Regulation of the Arachidonic Acid (AA) Cascade to treat Inflammatory Disease via aspirin, diet, lithium or better still calcium channels

A rather simpler type of cascade

Today’s post was really to explain why for some people with autism their GI problems disappear when they take the calcium channel blocker verapamil.  Along the way, we will see that a similar mechanism is behind the effectiveness of both low dose aspirin and even high doses of omega 3 oil, when combined with lower dietary intake of omega 6.

There have been several studies regarding omega 3 oil in autism, but overall they are not very conclusive.  A small number of people with autism and ADHD seem to benefit.

Low dose aspirin is now very commonly prescribed to people at risk of a heart attack.

In essence you can say that too much of the omega-6 fatty acid arachidonic acid (AA) is potentially bad for you;  it allows for the body to become inflamed, but more important seems to be the AA cascade which determines whether the AA is converted to prostaglandins or leukotrienes.  Fortunately prostaglandins and leukotrienes tend to act locally rather than circulate throughout your body because they degrade quickly.

You can inhibit this cascade for therapeutic benefit.

In inflammatory bowel disease (IBD), prostaglandins are mucosal protective whereas leukotrienes are pro-inflammatory.

IBD and IBS are common in autism.  In some people with autism it appears that too much arachidonic acid in the gut is being converted to leukotrienes and too little to prostaglandins, the result is inflammation.

The calcium channel blocker, verapamil, has a mucosal-protective effect that occurs as a consequence of reduced mucosal leukotriene synthesis and increased prostaglandin synthesis.

This very likely explains why some people’s chronic GI problems disappear when they take verapamil.

Arachidonic acid (AA) is also present in the brain and it appears to be dysfunctional in many neurological conditions, including autism, bipolar and Alzheimer’s.

We already know that some people with autism or bipolar respond well to verapamil.

We also know that mood stabilizing drugs, like lithium, work by affecting the arachidonic acid cascade in the brain.  

Aspirin enters the brain and inhibits the AA metabolism.  Aspirin is now being trialed as an add-on therapy in bipolar to decrease inflammation suggested to be present in the brain.  Some people do not tolerate aspirin.

In research models a diet high in omega 3 and low in omega 6 oils has been shown to reduce brain AA metabolism.  This would suggest eating fish and olive oil and avoiding junk food.

Modern western diets typically have ratios of omega 6 to omega 3 in excess of 10 to 1, the average ratio of omega 6 to omega 3 in the Western diet is 15:1.  Humans are thought to have evolved with a diet of a 1-to-1 ratio of omega-6 to omega 3 and the optimal ratio is thought to be 4 to 1 or lower.

The source of excessive omega-6 for most people is vegetable oil (corn, sunflower etc.) in junk food.

Most people eat so much omega 6, that buying some expensive omega 3 capsules is going to have minimal impact.  Maybe time to embrace a more Mediterranean diet?

For those trying to influence the AA cascade, you have plenty of choices.  I am happy with verapamil, and plenty of olive oil.

Conclusion

Treating IBS/IBD with a calcium channel blocker looks an interesting avenue for some researcher to develop.  It would be an extremely cheap therapy, so I do not see anyone rushing in that direction.

The many people giving their child expensive omega 3 supplements for autism or ADHD, might want to start by reducing excessive omega 6 consumed in fried food and processed food. 

If you have IBS/IBD yourself and a relative with autism you might well benefit from occasional use of moderate dose verapamil.

You might wonder how come so many things respond to verapamil; it seems that dysfunctional calcium signaling is at the core of many conditions including autism.  You will see in a later post that even autophagy/mitophagy, the cellular garbage collection service, that is dysfunctional in autism, can be treated via calcium channels.

The science

For those interested in the science here follows the more complicated part.

Arachidonic acid (AA) is a polyunsaturated omega-6 fatty acid.  It is abundant in the brain and performs very important roles.  docosahexaenoic acid (DHA) is present in the brain in similar quantities.

AA then undergoes a cascade forming so-called eicosanoids this happens by either producing prostaglandins or leukotrienes.  These eicosanoids have various roles in inflammation, fever, regulation of blood pressure, blood clotting, immune system modulation, control of reproductive processes and tissue growth, and regulation of the sleep/wake cycle.

Eicosanoids, derived from arachidonic acid, are formed when your cells are damaged or are under threat of damage. This stimulus activates enzymes that transform the arachidonic acid into eicosanoids such as prostaglandin, thromboxane and leukotrienes. Eicosanoids cause inflammation. Therefore, the more arachidonic acid that is present, the greater capacity your body has to become inflamed. Eicosanoids tend to act locally rather than circulate throughout your body because they degrade quickly. 

Corticosteroids are anti-inflammatory because they prevent inducible Phospholipase A₂ expression, reducing AA release

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and derivatives of ibuprofen, inhibit Cyclooxygenase activity of PGH₂ Synthase. They inhibit formation of prostaglandins involved in fever, pain and inflammation. They inhibit blood clotting by blocking thromboxane formation in blood platelets.

Arachidonic Acid and the Brain

In adults, the disturbed metabolism of ARA contributes to neurological disorders such as Alzheimer's disease and Bipolar disorder. This involves significant alterations in the conversion of arachidonic acid to other bioactive molecules (overexpression or disturbances in the ARA enzyme cascade).

Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients

Mood stabilizers that are approved for treating bipolar disorder (BD), when given chronically to rats, decrease expression of markers of the brain arachidonic metabolic cascade, and reduce excitotoxicity and neuroinflammation-induced upregulation of these markers. These observations, plus evidence for neuroinflammation and excitotoxicity in BD, suggest that arachidonic acid (AA) cascade markers are upregulated in the BD brain. To test this hypothesis, these markers were measured in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. Mean protein and mRNA levels of AA-selective cytosolic phospholipase A₂ (cPLA₂) IVA, secretory sPLA₂ IIA, cyclooxygenase (COX)-2 and membrane prostaglandin E synthase (mPGES) were significantly elevated in the BD cortex. Levels of COX-1 and cytosolic PGES (cPGES) were significantly reduced relative to controls, whereas Ca²⁺-independent iPLA₂VIA, 5-, 12-, and 15-lipoxygenase, thromboxane synthase and cytochrome p450 epoxygenase protein and mRNA levels were not significantly different. These results confirm that the brain AA cascade is disturbed in BD, and that certain enzymes associated with AA release from membrane phospholipid and with its downstream metabolism are upregulated. As mood stabilizers downregulate many of these brain enzymes in animal models, their clinical efficacy may depend on suppressing a pathologically upregulated cascade in BD. An upregulated cascade should be considered as a target for drug development and for neuroimaging in BD

Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade.

This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E₂ concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A₂ (cPLA₂) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D₂receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA₂ IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients.

3.1. Low Dose Aspirin

In a pharmacoepidemiological study of patients taking lithium for an average duration of 847 days, patients receiving low-dose (30 or 80 mg/day) acetylsalicylic acid (aspirin) were significantly less likely to have a “medication event” (evidence of disease worsening) than patients on lithium alone, independently of use duration.⁴⁴ High dose aspirin given for short periods of time, nonselective COX inhibitors, selective COX-2 inhibitors, or glucocorticoids were not beneficial. As low dose aspirin does not increase serum lithium,⁵²aspirin’s synergistic effect with lithium likely was centrally mediated, particularly because it can enter the brain and inhibit AA metabolism.⁵³ Clinical trials with aspirin in BD currently are underway.⁵⁴

A central positive effect of aspirin in BD is consistent with a report that aspirin given to men undergoing coronary angiography reduced depression and anxiety.⁵⁵ Of relevance, the COX-2 inhibitor celecoxib, although having low brain penetrability,⁵⁶ showed significant positive effects as adjunctive therapy in BD patients experiencing depressive or mixed episodes, and in depressed patients.⁵⁷

The clinical data are consistent with the AA cascade hypothesis. Acetylation of COX-2 by aspirin reduces the ability of the enzyme to convert AA to pro-inflammatory PGE₂. Additionally, acylated COX-2 can convert AA to anti-inflammatory mediators such as lipoxin A4 and 15-epi-lipoxin A4, as well as DHA to anti-inflammatory 17-(R)-OH-DHA.^43a Lithium similarly reduces rat brain COX-2 activity and PGE₂concentration (Table 2), while increasing brain concentrations of 17-hydroxy-DHA and other potential DHA-derived anti-inflammatory metabolites.^43b

3.2. Changing Dietary PUFA Composition Can Suppress Brain Arachidonic Acid Cascade

Brain concentrations of AA and DHA can be altered reciprocally by changing dietary PUFA concentrations, since brain AA and DHA concentrations depend on dietary intake and hepatic elongation from nutritionally essential LA and α-LNA, respectively.⁴⁹ Furthermore, decreases in dietary LA and increases in dietary α-LNA have been reported to be neuroprotective in animal models. In rats, reducing dietary α-LNA below a level considered to be PUFA “adequate” reduces brain DHA concentration and uptake, expression of DHA-selective iPLA₂ VIA, and of brain derived growth factor (BDNF) critical for neuronal integrity,⁵⁸ while it increases AA-metabolizing cPLA₂ IVA, sPLA₂ IIA and COX-2 activities. In contrast, reducing dietary LA below the “adequate” level reduces brain AA concentration, kinetics and enzyme expression, while reciprocally increasing corresponding DHA parameters.⁵⁹

While data are controversial with regard to dietary intervention in the clinic, a cross-national study did identify a significant relation between greater DHA-containing seafood consumption and lower prevalence rates of BD.⁶⁰ Also, a review of clinical trials reported that increased dietary n-3 PUFA in combination with standard treatment improved bipolar depression, even taking into account sample bias.⁶¹ In the future, one might maximize effects of dietary intervention by combining dietary n-3 PUFA supplementation with reduced dietary n-6 PUFA, which when compared to a standard diet was effective in a phase III trial in patients with migraine.⁶² Migraine occurs in 30% of BD patients.⁶³

Inhibitors of the Arachidonic Acid Cascade: Interfering with Multiple Pathways

Modulators of the arachidonic acid cascade have been in the focus of research for treatments of inflammation and pain for several decades. Targeting this complex pathway experiences a paradigm change towards the design and development of multi-target inhibitors, exhibiting improved efficacy and less undesired side effects. This minireview summarizes recent developments in the field of designed multi-target ligands of the arachidonic acid cascade. In addition to the well-known dual inhibitors of 5-lipoxygenase and cyclooxygenase-2 such as licofelone, very recent developments are discussed. Especially, multi-target inhibitors interfering with the cytochrome P450 pathway via inhibition of soluble epoxide hydrolase seem to offer a novel opportunity for development of novel anti-inflammatory drugs.

