Showing posts with label Omega-3. Show all posts
Showing posts with label Omega-3. Show all posts

Tuesday, 25 October 2016

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.

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


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.

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.

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

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.

Tuesday, 19 May 2015

ASD variants - (mis and missed) diagnoses. Calcium ion channel dysfunctions Cav1.1, 1.2, 1.3 and 1.4

This post serves to introduce some ideas relevant to a post that is will shortly arrive on calcium ion channel dysfunctions (Cav1.1, 1.2, 1.3 and 1.4).

As we have seen, nearly all behavioral and psychiatric disorders are just diagnosed based on observation.  Only in very rare cases is the underlying biological problem diagnosed.  So it is fair to say that these are not accurate medical diagnoses.

Under the wide umbrella term of ASD are likely hundreds of thousands of  discrete variants, since ASD generally results from the combination of multiple hits/dysfunctions.  A single one of these dysfunctions is usually not enough to trigger autism, but some may indeed trigger something else noticeable.  A small number of individual hits, like Fragile-X and Retts can trigger autism, but these are the exception.

Mis and Missed diagnoses

One reader of this blog received a diagnosis for his child as “late onset regressive autism or possible childhood disintegrative disorder”.  Neither of these options is very good, since you are talking about an entirely typical child who, after the age of four, begins to regress and lose his acquired skills.

After a long struggle, he found the biological diagnosis, which is mitochondrial disease.  After a few months of the Richard Kelley (from Johns Hopkins), therapy the regression was halted and now new skills are again being acquired.

This is another example of how unacceptable simple observational diagnoses are.  What would have happened if the reader had not stumbled upon this blog and then later sought out help from the leading experts (just look on my Dean’s list)?

Attention Deficit Disorder (ADHD)

ADHD is very commonly diagnosed in the US, much more so than in other countries.  More severe cases of ADHD look much like ASD, which is why I call them autism-lite.

Another group of ADHD may indeed be purely behavioral – too much time with smart phones, iPads and video games.  This is supported by the fact that the data on incidence of ADHD shows that a large group of children with ADHD, “grow out of it”, or were misdiagnosed in the first place.

However, it does look like there is another group of ADHD which is biological, but may be different to autism.  On this subject I will bring you the comments of Dr. Manuel Casanova, a neurologist and along with that, thoughtful and knowledgeable about autism. 

Then we have the recurring clinical trials on high EPA/DHA fish oil, which really do show an effect in most trials in ADHD, but fail in most trials in autism.  This will be developed further in the later post on calcium channels.  The suggested view is that either the vitamin A, or the omega 3 oil, is somehow helping and even perhaps some people have a problem absorbing some types of vitamin A.  I was always unconvinced by this. 

However, it has now been shown that the EPA in fish oil has an effect on certain L-type calcium channels.  If you had a mild dysfunction (channelopathy) of one of the L-type calcium channels, then a big enough dose of EPA might have an effect on them.  This becomes more interesting when you learn that some doctors in the US think that dyslexia is another autism-lite.

One suggested cause of dyslexia is visual deficit that makes reading difficult, but it also accompanied by a difficulty seeing in the dark.  This night blindness is known to be caused by vitamin A deficiency (or an inability to absorb it properly) and also by an ion channel dysfunction in Cav1.4.

It appears that the high EPA fish oil would increase vitamin A and also affect the function of Cav1.4.  The calcium ion channel Ca1.4 is widely expressed in your eyes.

Another interesting point is that it is thought that a dysfunction in one type of Calcium channel will often affect the function of others.  This is important because when you look at the effect of dysfunctions in these channels you will a listing including:-

·        Autism (Timothy Sydrome)
·        Mood disorder
·        Depression
·        Bipolar

As well as things like

·        Night blindness
·        Heart defects (Timothy Sydrome)

We also should note that many people (without autism) with sight problems claim improvement from taking high EPA fish oil.


Dyslexia is the most common learning disability. It affects about 3 to 7 percent of people. While it is diagnosed more often in males, some believed it affects males and females equally. Up to 20 percent of the population may have some degree of symptoms

Dyslexia and attention deficit hyperactivity disorder (ADHD) commonly occur together; about 15 percent of people with dyslexia also have ADHD and 35 percent of those with ADHD have dyslexia.

The causes appear to be genetic and epigenetic. For example the gene KIAA0319

People usually think of dyslexia only in children, but that may be because many adults do not read very much.  Or do they "grow out of it".


“It affects about 6–7% of children when diagnosed via the DSM-IV criteria and 1–2% when diagnosed via the ICD-10 criteria.  Rates are similar between countries and depend mostly on how it is diagnosed. ADHD is diagnosed approximately three times more in boys than in girls. About 30–50% of people diagnosed in childhood continue to have symptoms into adulthood.”

So it would seem that most people “grow out” of ADHD 

Dr. Manuel Casanova

Dr. Manuel Casanova is a neurologist and along with that is clever, thoughtful and knowledagable about autism.  He looks at measurable anatomical differences and how these may be related to behaviour.  So he is more into the consequences of unchangeable differences in brains.

