attack and stroke, but offers no Alzheimer’s benefit

·        MFA/Ponstan is very effective in reducing Monty’s sound sensitivity

 

The caveats 

As is always the case, there are caveats.

It is well known that low dose aspirin can cause dangerous bleeding events in specific sub-populations.

A study of 6 million people in Denmark showed that older people taking the Fenamate Diclofenac has a slightly higher risk of heart problems than other NSAIDs. The risk is actually very low and symptoms in those affected generally appear within a month (and disappear on cessation).

 

Incidence of Alzheimer’s

 

 

 Source:  https://www.intechopen.com/chapters/43129

 

The longer you live, the chance of developing Alzheimer’s rapidly increases. 

The signs are actual visible in a CT scan decades before the symptoms are evident.

Almost two-thirds of Americans with Alzheimer's are women.

Older Black Americans are about twice as likely to have Alzheimer's or other dementias as older Whites.

Of those with I/DD (Intellectual or Developmental Disability), it is people with Down Syndrome who are at major risk of early onset Alzheimer’s.  More than 50% will develop Alzheimer's. 

 

Non drug methods to protect against Alzheimer’s and other dementia 

In this blog we have encountered numerous dietary methods associated with reduced risk of all types of dementia and Alzheimer’s specifically.

·        Dietary nitrates (beetroot, spinach etc)

·        Betanin (the pigment in beetroot)

·        Ergothioneine (from mushrooms)

·        Spermidine (from wheatgerm and mushrooms)

·        Anthocyanin pigments from superfoods (bilberry, blueberry, purple sweet potato etc)

 

Maintaining normal blood pressure, blood glucose levels and cholesterol levels are big advantages. Normal body mass and regular exercise are also important.

Fenamates are a class of NSAID pain medication that many people have at home. In the US there are 10 million prescriptions a year of Diclofenac / Voltaren.

Another common Fenamate is Mefenamic Acid (MFA), commonly sold as Ponstan.  Ponstan is only expensive in North America. 

Most people’s reaction would be “Ah, yes those are pain medications, how could they help Alzheimer’s or other neurological conditions. Aren’t they the ones with those GI side effects?” 

NSAIDS deaden pain by blocking an enzyme called cyclooxygenase-2 (COX-2). Unfortunately, they also block to some extent a very similar enzyme called  cyclooxygenase-1 (COX-1). COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion.  Blocking COX-1 will cause GI side effects. Most people want to take an NSAID that is selective for COX-2.

 

Low dose Aspirin – the good COX-1 effect

There is a good effect from blocking COX-1, as from low dose aspirin (LDA), because it stops blood platelets sticking together and blocking blood flow.  LDA is also substantially chemoprotective and nobody has figured out why and it likely has nothing to do with COX1 or COX2. 

“Ishikawa et al. analyzed 51 randomized controlled trials (RCTs) and the cumulative evidence strongly supports the hypothesis that daily use of aspirin results in the prevention of cardiovascular disease (CVD), as well as a reduction in cancer-associated mortality [3].”

 

Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate? 

Epidemiological evidence suggests non-steroidal anti-inflammatory drugs reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of non-steroidal anti-inflammatory drug efficacy. This incongruence may be due to the wrong non-steroidal anti-inflammatory drugs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalized linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease Neuroimaging dataset for each commonly used non-steroidal anti-inflammatory drug and paracetamol. Use of most non-steroidal anti-inflammatories was associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these non-steroidal anti-inflammatory drugs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease.

 

  

Diclofenac Use Slows Cognitive Decline in Alzheimer Disease 

CHICAGO — While most common non-steroidal anti-inflammatory drugs (NSAIDs) do not significantly affect cognitive decline in patients with Alzheimer disease or mild cognitive impairment, research presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018, in Chicago, Illinois suggests that diclofenac actually reduces cognitive deterioration, while paracetamol accelerates decline. 

The study investigated cognitive decline associated with NSAID use in 1619 patients from the Alzheimer’s Disease Neuroimaging Initiative dataset. The Mini-Mental State Examination and the Alzheimer disease assessment scale were used to evaluate cognitive functioning. Additional variables that potentially explain cognitive decline were identified for the cohort including gender, apolipoprotein E genotype, level of education, vascular disorders, diabetes, and medication use. 

