¶ arachidonic acid
Merged from 2 sources — review for redundancy.
¶ From nutrition/
¶ Definition
Arachidonic acid (AA, 20:4 n-6) is an omega-6 polyunsaturated fatty acid synthesized from dietary linoleic acid via delta-6 and delta-5 desaturases. Stored in neuronal and immune cell membrane phospholipids, AA serves as the primary precursor to pro-inflammatory eicosanoid mediators (Prostaglandins, thromboxanes, leukotrienes) and the substrate for PLA2G7-mediated production of pronociceptive oxylipins that activate TRPV1 pain receptors. In evolutionary context, AA was scarce and tightly regulated; modern Western diets create chronic AA excess, driving peripheral neuropathy, chronic inflammation, and pain syndromes.
¶ Picture It
Think of arachidonic acid as pre-cut kindling stored in your cell membranes. In evolutionary times, this kindling was rare and precious—just enough to start a controlled fire (acute inflammation) when needed. PLA2G7 is the match that ignites it: when struck by stress or injury, it cleaves AA from the membrane and tosses it into three different furnaces (COX, LOX, P450 enzymes), each producing different types of inflammatory "smoke signals"—Prostaglandins that recruit immune cells, thromboxanes that make blood sticky, leukotrienes that dilate blood vessels, and oxylipins that directly scream at pain nerves.
Now imagine a modern warehouse (your neurons) packed floor-to-ceiling with kindling because your diet delivers truck-loads of linoleic acid daily (15-20% of calories vs. 2-3% ancestrally). The matches haven't changed, but now every spark creates an inferno. Worse, this kindling doesn't just sit in storage—it literally becomes part of the membrane structure, replacing the fireproof insulation (omega-3s like DHA) that should be there. The warehouse becomes inherently flammable. In dorsal root ganglia neurons, this means constant low-grade burning—the oxylipins keep activating TRPV1 pain channels even without injury. The fire alarm (pain) never stops ringing because the building itself is made of matches.
The evolutionary mismatch is stark: omega-6:omega-3 ratios of 15-20:1 in modern diets versus 1-4:1 ancestrally means we're running a chronic inflammatory state as baseline—what should be an acute response tool (AA → eicosanoids → resolve) has become permanent background noise.
¶ Mechanism
¶ AA Liberation and Metabolism
Arachidonic acid is released from membrane phospholipids via two pathways:
- Phospholipase A2 (especially PLA2G7) cleaves AA directly from sn-2 position → produces free AA + lysophospholipids
- Phospholipase C → diacylglycerol → diacylglycerol lipase → AA release
Once liberated, AA enters three enzymatic pathways:
¶ COX Pathway (Cyclooxygenase)
- COX-1 (constitutive): AA → PGG₂ → PGH₂ → tissue-specific synthases
- COX-2 (inducible by NF-κB, IL-1β, TNF-α): AA → PGG₂ → PGH₂
- PGH₂ → prostaglandin E2 (PGE2) via PGE synthase → binds EP receptors → ↑ cAMP → sensitizes nociceptors, ↑ fever, ↑ vascular permeability
- PGH₂ → thromboxane A₂ (TXA₂) → TP receptor → platelet aggregation, vasoconstriction
- PGH₂ → prostacyclin (PGI₂) → IP receptor → vasodilation, ↓ platelet aggregation
¶ LOX Pathway (Lipoxygenase)
- 5-LOX: AA → 5-HPETE → leukotriene A₄ (LTA₄)
- LTA₄ → leukotriene B4 (LTB₄) via LTA₄ hydrolase → BLT1 receptor → neutrophil chemotaxis
- LTA₄ → cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) → CysLT receptors → bronchoconstriction, mucus secretion
- 12-LOX: AA → 12-HPETE → platelet activation
- 15-LOX: AA → 15-HPETE → eosinophil recruitment (also generates lipoxins in presence of aspirin)
¶ CYP450 Pathway
- Epoxygenases: AA → epoxyeicosatrienoic acids (EETs) → vasodilation, anti-inflammatory (rapidly degraded by soluble epoxide hydrolase)
- Hydroxylases: AA → hydroxyeicosatetraenoic acids (HETEs) → chemotaxis, inflammation, TRPV1 activation
¶ Neuronal AA Accumulation and Pain
Linoleic acid → delta-6 desaturase → gamma-linolenic acid → delta-5 desaturase → arachidonic acid → incorporates into neuronal membrane phospholipids (half-life: months to years)
High-LA diets → ↑ AA in dorsal root ganglia phospholipids → PLA2G7 activation → oxylipins (9-HODE, 13-HODE, 9,10-DiHOME) → direct TRPV1 activation → neuropathic pain
This is NOT mediated by prostaglandins (NSAIDs ineffective) but by oxidized linoleic acid metabolites (oxylipins) produced via PLA2G7 and Cytochrome P450 enzymes.
