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.
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.