 

Study results showed that most common NSAIDs, including aspirin, ibuprofen, naproxen, and celecoxib did not alter cognitive degeneration in patients with mild cognitive impairment or Alzheimer disease. Diclofenac was the only NSAID that demonstrated a correlation with a slower rate of cognitive decline (ADAS χ2=4.0, P =.0455, MMSE χ2=4.8, P =.029). Conversely, paracetamol was correlated with accelerated cognitive deterioration (ADAS χ2=6.6, P =.010, MMSE χ2=8.4, P =.004), as well as apolipoprotein E ε4 genotype (ADAS χ2=316.0, P <.0001, MMSE χ2=191.0, P <.0001). 

Diclofenac’s correlation with slowed cognitive deterioration provides “exciting evidence for a potential disease modifying therapeutic,” the study authors wrote. If paracetamol’s deleterious effects are confirmed to be causative, it “would have massive ramifications for the recommended use of this prolific drug.”

 

One reason why paracetamol use might harm Alzheimer’s brains is the same reason it harms autistic brains; it depletes the level of the key antioxidant glutathione (GSH).  GSH will be in big demand in a damaged brain. 

As we will see later in this post, Fenamate class NSAIDs affect numerous ion channels, specifically Kv7.1, as a result some people with heart conditions will get side effects linked to arrhythmia and should therefore discontinue use.

 

Common painkiller linked to increased risk of major heart problems: Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers -- ScienceDaily

Common painkiller linked to increased risk of major heart problems

Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers 

The commonly used painkiller diclofenac is associated with an increased risk of major cardiovascular events, such as heart attack and stroke, compared with no use, paracetamol use, and use of other traditional painkillers, a new study finds.

 

The risk is actual quite low and is going to appear straight away, in terms of arrhythmia. If any drug or supplement makes you feel unwell, stop taking it and tell your doctor.

 

Which Fenamate for Alzheimer’s?

To decide which Fenamate is best for Alzheimer’s and indeed which might be helpful in some autism, it helps to ponder the various modes of action unrelated to COX-1 and COX-2. 

We have the NLRP3 inflammasome, which is suggested as the mechanism in Alzheimer’s.

Here we want to block inflammatory messenger like IL-1beta. In the chart below we see that Ibuprofen is useless, Diclofenac has an effect, Mefenamic acid is better, but Meclofenamic acid is the star.

 

  

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.

 

Fenamates and Ion Channels

https://scholarworks.wm.edu/cgi/viewcontent.cgi?article=2671&context=aspubs

 

A very broad range of ion channels are affected by Fenamates.

Researcher Knut Wittkowski focuses on the effect on potassium channels in his theory that Fenamates can treat autism and prevent non-verbal autism if given to toddlers.

• PATENT SUMMARY - Treatment and prevention of autism and autism spectrum disorders

Fenamates actually affect numerous ion channels.

·        Chloride channels

·        Non-selective cation channels

·        Potassium channels (Kv 7.1 , KCa 4.2, K2p 2.1, K2p 4.1, K2p 10.1)

·        Opens large conductance calcium-activated K⁺ channels (BK_Ca channels) 

https://www.researchgate.net/publication/348973521_Pharmacological_inhibition_of_BKCa_channels_induces_a_specific_social_deficit_in_adult_C57BL6J_mice

“Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability… These findings support the relationship between BKCa channel impairment and social behavior. This demonstrates a need for future studies which further examine the contribution of BKCa channels to social behavior, particularly during critical periods of development.

 

·        Sodium channels

·        Blockage of acid-sensing ion channels (ASICs), which are implicated in numerous disorders and had their own post.

https://epiphanyasd.blogspot.com/2017/08/acid-sensing-ion-channels-asics-and.html

 

Fig. 2. Ion channels targeted by flufenamic acid. Flufenamic acid produces inhibition or activation of ion channels. Colored bars near ionic channel name correspond to the estimated EC50 for flufenamic effect. References are provided within the text.

 Having noted the above graphic, which actually applies to the closely related flufenamic acid, a logical question is to ask about the effect of Flufenamic acid on seizures. 

Flufenamic acid shows promise as an epilepsy drug

I am not looking for a seizure therapy, so I leave that loose end for someone who is.

 

Conclusion

The best initial defence against dementia is good diet and exercise. Sometimes that will not be enough, because the healthier you are, the longer you will live and so the threat from dementia increases. Some people have genes that predispose them to dementia.

Since most of us struggle to follow diets like those of ultra healthy people in Okinawa, or on a Greek island, it might be worthwhile adding beneficial functional foods (neutraceuticals) to your existing diet.