If you start looking at ion channels and transporters as being key drivers in behaviour then you have the chance to make alterations.  We saw that the same applies to fine tuning the function and indeed structure of key neurotransmitter receptors.

In lay terms, Manuel is showing how brains are indeed “hardwired” differently in many cases of autism, ADHD and even dyslexia.  This might reinforce the old view that really it is “case closed” and nothing more can be done.

However the really clever scientists looking in greater depth show us that notwithstanding some structural variation, much of the problem lies in the aspects of the brain that can be modified and indeed some are constantly in a state of change, for example the shape of dendritric spines and indeed the very substructure of those  GABAA receptors.

He groups dyslexia with ADHD and sees them as fundamentally different to autsim.  Having said that, Manuel tells us that attention disorders may be found in close to 30% of autistic individuals

 He has his own blog.

I suggest you read his full article, but here are some excerpts:-

“Claiming that there is comorbidity across neurodevelopmental disorders based on a single behavioral symptom negates many aspects of the individuality of each condition. In this regard, there are marked differences in the cognitive styles of dyslexic or ADHD individuals and those within the autism spectrum. Dyslexics enjoy a top-down cognitive style, tend to be holistically-oriented and have a gestalt processing bias (e.g., they see the forest but lose track of the individual trees). They are considered to have strong central coherence and excel in synthesizing sensory or cognitive experiences. Individuals within the autism spectrum enjoy a bottom-up cognitive style which makes them detail-oriented. Thus, contrary to dyslexic/ADHD subjects, ASD individuals see the tree but tend to lose sight of the forrest. In addition, they have a local processing bias with weak central coherence and appear to be good analyzers.”

“The above related differences in cognitive style appear to have anatomical correlates. As compared to neurotypicals, dyslexics tend to have smaller brain volumes with a concomitant striking increase in the size of their corpus callosum (the white matter projections that join homologous areas in both cerebral hemispheres). In addition, they have a simplification of their convolutional pattern and their cortical modules for information processing (minicolumns) are wider than expected. We find completely the opposite in patients within the autism spectrum.”

Yet more labels

Since we will be looking at calcium channels and one thing that does affect them is EPA, we should look at another label, dyspraxia, which also is reportedy  affected by fatty acids.
Fatty Acids in Dyslexia, Dyspraxia, ADHD and the Autistic Spectrum

What is Dyspraxia, also known as Developmental Coordination Disorder (DCD) ?

Dyspraxia, also known as Developmental coordination disorder (DCD), is is a chronic neurological disorder beginning in childhood that can affect planning of movements and co-ordination as a result of brain messages not being accurately transmitted to the body.

People with developmental coordination disorder sometimes have difficulty moderating the amount of sensory information that their body is constantly sending them, so as a result dyspraxics are prone to sensory overload and panic attacks.
Many dyspraxics struggle to distinguish left from right, even as adults, and have extremely poor sense of direction generally.

Moderate to extreme difficulty doing physical tasks is experienced by some dyspraxics, and fatigue is common because so much extra energy is expended while trying to execute physical movements correctly. Some (but not all) dyspraxics suffer from hypotonia, low muscle tone, which like DCD can detrimentally affect balance.

Gross motor control

Whole body movement, motor coordination, and body image issues mean that major developmental targets including walking, running, climbing and jumping can be affected. The difficulties vary from person to person and can include the following:

  • Poor timing
  • Poor balance (sometimes even falling over in mid-step). Tripping over one's own feet is also common.
  • Difficulty combining movements into a controlled sequence.
  • Difficulty remembering the next movement in a sequence.
  • Problems with spatial awareness, or proprioception.
  • Some people with developmental coordination disorder have trouble picking up and holding onto simple objects such as pencils, owing to poor muscle tone and/or proprioception.
  • This disorder can cause an individual to be clumsy to the point of knocking things over and bumping into people accidentally.
  • Some people with developmental coordination disorder have difficulty in determining left from right.
  • Cross-laterality, ambidexterity, and a shift in the preferred hand are also common in people with developmental coordination disorder.
  • Problems with chewing foods.

Fine motor control

Fine-motor problems can cause difficulty with a wide variety of other tasks such as using a knife and fork, fastening buttons and shoelaces, cooking, brushing one's teeth, styling one's hair, shaving, applying cosmetics, opening jars and packets, locking and unlocking doors, and doing housework.

Difficulties with fine motor co-ordination lead to problems with handwriting, which may be due to either ideational or ideo-motor difficulties. Problems associated with this area may include:
  • Learning basic movement patterns.
  • Developing a desired writing speed.
  • Establishing the correct pencil grip
  • The acquisition of graphemes – e.g. the letters of the Latin alphabet, as well as numbers.

Associated disorders

People who have developmental coordination disorder may also have one or more of these co-morbid problems:

Dysjustabouteverything (DJE)

If you consider the early years of classic autism, you will see that, in many cases, it includes all of the above disorders, even hypertonia.