  

Low-dose aspirin(acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxinA4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders

Conclusion

Chronic low-dose ASA reduces AA-metabolite markers of neuroinflammation and oxidative stress in a rat model for HAND.

Aspirin:a review of its neurobiological properties and therapeutic potential for mentalillness

There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)--6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.

Inflammation, particularly the M1 macrophage response, is accompanied by increased levels of free radicals and O&NS, creating a state in which levels of available antioxidants are reduced. Activation of the immune-inflammatory and O&NS pathways and lowered levels of antioxidants are key phenomena in clinical depression (both unipolar and bipolar), autism, and schizophrenia [2, 3, 4]. Indeed, there is now strong evidence of the involvement of a progressive neuropathologic process in these conditions, with stage-related structural and neurocognitive changes well described for each. Incorporation of these wider factors into traditional monoamine neurotransmitter-system models has facilitated a more comprehensive model of disease, capable of explaining the observed process of neuroprogression. This understanding has facilitated the identification of new therapeutic targets and treatments that have the potential to interrupt the identified neurotoxic cascades [5, 6, 7, 8]. The neuroprotective potential is one of the key promises of agents that target the components of the cascade.

Working mechanisms of aspirin

Aspirin is a non-steroidal anti-inflammatory drug (NSAID), and an irreversible inhibitor of both COX-1 and COX-2. It is more potent in its inhibition of COX-1 than COX-2, and targeting COX-2 alone may be a less viable therapeutic approach in neuropsychiatric disorders such as depression [102]. COX-2 inhibitors may theoretically cause neuroinflammatory reactions, and potentially might augment the Th1 predominance, increase O&NS levels and O&NS-induced damage, decrease antioxidant defenses, and even aggravate neuroprogression [102]. In addition, COX-2 inhibition may interfere with the resolution of inflammation [103]. Thus, COX-2 inhibition decreases the production of prostaglandin E2 (PGE2), which drives the negative immunoregulatory effects on ongoing inflammatory responses. In autoimmune arthritis, for example, PGE2 is part of a negative-feedback mechanism that attenuates the chronic inflammatory response [103]. Therefore, in order to understand the clinical efficacy of aspirin in neuropsychiatric disorders such as depression and schizophrenia, it is more important to consider how its inhibition of COX-1 affects the five aforementioned pathways. This is supported by data suggesting lower response rates to antidepressants in people receiving NSAIDs [104], but is at odds with some recent studies suggesting a benefit for celecoxib, a COX-2 inhibitor, in several disorders including autism and depression [105, 106]. In the following sections, we will discuss the effects of aspirin on these pathways. 

 Arachidonic acid is a type of omega-6 fatty acid that is involved in inflammation. Like other omega-6 fatty acids, arachidonic acid is essential to your health. Omega-6 fatty acids help maintain your brain function and regulate growth. Eating a diet that has a combination of omega-6 and omega-3 fatty acids will lower your risk of developing heart disease. Arachidonic acid in particular helps regulate neuronal activity, the American College of Neuropsychopharmacology explains.

Arachidonic Acid and Eicosanoids

Eicosanoids, derived from arachidonic acid, are formed when your cells are damaged or are under threat of damage. This stimulus activates enzymes that transform the arachidonic acid into eicosanoids such as prostaglandin, thromboxane and leukotrienes. Eicosanoids cause inflammation. Therefore, the more arachidonic acid that is present, the greater capacity your body has to become inflamed. Eicosanoids tend to act locally rather than circulate throughout your body because they degrade quickly.

Other Functions

Arachidonic acid and its metabolites help regulate neurotransmitter release, the American College of Neuropsychopharmacology writes. Arachidonic acid is metabolized so that it may be used to modulate ion channel activities, protein kinases and neurotransmitter uptake systems. Arachidonic acid acts as a substrate that is changed to useful metabolites.

   

Arachidonic Acid and the Gut

In inflammatory bowel disease, prostaglandins are mucosal protective whereas leukotrienes are proinflammatory.

   

The Treatment of Irritable Bowel Syndrome 

Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder routinely encountered by healthcare providers. Although not life-threatening, this chronic disorder reduces patients’ quality of life and imposes a significant economic burden to the healthcare system. IBS is no longer considered a diagnosis of exclusion that can only be made after performing a battery of expensive diagnostic tests. Rather, IBS should be confidently diagnosed in the clinic at the time of the first visit using the Rome III criteria and a careful history and physical examination. Treatment options for IBS have increased in number in the past decade and clinicians should not be limited to using only fiber supplements and smooth muscle relaxants. Although all patients with IBS have symptoms of abdominal pain and disordered defecation, treatment needs to be individualized and should focus on the predominant symptom. This paper will review therapeutic options for the treatment of IBS using a tailored approach based on the predominant symptom. Abdominal pain, bloating, constipation and diarrhea are the four main symptoms that can be addressed using a combination of dietary interventions and medications. Treatment options include probiotics, antibiotics, tricyclic antidepressants, selective serotonin reuptake inhibitors and agents that modulate chloride channels and serotonin. Each class of agent will be reviewed using the latest data from the literature

The efficacy of the calcium channel blocker verapamil was prospectively studied in a group of 129 nonconstipated IBS patients meeting Rome II criteria [Quigley et al. 2007]. In this double-blind study, 12-week study, patients were randomized to receive either placebo or the r-enantiomer of verapamil. Doses were adjusted at 4-week intervals, increasing from 20 mg p.o. t.i.d. to 80 mg p.o. t.i.d. as tolerated. The authors reported that the medication was generally well tolerated, without any significant adverse events being reported. Intention-to-treat analysis showed a significant improvement for the r-verapamil group for both primary efficacy variables compared with control, including global symptom scores (p¼0.0057) and abdominal pain/discomfort (p ¼ 0.05). Although not discussed in this preliminary report, verapamil may improve symptoms by modulating smooth muscle function in the gastrointestinal tract. Further studies are forthcoming from this active research group.