I drink a small amount of beetroot juice daily, which is not such a hard step to take. In addition to benefits to your heart and brain, another benefit has just been discovered; now it improves the oral microbiome :-

 

Research suggests changes in mouth bacteria after drinking beetroot juice may promote healthy ageing 

“Our findings suggest that adding nitrate-rich foods to the diet – in this case via beetroot juice – for just ten days can substantially alter the oral microbiome (mix of bacteria) for the better.”

 

Many older people take NSAIDs to treat painful conditions like arthritis, switching to a Fenamate NSAID would not be a difficult option and would give some protection from Alzheimer’s.

People already diagnosed with Alzheimer’s currently do not have any effective therapies. Drugs like memantine exist, but are not so effective.  If I was in that position, I would want to take a low dose of Mefenamic Acid, if that was unavailable, I would settle for Diclofenac.

Diclofenac (25mg to 100mg) is prescribed in much lower doses than Mefenamic Acid (250 to 500mg tablets). We see that the effect on the NLRP3 inflammasome is actually far greater from Mefenamic Acid than Diclofenac. If the Alzheimer’s effect is via inhibiting the NLRP3 inflammasome, then you might expect that only a fraction of a standard capsule of Mefenamic would be needed.  That would then really reduce any GI side effects via the unwanted effect on COX-1 or any chance of arrhythmia. 

The ketone BHB, like fenamate NSAIDs, inhibits the NLRP3 inflammasome.  Since in Alzheimer’s the brain loses the ability to transport enough glucose across the blood brain barrier, ketones can also be used as a supplementary fuel for the brain. In one of my old posts on BHB I remember the doctor treating her husband with early onset Alzheimer’s with large doses of ketones – with some success.

 

And Autism?

Is Knut right that the potassium channel modulation from Mefenamic Acid will benefit autism, or at least a sub-set of severe autism? We do not know.

Mefenamic Acid (MFA) has so many biologic effects, I very much doubt Alzheimer’s is the only neurological condition where it could be beneficial. 

I should add that MFA undoubtedly will have negative effects in some people, this is inevitable.

Stop the noise !!

We did have a problem recently with extreme sound sensitivity. Monty, aged 18 with ASD, has had increasing sound sensitivity (Misophonia) for a year, but the only real issue was with sounds at mealtimes.  Over a recent weekend the sensitivity increased so much he could not sleep and also drank unusually large amounts of water (this also connects to K⁺). 

The next day at school he had a geography exam and he was completely dysfunctional. Monty’s assistant had prewarned the teacher and she agreed that he can sit the exam again next week.   

Fortunately, in the meantime the problem has been now been fixed (see below).

I was suggested to take to Monty to a Neurologist, but since there is no Dr Chez where we live, I did ignore that idea. In mainstream neurology sound sensitivity is just something you have got to learn to live with, perhaps with some Cognitive Behavioral Therapy (CBT) or just a pair of ear defenders, or those noise-cancelling headphones.

I did experiment years ago on the effect of an oral potassium supplement on reducing sound sensitivity, so I have long considered potassium ion channels a prime target.

Both hearing and the processing of the inputs is highly dependent on potassium channels, so I did return to MFA.  It has also been a topic in some recent email exchanges and I have long had some unopened packs of MFA at home.  The answer would be found in the kitchen cabinet and not in the neurology department

In bumetanide responders the Na-K-2Cl cotransporter (NKCC1) is over-expressed; it mediates the “coupled electroneutral movement of 1Na⁺, 1K⁺, and 2Cl^– ions across the plasma membrane of neurons”. This means that with each two chloride ions entering the neuron, come one sodium ion and one potassium ion.

 

Source: https://www.frontiersin.org/articles/10.3389/fncel.2019.00048/full

 

In summary, bumetanide responders have too much chloride in their neurons, the bubble on the left, above.

 

Knut’s theory was put to me recently as “MFA works on reducing neuron excitation by opening K+ channels, emptying the cell, which in return fills up with Cl- “.

If this is the case, MFA would do the opposite of Bumetanide.

I actually think MFA’s effect is much more complex.

The original idea of Knut was to prevent severe non-verbal autism developing in toddlers, by blocking the progression of the disease. MFA was essentially a medium-term treatment for toddlers, until the critical periods in brain development were past.  It was not a treatment for teenagers, by then the damage would have been done.