¶ Resolution Interference
Excess AA competes with EPA and DHA for COX-2 and LOX enzymes, blocking production of:
- Resolvins (RvE1, RvD1-6)
- Protectins (PD1)
- Maresins (MaR1)
This shifts the system from acute inflammation → resolution to chronic inflammation → failed resolution.
¶ Clinical Significance
¶ Evolutionary Mismatch and Modern Disease
The modern Western diet creates an AA-driven inflammatory phenotype that was never present in human evolution:
- Ancestral ω-6:ω-3 ratio: 1-4:1 (hunter-gatherer diets: fish, game, wild plants)
- Modern ratio: 15-20:1 (industrial seed oils: soybean, corn, sunflower)
- Result: Chronic pro-inflammatory eicosanoid dominance as baseline state
This maps directly to the 5 plus 2 metamodel:
- Metamodel 1 (Nutrition): Excess linoleic acid from seed oils
- Metamodel 2 (Movement): Sedentarism ↑ COX-2 expression in muscle
- Metamodel 3 (Stress): Cortisol ↑ PLA2G7 activity
- Metamodel 4 (Circadian): Disrupted rhythms ↑ nocturnal IL-6 → COX-2
- Metamodel 5 (Social): Loneliness ↑ CTRA gene expression → NF-κB → COX-2
¶ Selfish Brain and Selfish Immune System
The selfish brain theory and selfish immune system converge on AA metabolism:
- Brain preferentially accumulates AA in neuronal membranes (energy-independent process)
- Immune cells use AA → PGE2 to create fever (↑ glucose delivery to brain)
- But chronic AA excess means neurons become self-inflicting pain generators—the selfish brain inadvertently creates neuropathy by hoarding inflammatory lipids
¶ Clinical Conditions Driven by AA Excess
-
Peripheral neuropathy and small fiber neuropathy
- High linoleic acid + low DHA → ↓ intraepidermal nerve fibre density
- PLA2G7 inhibitors (darapladib) reduce pain by blocking oxylipins
- Not responsive to NSAIDs (prostaglandin-independent mechanism)
-
Chronic pain syndromes (fibromyalgia, widespread pain)
-
Inflammatory bowel disease (Crohn's disease, Ulcerative Colitis)
- leukotriene B4 (AA-derived) → neutrophil recruitment to gut mucosa
- PGE2 → ↓ intestinal permeability regulation (EP4 receptor dysfunction)
-
- TXA₂ (AA-derived) → platelet aggregation, thrombosis
- PGI2/TXA₂ imbalance in endothelial dysfunction
-
Asthma and allergic disease
- Cysteinyl leukotrienes (AA-derived) → bronchoconstriction
- High ω-6:ω-3 ratio → ↑ Th2 polarization → allergic inflammation
¶ Intervention Strategies
Target ω-6:ω-3 ratio <4:1 (ideally 2:1):
-
Reduce LA intake (<5% calories):
- Eliminate seed oils (soybean, corn, safflower, sunflower)
- Avoid grain-fed meat (fattier cuts accumulate dietary LA)
- Limit poultry skin, pork
-
Increase EPA/DHA (2-4g/day):
- Fatty fish (salmon, mackerel, sardines)
- Fish oil or algal oil supplements
- Competes with AA for COX/LOX enzymes → ↑ Resolvins, Protectins
-
Pharmacological modulation:
- darapladib (PLA2G7 inhibitor): reduces neuropathic pain in clinical trials
- Aspirin (low-dose): acetylates COX-2 → switches to aspirin-triggered lipoxins/resolvins
- LOX inhibitors (zileuton): blocks leukotriene production in asthma
-
Membrane remodeling timeline:
- Red blood cell phospholipids: 4 months turnover
- Neuronal membranes: 6-12 months for significant AA replacement
- Clinical improvements may lag dietary changes by 3-6 months
¶ Clinical Biomarkers
- Omega-3 Index (EPA+DHA % of RBC fatty acids): target >8%
- AA/EPA ratio: target
:1 (inflammatory balance marker) - Prostaglandin E2 (urine PGE-M metabolite): marker of COX-2 activity
- leukotriene B4 (serum): marker of 5-LOX activity, neutrophilic inflammation
- oxylipins panel (specialized labs): 9-HODE, 13-HODE correlate with neuropathic pain
¶ Key Facts
- Evolutionary ω-6:ω-3 ratio: 1-4:1 vs. modern 15-20:1 (3.75-fold to 20-fold increase in pro-inflammatory potential)
- AA half-life in neuronal membranes: months to years, not days—membrane remodeling is slow
- linoleic acid conversion efficiency: ~5-10% of dietary LA converts to AA in humans (delta-6 desaturase rate-limiting)
- PLA2G7 selectivity: preferentially cleaves oxidized phospholipids containing AA, producing oxylipins not Prostaglandins
- PGE2 pain threshold: >100 pg/mL in CSF associated with central sensitization
- darapladib dosing: 160mg/day reduces plasma oxylipins by 65% in 4 weeks
- TRPV1 activation: oxylipins (9-HODE, 13-HODE) activate at EC₅₀ ~1-10 μM, independent of heat or capsaicin
- COX-2 induction kinetics: NF-κB activation → COX-2 mRNA peak at 2-4 hours → protein peak at 6-12 hours post-stimulus