Verapamil alters eicosanoid synthesis and accelerates healing during experimental colitis inrats.

In inflammatory bowel disease, prostaglandins are mucosal protective whereas leukotrienes are proinflammatory. Recent evidence suggests that the formation and action of leukotrienes are calcium-dependent, whereas the formation and action of prostaglandins are not. To examine the possibility that, because of differential regulation of arachidonic acid metabolism, calcium channel blockade might alter mucosal eicosanoid synthesis and accelerate healing during inflammatory bowel disease, we treated a 4% acetic acid-induced colitis model with verapamil and/or misoprostol and determined the effects on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, in vivo intestinal fluid absorption, and mucosal prostaglandin E2 and leukotriene B4 (LTB4) levels as measured by in vivo rectal dialysis. In colitic animals, verapamil treatment significantly improved colonic fluid absorption and macroscopic ulceration. This mucosal-protective effect of verapamil occurred in the presence of a twofold reduction in mucosal LTB4 synthesis. In noncolitic animals, verapamil alone had no effect on in vivo fluid absorption, macroscopic ulceration, or myeloperoxidase activity but did induce a threefold reduction in LTB4 synthesis in addition to shifting arachidonic acid metabolism towards a sixfold stimulation of prostaglandin E2 synthesis. Our results show that, when administered before the experimental induction of colitis, the calcium channel blocker, verapamil, has a mucosal-protective effect that occurs as a consequence of reduced mucosal leukotriene synthesis and increased prostaglandin synthesis. This differential regulation of arachidonic acid metabolism may play an important role in the development of novel therapeutic agents for inflammatory bowel disease.

The comparative effects of calciumchannel blockers in an experimental colitis model in rats

Background/aims: In this study two calcium channel blockers (CCB), diltiazem and verapamil, which demonstrate their effects on two different receptor blockage mechanisms, were assessed comparatively in an experimental colitis model regarding the local and systemic effect spectrum. Methods: Eighty male Swiss albino rats were divided into eight groups (n:10 each): Group I) colitis was induced with 1 ml 4% acetic acid without any medication. Group II) Sham group. Group III) Intra-muscular (IM) diltiazem was administered daily for five days before inducing colitis. Group IV) IM verapamil was administered daily for five days before inducing colitis. Group V) Transrectal (TR) diltiazem was administered with enema daily for two days before inducing colitis. Group VI) TR saline was administered four hours before inducing colitis. Group VII) TR diltiazem was administered with enema four hours before inducing colitis. Group VIII) TR verapamil was administered with enema four hours before inducing colitis. All subjects were sacrified 48 hours after the colitis induction. The distal colon segment was assessed macroscopically and microscopically for the grade of damage, and myeloperoxidase (MPO) activity was measured. Results: All the data of the control colitis group (group I), including the microscopic, macroscopic and MPO activity measurements, were significantly higher than in the groups in which verapamil and diltiazem were administered over seven days (3.100±0.7379 to 1.300+0.9487 and 1.600±0.9661) (p

Ion channel remodelingin gastrointestinal inflammation

Background Gastrointestinal inflammation significantly affects the electrical excitability of smooth muscle cells. Considerable progress over the last few years have been made to establish the mechanisms by which ion channel function is altered in the setting of gastrointestinal inflammation. Details have begun to emerge on the molecular basis by which ion channel function may be regulated in smooth muscle following inflammation. These include changes in protein and gene expression of the smooth muscle isoform of L-type Ca2+ channels and ATP-sensitive K+ channels. Recent attention has also focused on post-translational modifications as a primary means of altering ion channel function in the absence of changes in protein/gene expression. Protein phosphorylation of serine/theronine or tyrosine residues, cysteine thiol modifications, and tyrosine nitration are potential mechanisms affected by oxidative/nitrosative stress that alter the gating kinetics of ion channels. Collectively, these findings suggest that inflammation results in electrical remodeling of smooth muscle cells in addition to structural remodeling. Purpose The purpose of this review is to synthesize our current understanding regarding molecular mechanisms that result in altered ion channel function during gastrointestinal inflammation and to address potential areas that can lead to targeted new therapies.