I think changing the baseline level of K+ inside neurons is going to have many effects.  Changing the baseline level of Cl- has a profound impact on cognition.

Unfortunately, everything is interrelated and so nothing is simple.

I did try MFA to eradicate the extreme sound sensitivity. I was concerned it might reduce cognition, by raising intracellular chloride and undo the bumetanide effect.

The extreme sound sensitivity did disappear following a day or two of starting 250mg a day of MFA, but that may just have been a coincidence.  The more mild sound sensitivity, that we had all learned to live with for months, also vanished; I do not see how that could be a coincidence.  Mood also became very good, perhaps a bit uncontrollably happy.

The next question is what happens to sound sensitivity when I stop giving MFA.  Time will tell, but so far the benefits have been maintained.

Sound sensitivity/Misophonia is a classic feature of autism;  TV depictions often portray a lonely looking boy wearing ear defenders. For many with Asperger’s misophonia is their main troubling issue. None of these people are taking bumetanide.  Monty has taken Bumetanide for nearly 10 years and never needed ear defenders.

You, like Prof Ben-Ari, might wonder if bumetanide use might cause a problem with potassium and hence hearing.  There is indeed a known risk of ototoxicity, which is actually a rare but possible side effect of loop-diuretic use, particularly furosemide.

Fluid in the inner ear is dependent upon a rich supply of potassium, especially in that part of the ear that translates the noises we hear into electrical impulses the brain interprets as sound.

 

Source: http://www.cochlea.eu/en/cochlea/cochlear-fluids

 

“Endolymph (in green) is limited to the scala media (= cochlear duct; 3), is very rich in potassium, secreted by the stria vascularis, and has a positive potential (+80mV) compared to perilymph.

Note that only the surface of the organ of Corti is bathed in endolymph (notably the stereocilia of the hair cells), whilst the main body of hair cells and support cells are bathed in perilymph.”

 

It is important to maintain a high level of potassium (K+) in the endolymph.

How the potassium gets there is a little bit complicated but it relies on:

·        The NKCC1 transporter

·        Potassium channel Kir4.1

·        Potassium channel KCNQ1 (Kv7.1) and in particular subunit KCNE1

 

Bumetanide blocks NKCC1 and so can potentially reduce potassium in the endolymph. Very high dose bumetanide would indeed risk ototoxicity.

We saw earlier in this post that Fenamates affect Kv7.1.

It is very poorly documented in the research, but Fenamates also affect Kir4.1.

 

The cochlea functions like a microphone. The auditory nerve then runs from the cochlea, hopefully bathed in potassium, to a station in the brainstem. From that station, neural impulses travel to the brain – specifically the temporal lobe, containing the primary auditory complex, where sound is attached meaning and we “hear”.

 

The auditory cortex is highlighted in pink and interacts with the other areas highlighted above

 

   Angular Gyrus   Supramarginal Gyrus   Broca's Area   Wernicke's Area 

 

By James.mcd.nz - self-made - reproduction of combined images Surfacegyri.JPG by Reid Offringa and Ventral-dorsal streams.svg by Selket, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=3226132

 

The peripheral auditory system links the microphone/cochlea to the brain. The Primary Auditory Neurons begin in the cochlea and terminate in the Brainstem (in the Cochlear Nuclei). In these neurons potassium channels play a key role.  These channels include K_Na1.1 and K_Na1.2, which are regulated by intracellular Na⁺ and Cl⁻, are found in a variety of neurons.

We assume that intracellular Cl⁻ is disturbed in bumetanide responsive autism.

Everything has to function to ensure normal hearing and with normal perception attached to that hearing.  Problems can arise in the cochlea (microphone) or in any of the above areas in the brain involved in transmitting or processing those signals.

 

Fenamates for some Aspie’s with Misophonia?

Misophonia has been covered in previous posts and we saw that therapies do exist in the research.  I think that there are multiple causes of sound sensitivity and likely also for those with Misophonia.

Low dose roflumilast was one interesting therapy, that works for some people but not others.  It does nothing for Monty regarding misophonia/sensory gating.

I wonder if some sound-troubled Aspies will respond to low dose MFA?

 

The top shelf

In our case, the answer to good health is usually found in the kitchen, but sometimes tucked away out of reach, up high at the back of a shelf, gathering dust, next to my stockpile of NAC.

There will be a dedicated post on sound issues in autism, which will draw everything together to include information from earlier posts.

and, not to forget, 

Danke vielmals Knut !

(Thanks to Knut!)