- Aspirin's dual action: irreversibly acetylates COX-2 Ser-530 → blocks PG synthesis BUT enables 15-epi-lipoxin/resolvin production
- Membrane AA incorporation: high-LA diets increase neuronal membrane AA from 8% to 15% of total phospholipids over 12 months
- 5-LOX calcium dependence: requires intracellular Ca²⁺ >100 nM and translocation to nuclear membrane
- AA storage sites: highest concentrations in brain (12-15% of membrane fatty acids), adrenal glands, liver (not primarily adipose tissue)
- Clinical threshold for neuropathy: AA >10% of RBC membrane phospholipids + DHA <4% = 5-fold increased risk
- Resolution failure: ω-6:ω-3 >10:1 reduces resolvin production by 70-90%, prolonging inflammatory phase
¶ Connections
- linoleic acid — dietary precursor converted to AA via delta-6 and delta-5 desaturases; modern diets provide 10-20g/day LA
- PLA2G7 — calcium-independent phospholipase A2 that cleaves AA from neuronal membranes and produces oxylipins, critical for diet-induced neuropathy
- prostaglandin E2 — primary AA-derived pain mediator via COX pathway; activates EP receptors on nociceptors and spinal cord neurons
- oxylipins — oxidized AA and LA metabolites (9-HODE, 13-HODE) that directly activate TRPV1 independent of prostaglandins
- TRPV1 — capsaicin/heat receptor activated by AA-derived oxylipins, mediates neuropathic pain in dorsal root ganglia
- omega-6 to omega-3 ratio — determines balance between pro-inflammatory (AA) and pro-resolving (EPA/DHA) eicosanoid production
- COX-2 — inducible cyclooxygenase that converts AA to Prostaglandins; upregulated by NF-κB, IL-1β, TNF-α
- 5-LOX — produces leukotriene B4 and cysteinyl leukotrienes from AA; drives neutrophil recruitment and bronchoconstriction
- darapladib — selective PLA2G7 inhibitor that reduces neuropathic pain by blocking oxylipins production; 160mg/day in trials
- DHA — omega-3 fatty acid that competes with AA for membrane incorporation and enzymatic metabolism; generates Protectins and Resolvins
- EPA — omega-3 fatty acid that competes with AA for COX-2 and 5-LOX; produces E-series Resolvins and reduces leukotriene B4
- Resolvins — specialized pro-resolving mediators derived from EPA/DHA that counter AA-driven inflammation and promote resolution
- peripheral neuropathy — caused by AA accumulation in neuronal membranes + PLA2G7 activity → oxylipins → TRPV1 activation
- dorsal root ganglia — sensory neuron cell bodies where AA accumulates and oxylipins are produced, driving neuropathic pain
- NF-κB — transcription factor activated by inflammatory stimuli (TNF-α, IL-1β, LPS) that upregulates COX-2 and PLA2G7
- chronic inflammation — sustained state driven by ω-6:ω-3 imbalance favoring AA → eicosanoid production over resolution
- aspirin — irreversibly acetylates COX-2, blocking prostaglandin synthesis but enabling production of aspirin-triggered Resolvins
- diet — modern seed oils (soybean, corn, sunflower) provide 15-20% calories as linoleic acid, driving AA excess
- intraepidermal nerve fibre density — reduced by high AA + low DHA diets, marker of small fiber neuropathy severity
- IL-6 — cytokine that induces COX-2 expression and AA release, linking systemic inflammation to eicosanoid production
- TNF-α — activates NF-κB → COX-2 upregulation, and directly stimulates PLA2G7 activity for AA release
- central sensitization — amplified spinal nociceptive processing driven by AA → PGE2 → EP receptor activation in dorsal horn
- fibromyalgia — chronic pain syndrome associated with elevated ω-6:ω-3 ratios and impaired Resolvins production
- inflammatory bowel disease — AA-derived leukotriene B4 drives neutrophil infiltration; high ω-6 diets worsen disease activity
- Cytochrome P450 — metabolizes AA to epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), some activate TRPV1
¶ Module References
- Module 1
¶ From metabolism/
¶ Definition
A 20-carbon omega-6 polyunsaturated fatty acid (20:4n-6) esterified in membrane phospholipids that serves dual roles as structural component and inflammatory precursor. Arachidonic acid (AA) is synthesized from dietary linoleic acid via delta-6-desaturase and elongase enzymes, or obtained directly from animal tissues. When released by phospholipase A2 enzymes, AA becomes substrate for three competing metabolic pathways that determine whether inflammation progresses or resolves.