CONCLUSIONS AND FUTURE DIRECTIONS Inflammation induced changes in electrical excitability of gastrointestinal smooth muscle cells were first established over twenty years ago by sharp microelectrode studies in whole tissue segments.74 We now know of specific changes in both protein expression and post-translational modifications of ion channels that results in electrical remodeling in pathophysiological settings. Important questions still remain with regard to identifying these changes in human GI smooth muscle cells, and what alterations occur in the acute vs. the chronic phases of inflammation. Studies to delineate the pathways for membrane trafficking and ion channel degradation and the influence of inflammation need to be established. It is important to note that each individual ion channel may be modulated at various sites by different ‘oxidative’ elements. Although oxidative stress has been recognized as a key component in gastrointestinal inflammation and alterations in endogenous anti-oxidants have been reported in inflammatory bowel disease, antioxidant therapy still remains in its infancy.  The focus of this review was to highlight the possible mechanisms involved in altered ion channel activity and the different facets of post-translational modifications. The latter also brings into question the role of various endogenous anti-oxidant mechanisms. For example, de-nitrosylation requires specific thioredoxins, oxidation of cysteine residues may be reduced by ascorbate and glutathione, while S-sulfhydration appears to be more stable. Recent studies have also addressed the potential of a ‘denitrase’ which may allow for recovery of tyrosine nitrated proteins. A combination that takes into account the various antioxidant mechanisms could provide an important therapeutic approach in the treatment of gastrointestinal inflammatory disorders particularly towards restoring cellular excitability

Arachidonic Acid and Asthma

Arachidonic acid metabolites: mediators of inflammation in asthma.

Asthma is increasingly recognized as a mediator-driven inflammatory process in the lungs. The leukotrienes (LTs) and prostaglandins (PGs), two families of proinflammatory mediators arising via arachidonic acid metabolism, have been implicated in the inflammatory cascade that occurs in asthmatic airways. The PG pathway normally maintains a balance in the airways; both PGD2 and thromboxane A2 are bronchoconstrictors, whereas PGE2 and prostacyclin are bronchoprotective. The actions of the LTs, however, appear to be exclusively proinflammatory in nature. The dihydroxy-LT, LTB4, may play an important role in attracting neutrophils and eosinophils into the airways, whereas the sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4) produce effects that are characteristic of asthma, such as potent bronchoconstriction, increased endothelial membrane permeability leading to airway edema, and enhanced secretion of thick, viscous mucus. Given the significant role of the inflammatory process in asthma, newer pharmacologic agents, such as the sulfidopeptide-LT antagonists, zafirlukast, montelukast, and pranlukast and the 5-lipoxygenase (5-LO) inhibitor, zileuton, have been developed with the goal of targeting specific elements of the inflammatory cascade. These drugs appear to represent improvements to the existing therapeutic armamentarium. In addition, the results of clinical trials with these agents have helped to expand our understanding of the pathogenesis of asthma.

Arachidonic Acid metabolites and inflammation generally

Prostaglandins and Inflammation

Prostanoids can promote or restrain acute inflammation. Products of COX-2 in particular may also contribute to resolution of inflammation in certain settings. Presently, we have little information on which products of COX-2 might subserve this role or indeed if the dominant factors reflect rediversion of the arachidonic acid substrate to other metabolic pathways consequent to deletion or inhibition of COX-2. As with cyclopentanone prostanoids, many arachidonate derivatives, including transcellular products, when synthesized and administered as exogenous compounds, can promote resolution in models of inflammation. However, rigorous physico-chemical evidence for the formation of the endogenous species in relevant quantities to subserve this role in vivo is limited. Elucidation of whether and how prostanoids might restrain inflammation and how substrate modification, such as with fish oils, might exploit this understanding is currently a focus of much research from which novel therapeutic strategies are likely to emerge.

Autism, Allergies and Summertime Raging in 2016

  

This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.

Not just for Stomach Health

It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.

A single species of gut bacteria can reverse autism-related social behavior in mice

In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.

Mefenamic acid (Ponstan) for some Autism

Caution:-

Ponstan (Mefenamic Acid) contains a warning:-

Caution should be exercised when treating patients suffering from epilepsy.

At lower doses Ponstan is antiepileptic, but at high doses it can have the opposite effect.  This effect depends on the biological origin of the seizures.

In an earlier post I wrote about a paper by Knut Wittkowski who applied statistics to interpret the existing genetic data on autism. 

“Autism treatments proposed by clinical studies and human genetics are complementary” & the NSAID Ponstan as a Novel AutismTherapy

His analysis suggested the early use of Fenamate drugs could potentially reduce the neurological anomalies that develop in autism as the brain develops.  The natural question arose in the comments was to whether it is too late to use Fenamates in later life.

Knut was particularly looking at a handful of commonly affected genes (ANO 2/4/7 & KCNMA1) where defects should partially be remedied by use of fenamates.

I recently received a comment from a South African reader who finds that his children’s autism improves when he gives them Ponstan and he wondered why.  Ponstan (Mefenamic Acid) is a fenamate drug often used in many countries as a pain killer, particularly in young children.

Ponstan is a cheap NSAID-type drug very widely used in some countries and very rarely used in other countries like the US.  It is available without prescription in some English-speaking countries (try a pharmacy in New Zealand, who sell online) and, as Petra has pointed out, it is widely available in Greece.

I did some more digging and was surprised what other potentially very relevant effects Ponstan has.  Ponstan affects GABA_A receptors, where it is a positive allosteric modulator (PAM).  This may be very relevant to many people with autism because we have seen that fine-tuning the response of the sub-units that comprise GABA_A receptors you can potentially improve cognition and also modulate anxiety. 

Anxiety seems to be a core issue in Asperger’s, whereas in Classic Autism, or Strict Definition Autism (SDA) the core issue is often actually cognitive function rather than “autism” as such.

In this post I will bring together the science showing why Ponstan should indeed be helpful in some types of autism.

Professor Ritvo from UCLA read Knut’s paper and also the bumetanide research and suggested that babies could be treated with Ponstan and then, later on, with  Bumetanide.