But some people are otherwise pretty much typical/normal, are diagnosed with a single disorder like dyscalculia.

The problem is that these are all just observational diagnoses.  Does something biological underlie and connect them?  I think it does.

An autistic person’s struggles with mathematics may be more to do with a problem of understanding the language used to explain it.  This is why, in many cases, they struggle to move beyond counting.  Special methods of teaching maths have been created for such people, but they only take you to an elementary level.

If you have Asperger’s, you have no problem with the language used to explain the concepts or to frame the questions.  Some people with Asperger’s excel at mathematics.

The same is true for dysgraphia, autistic people tend to have very scruffy handwriting, but does this mean that they have dysgraphia? 

Hypotonia is an interesting one.  Many parents report low muscle tone and indeed DAN doctors actually treat it (apparently with Creatine).  I think hypotonia, if present in autism, is likely to be connected to the disruption in the various growth factors that has occurred and this itself may related to GABAB dysfunctions. (I mentioned this connection in an earlier post).  In Monty, aged 11 with ASD, when he was a baby he had Hypertonia.  He was big and all muscle.  As he got older he slid down from the 80-90Th percentile to the 20th percentile.  This fits one very distinct pattern of classic autism.

In the case of Monty, almost all the earlier signs of Dysjustabouteverything have now vanished.  Is this always the case?  Why would that happen in some people and not others?  Did his Polypill interventions play a role?

To investigate

What we need to know is whether there is a common link between all these various “dys-disorders”.

Probably in some (mis/over-diagnosed) people there is no link; but in others there may well be.

In some people there really is a link.  I did not tell you that my old “favourite”, hypokalemic periodic paralysis (HPP), can be caused by a Cav1.1 dysfunction.  HPP-lite is something called hypokalemic sensory overload.  In a little experiment I demonstrated that autistic sensory overload can be just hypokalemic sensory overload.  You just need 250 mg of potassium and a disturbing noise or light to illustrate it.  This is also a symptom of what they call Dyspraxia.

So Cav1.1 associates with HPP (hypokalemic periodic paralysis) and by my inference, sensory overload and some hypotonia;  Cav1.2 associates directly with autism (Timothy Syndrome) and bipolar; Cav1.3 associates with mood disorders, depression, bipolar; Cav1.4 associates with night blindness and perhaps some dyslexia.
A dysfunction in one L-type channel (Cav1.1, Cav1.2, Cav1.3 and Cav1.4) can apparently cause dysfunction in the others.  This surprised me.

So if you have autism, is not surprising if you appear afraid of the dark, feel depressed, experience sensory overload and are not very muscular.

The good news is that much of this appears to be treatable.

For the scientists among you:-


Voltage-dependent L-type calcium channel subunit beta-2 is a protein that in humans is encoded by the CACNB2 gene

I did forget to remind readers that I see the label schizophrenia as just another name for adult onset autism.

So it is no surprise that adults with autism have a 22 times higher chance of also being diagnosed with schizophrenia compared to non-ASD people.  Note bipolar, OCD etc; and this does not include all those adults with autism who get forgotten.


I am not suggesting “medicalizing” people with dyslexia, or indeed most with ADHD. 
However, it might be useful for somebody affected to know if Cav1.1 to 1.4 were dysfunctional, then at critical moments, like exam time at school, you could indeed give them some extra help.

People with dyslexia, and I presume other “dys-disorders” do often get given extra time at school for exams.  People with ADHD are often entitled to financial benefits in developed countries, and it has been suggested that these countries are the ones with high incidence of diagnosis.  In the US 11% of children and 4.4% of adults have a diagnosis.   ADHD has been medicalized in the U.S. since the 1960s.  In the UK, 3.62% of boys and 0.85% of girls have an ADHD diagnosis.  In France less than 0.5% of children are taking medication for ADHD.

Here is a nice quote:-

Why Are ADHD Rates 20 Times Higher in the U.S. Than in  France?

“it makes perfect sense to me that French children don't need medications to control their behavior because they learn self-control early in their lives. The children grow up in families in which the rules are well-understood, and a clear family hierarchy is firmly in place.

In French families, as Druckerman describes them, parents are firmly in charge of their kids—instead of the American family style, in which the situation is all too often vice versa.”

In the case of ADHD, it looks like the French have got it right; but not sadly for autism.

Knowing many different nationalities, I can certainly confirm that French parenting is much tougher than the UK or US variety.  The UK variety is very similar to the US, but without the liberal use of drugs for ADHD or indeed autism.

In tough cases of ADHD, that even French parenting cannot control, perhaps it really is a calcium channelopathy.  Perhaps in these cases a mild calcium channel blocker like fish oil, or indeed Olive Leaf Extract may be potent enough, so you could use these daily without the need for any prescription medication.

In any case, Verapamil, if shown effective, looks a much safer bet than the usual ADHD stimulants like Ritalin.  If your ADHD was caused by calcium channel dysfunction, it would likely later appear elsewhere in your body; all those years on stimulants would not have helped you.

Recall that Verapamil can also be effective in bipolar.