Autism treatments proposed by clinical studies and human genetics are complementary

I do not think the professor or Knut are aware of Ponstan’s effect on GABA.

The benefits from Ponstan may very well be greater if given to babies at risk of autism, but there does seem to be potential benefit for older children and adults, depending on their type of autism.

Professor Ritvo points out that that Ponstan is safely used in 6 month old babies, so trialing it in children and adults with autism should not be troubling.

Being an NSAID, long term use at high doses may well cause GI side effects.  An open question is the dosage at which Ponstan modulates the calcium activated ion channels that are implicated in some autism and also what dosage affects GABA_A receptors.  It might well be lower than that required for Ponstan’s known ant-inflammatory effects.

Ponstan vs Ibuprofen

Ibuprofen is quite widely used in autism.  Ibuprofen is an NSAID but also a PPAR gamma agonist.  Ponstan is an NSAID but has no effect on PPAR gamma.

Research shows that some types of autism respond to PPAR gamma agonists.

So it is worth trying both Ponstan and Ibuprofen, but for somewhat different reasons.

They are both interesting to deal with autism flare-ups, which seem common.

Other drugs that people use short term, but are used long term in asthma therapy,  are Singulair (Montelukast) and an interesting Japanese drug called Ibudilast.  Singulair is a Western drug for maintenance therapy in asthma.  Ibudilast is widely used in Japan as maintenance therapy in Asthma, but works in a different way.  Ibudilast is being used in clinical trials in the US to treat Multiple Sclerosis.  Singulair is cheap and widely available, Ibudilast is more expensive and available mainly in Japan.

Pre-vaccination Immunomodulation

In spite of there being no publicly acknowledged link between vaccinations and autism secondary to mitochondrial disease (AMD), I read that short term immunomodulation is used prior to vaccination at Johns Hopkins, for some babies.

Singulair is used, as is apparently ibuprofen.  Ponstan and Ibudilast would also likely be protective.   Ponstan might well be the best choice; it lowers fevers better than ibuprofen.

For those open minded people, here is what a former head of the US National Institutes of Health, Bernadine Healy, had to say about the safe vaccination.  Not surprisingly she was another Johns Hopkins trained doctor, as is Hannah Poling’s Neurologist father.

The Vaccines-Autism War: Détente Needed

“Finally, are certain groups of people especially susceptible to side effects from vaccines, and can we identify them? Youngsters like Hannah Poling, for example, who has an underlying mitochondrial disorder and developed a sudden and dramatic case of regressive autism after receiving nine immunizations, later determined to be the precipitating factor. Other children may have a genetic predisposition to autism, a pre-existing neurological condition worsened by vaccines, or an immune system that is sent into overdrive by too many vaccines, and thus they might deserve special care. This approach challenges the notion that every child must be vaccinated for every pathogen on the government's schedule with almost no exception, a policy that means some will be sacrificed so the vast majority benefit.”

So if I was an American running the FDA/CDC I would suggest giving parents the option of paying a couple of dollars for 10 days of Ponstan prior to these megadose vaccinations and a few days afterwards.  No harm or good done in 99.9% of cases, but maybe some good done for the remainder.

The fact the fact that nobody paid any attention to the late Dr Healy on this subject tells you a lot.

Fenamates (ANO 2/4/7 & KCNMA1)

Here Knut is trying to target the ion channels expressed by the genes ANO 2/4/7 & KCNMA1. 

·        ANO 2/4/7 are calcium activated chloride channels. (CACCs)

·        KCNMA1 is a calcium activated potassium channel.  KCNMA1encodes the ion channel K_Ca1.1, otherwise known as BK (big potassium).  This was the subject of post that I never got round to publishing.

  

Fenamates are an important group of clinically used non-steroidal anti-inflammatory drugs (NSAIDs), but they have other effects beyond being anti-inflammatory.  They act as CaCC inhibitors and also stimulate BKCa channel activity.

But fenamates also have a potent effect on what seems to be the most dysfunctional receptor in classic autism, the GABAA receptor.

Characterization of the interaction between fenamates and hippocampal neuron GABAA receptors

The fenamate NSAID, mefenamic acid (MFA) prevents convulsions and protects rats from seizure-induced forebrain damage evoked by pilocarpine (Ikonomidou-Turski et al., 1988) and is anti-epileptogenic against pentylenetetrazol (PTZ)-induced seizure activity, but at high doses induces seizures (Wallenstein, 1991). In humans, MFA overdose can lead to convulsions and coma (Balali-Mood et al, 1981; Young et al., 1979; Smolinske et al., 1990). More recent data by Chen and colleagues (1998) have shown that the fenamates, flufenamic, meclofenamic and mefenamic acid, protect chick embryo retinal neurons against ischaemic and excitotoxic (kainate and NMDA) induced neuronal cell death in vitro (Chen et al., 1998a; 1998b). MFA has also been reported to reduce neuronal damage induced by intraventricular amyloid beta peptide (Aβ1-42) and improve learning in rats treated with Aβ1-42 (Joo et al., 2006). The mechanisms underlying these anti-epileptic and neuroprotective effects are not well understood but together suggest that fenamates may influence neuronal excitability through modulation of ligand and/or voltage-gated ion channels. In the present study, therefore, we have investigated this hypothesis by determining the actions of five representative fenamate NSAIDs at the major excitatory and inhibitory ligand-gated ion channels in cultured hippocampal neurons

This study demonstrates for the first time that mefenamic acid and 4 other representatives of the fenamate NSAIDs are highly effective and potent modulators of native hippocampal neuron GABAA receptors. MFA was the most potent and at concentrations equal to or greater than 10 μM was also able to directly activate the GABAA gated chloride channel. A previous study from this laboratory reported that mefenamic acid potentiated recombinant GABAA receptors expressed in HEK-293 cells and in Xenopus laevis oocytes (Halliwell et al., 1999). Together these studies lead to the conclusion that fenamate NSAIDs should now also be considered a robust class of GABAA receptor modulators.

Also demonstrated for the first time here is the direct activation of neuronal GABAA receptors by mefenamic acid. Other allosteric potentiators, including the neuroactive steroids and the depressant barbiturates share this property, with MFA at least equipotent to neurosteroids and significantly more potent than the barbiturates. The mechanism(s) of the direct gating of GABAA receptor chloride channels by MFA requires further investigation using ultra-fast perfusion techniques but may be distinct from that reported for neurosteroids (see, Hosie et al., 2006). Mefenamic acid induced a leftward shift in the GABA dose-response curve consistent with an increase in receptor affinity for the agonist. This is an action observed with other positive allosteric GABAA receptor modulators, including the benzodiazepine agonist, diazepam, the neuroactive steroid, allopregnanolone, and the intravenous anesthetics, pentobarbitone and propofol (e.g. Johnston, 2005). To our knowledge, a unique property of MFA was that it was significantly (F = 10.35; p≤ 0.001) more effective potentiating GABA currents at hyperpolarized holding potentials (especially greater than −60mV). Further experiments are required however to determine the underlying mechanism(s).

The highly effective modulation of GABAA receptors in cultured hippocampal neurons suggests the fenamates may have central actions. Consistent with this hypothesis, mefenamic acid concentrations are 40–80μM in plasma with therapeutic doses (Cryer & Feldman, 1998); fenamates can also cross the blood brain barrier (Houin et al., 1983; Bannwarth et al., 1989) Coyne et al. Page 5 Neurochem Int. Author manuscript; available in PMC 2008 November 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript and in overdose in humans are associated with coma and convulsions (Smolinske et al., 1990). In animal studies, mefenamic acid is anticonvulsant and neuroprotective against seizureinduced forebrain damage in rodents (Ikonomidou-Turski et al., 1988). The present study would suggest that the anticonvulsant effects of fenamates may be related, in part, to their efficacy to potentiate native GABAA receptors in the brain, although a recent study has suggested that activation of M-type K+ channels may contribute to this action (Peretz et al., 2005) Finally, Joo and co-workers (2006) have recently reported that mefenamic acid provided neuroprotection against β-amyloid (Aβ1-42) induced neurodegeneration and attenuated cognitive impairments in this animal model of Alzheimer’s disease. The authors proposed that neuroprotection may have resulted from inhibition of cytochrome c release from mitochondria and reduced caspase-3 activation by mefenamic acid. Clearly it would also be of interest to evaluate the role of GABA receptor modulation in this in vivo model of Alzheimer’s disease. Moreover, considerable evidence has emerged in the last few years indicating that GABA receptor subtypes are involved in distinct neuronal functions and subtype modulators may provide novel pharmacological therapies (Rudolf & Mohler, 2006). Our present data showing that fenamates are highly effective modulators of native GABAA receptors and that mefenamic acid is highly subtype-selective (Halliwell et al., 1999) suggests that further studies of its cognitive and behavioral effects would be of value.

  

Note in the above paper that NSAIDs other than mefenamic acid also modulate GABAA receptors.

Just a couple of months ago a rather complicated paper was published, again showing that NSAIDs modulate GABA_A receptors and showing that this is achieved via the same calcium activated chloride channels (CaCC) referred to by Knut.

NSAIDs modulate GABA-activated currents via Ca²⁺-activated Cl⁻ channels in rat dorsal root ganglion neurons

"Schematic displaying the effects of CaCCs on GABA-activated inward currents and depolarization. GABA activates the GABA_A receptor to open the Cl ⁻ channel and the Cl⁻ efflux induces the depolarization response (inward current) of the membrane of dorsal root ganglion (DRG) neurons. Then, voltage dependent L-type Ca²⁺ channels are activated by the depolarization, and give rise to an increase in intracellular Ca²⁺. CaCCs are activated by an increase in intracellular Ca²⁺ concentration which, in turn, increases the driving force for Cl⁻ efflux. Finally, the synergistic action of the chloride ion efflux through GABA_A receptors and NFA-sensitive CaCCs causes GABA-activated currents or depolarization response in rat DRG neurons."

Note in the complex explanation above the L-type calcium channels, which are already being targeted by Verapamil, in the PolyPill.

Mefenamic Acid and Potassium Channels

We know that Mefenamic acid also affects K_v7.1 (KvLQT1).

A closely related substance called meclofenamic acid is known to act as novel KCNQ2/Q3 channel openers and is seen as having potential for the treatment of neuronal hyper-excitability including epilepsy, migraine, or neuropathic pain.

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel  subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC50  25 M) and diclofenac (EC50  2.6 M) resulted in the activation of KCNQ2/Q3 K currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (23 and 15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel  subunits. In contrast, they did not enhance KCNQ1 K currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED50  43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain. Volt

BK channel

KCNMA1encodes the ion channel K_Ca1.1, otherwise known as BK (big potassium). BK channels are implicated not only by Knut’s statistics, but numerous studies ranging from schizophrenia to Fragile X. 

Usually it is a case of too little BK channel activity.

The BK channel is implicated in some epilepsy.

  

Pharmacology

BK channels are pharmacological targets for the treatment of several medical disorders including stroke and overactive bladder. Although pharmaceutical companies have attempted to develop synthetic molecules targeting BK channels, their efforts have proved largely ineffective. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo. However, BKCa channels are reduced in patients suffering from the Fragile X syndrome and the agonist, BMS-204352, corrects some of the deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome.

BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide and hydrogen sulphide.

BK channels can be readily inhibited by a range of compounds including tetraethylammonium (TEA), paxilline and iberiotoxin.

BK channel dysfunction and neurological disorders

Achieving a better understanding of BK channel function is important not only for furthering our knowledge of the involvement of these channels in physiological processes, but also for pathophysiological conditions, as has been demonstrated by recent discoveries implicating these channels in neurological disorders. One such disorder is schizophrenia where BK channels are hypothesized to play a role in the etiology of the disease due to the effects of commonly used antipsychotic drugs on enhancing K⁺ conductance [101]. Furthermore, this same study found that the mRNA expression levels of the BK channel were significantly lower in the prefrontal cortex of the schizophrenic group than in the control group [101]. Similarly, autism and mental retardation have been linked to haploinsufficiency of the Slo1 gene and decreased BK channel expression [102].

Two mutations in BK channel genes have been associated with epilepsy. One mutation has been identified on the accessory β3 subunit, which results in an early truncation of the protein and has been significantly correlated in patients with idiopathic generalized epilepsy [103]. The other mutation is located on the Slo1gene, and was identified through genetic screening of a family with generalized epilepsy and paroxysmal dyskinesia [104]. The biophysical properties of this Slo1 mutation indicates enhanced sensitivity to Ca²⁺ and an increased average time that the channel remains open [104–107]. This increased Ca²⁺ sensitivity is dependent on the specific type of β subunit associating with the BK channel [106, 107]. In association with the β3 subunit, the mutation does not alter the Ca²⁺-dependent properties of the channel, but with the β4 subunit the mutation increases the Ca²⁺ sensitivity [105–107]. This is significant considering the relatively high abundance of the β4 subunit compared to the weak distribution of the β3 subunit in the brain [12, 13,15, 106, 107]. It has been proposed that a gain of BK channel function may result in increases in the firing frequency due to rapid repolarization of APs, which allows a quick recovery of Na⁺ channels from inactivation, thereby facilitating the firing of subsequent APs [104]. Supporting this hypothesis, mice null for the β4 subunit showed enhanced Ca²⁺ sensitivity of BK channels, resulting in temporal lobe epilepsy, which was likely due to a shortened duration and increased frequency of APs [108]. An interesting relevance to the mechanisms of BK channel activation as discussed above, the Slo1 mutation associated with epilepsy only alters Ca²⁺ dependent activation originated from the Ca²⁺ binding site in RCK1, but not from the Ca²⁺bowl, by altering the coupling mechanism between Ca²⁺ binding and gate opening [100]. Since Ca²⁺dependent activation originated from the Ca²⁺ binding site in RCK1 is enhanced by membrane depolarization, at the peak of an action potential the binding of Ca²⁺ to the site in RCK1 contributes much more than binding to the Ca²⁺ bowl to activating the channel [84, 109].

Although these associations between specific mutations in BK channel subunits and various neurological disorders have been demonstrated by numerous studies, it is also important to point out certain caveats with these studies, such as genetic linkage between BK channels and different diseases do not necessary show causation as these studies were performed based on correlation between changes in the protein/genetic marker and overall phenotype. Furthermore, studies performed using a mouse model also can fail to indicate what may happen in higher-order species, and this is especially true for BK channels, where certain β subunits are only primate specific [110].

  

Possible role of potassium channel, big K in etiology of schizophrenia.

Schizophrenia (SZ), a common severe mental disorder, affecting about 1% of the world population. However, the etiology of SZ is still largely unknown. It is believed that molecules that are in an association with the etiology and pathology of SZ are neurotransmitters including dopamine, 5-HT and gamma-aminobutyric acid (GABA). But several lines of evidences indicate that potassium large conductance calcium-activated channel, known as BK channel, is likely to be included. BK channel belongs to a group of ion channels that plays an important role in regulating neuronal excitability and transmitter releasing. Its involvement in SZ emerges as a great interest. For example, commonly used neuroleptics, in clinical therapeutic concentrations, alter calcium-activated potassium conductance in central neurons. Diazoxide, a potassium channel opener/activator, showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms in SZ. Additionally, estrogen, which regulates the activity of BK channel, modulates dopaminergic D2 receptor and has an antipsychotic-like effect. Therefore, we hypothesize that BK channel may play a role in SZ and those agents, which can target either BK channel functions or its expression may contribute to the therapeutic actions of SZ treatment.

Conclusion

It appears that Ponstan and related substances have some interesting effects that are only now emerging in the research.

People with autism, and indeed schizophrenia, may potentially benefit from Ponstan and for a variety of different reasons.

I think it will take many decades for any conclusive research to be published on this subject, because this is an off-patent generic drug.

As with most NSAIDS, it is simple to trial Ponstan.

Thanks to Knut for the idea, Professor Ritvo for his endorsement of the idea and our reader from South Africa for sharing his positive experience with Ponstan.