¶ Picture It
Arachidonic acid is the munitions factory built inside your cell walls.
Imagine every cell membrane contains stockpiled ammunition—not bullets yet, just raw gunpowder (arachidonic acid) carefully packed into the bricks of the wall itself. During peacetime, this gunpowder serves as structural material, making membranes flexible and functional. But when the alarm sounds—injury, infection, stress—an enzyme team (phospholipase A2) breaks open the bricks and releases the gunpowder into the cytoplasm.
Now three foreman teams compete for this raw material: The COX foreman makes inflammatory grenades (Prostaglandins, thromboxanes). The LOX foreman makes chemical warfare agents (leukotrienes) that call in more troops. The P450 foreman makes fire extinguishers (anti-inflammatory mediators). Which foreman gets the most gunpowder depends on how much Omega-3 fish oil is around—because omega-3s physically block access to the inflammatory foremen. In Western diets (20:1 omega-6 to omega-3 ratio), the inflammatory foremen have unlimited access to gunpowder, and they manufacture weapons 24/7. This is why reducing dietary linoleic acid from seed oils is like cutting off the ammunition supply chain before the gunpowder even gets installed in your walls.
¶ Mechanism
Synthesis pathway: Dietary linoleic acid (18:2n-6) undergoes two desaturation steps (Δ6-desaturase, Δ5-desaturase) and one elongation to form arachidonic acid. The rate-limiting enzyme is Delta-6 Desaturase, which is inhibited by trans fats, alcohol, cortisol, and aging, but also processes Omega-3 precursors—creating substrate competition. Synthesized AA is esterified by acyl-CoA synthetase into the sn-2 position of membrane phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, where it comprises 5-15% of total fatty acids in most tissues and up to 20% in immune cells and neurons.
Liberation: Inflammatory signals (IL-1β, TNF-α, oxidative stress, calcium influx) activate calcium-dependent cytosolic phospholipase A2 (cPLA2α/PLA2G7) via MAPK-mediated phosphorylation and calcium binding. PLA2G7 translocates to membranes and cleaves AA from the sn-2 position, releasing both free AA and lysophospholipids. Oxidized phospholipids containing oxidized AA derivatives are preferentially cleaved by lipoprotein-associated PLA2 (Lp-PLA2), generating oxylipins with direct nociceptive properties.
Metabolic fate—Three competing pathways:
-
Cyclooxygenase pathway: COX-1 (constitutive) and COX-2 (inducible) convert AA → PGG2 → PGH2 → tissue-specific prostaglandins and thromboxanes. PGE2 (via mPGES-1) binds EP1-4 receptors causing fever (EP3 in hypothalamus), pain sensitization (EP2 on nociceptors), and immune activation. COX-2 is induced 10-80-fold by NF-κB and AP-1 in response to inflammatory cytokines. Aspirin irreversibly acetylates COX-2, switching its activity to produce anti-inflammatory Aspirin-triggered resolvins when EPA is substrate.
-
Lipoxygenase pathway: 5-LOX (requires FLAP accessory protein) converts AA → 5-HPETE → LTB4 (neutrophil chemoattractant) and cysteinyl leukotrienes (LTC4, LTD4, LTE4 causing bronchoconstriction, vascular permeability). 12-LOX produces 12-HETE (platelet activation, tumor metastasis). 15-LOX produces 15-HETE, which can be further metabolized to lipoxins (resolution mediators) in transcellular metabolism with neutrophil 5-LOX.
-
Cytochrome P450 pathway: CYP450 epoxygenases (CYP2C, CYP2J) produce epoxyeicosatrienoic acids (EETs: 5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET) with anti-inflammatory, vasodilatory, and analgesic properties. EETs activate KATP channels, inhibit NF-κB, and reduce endothelial dysfunction. Soluble epoxide hydrolase (sEH) rapidly converts EETs to inactive diols (DHETs).
Neuronal AA accumulation: In dorsal root ganglia neurons and peripheral nerve membranes, high dietary linoleic acid (>6% energy) increases neuronal phospholipid AA content from ~8% to >12%. PLA2G7 cleaves oxidized AA-containing phospholipids generating 9-HODE, 13-HODE, and hydroxy-eicosatetraenoic acids that directly activate TRPV1 (capsaicin receptor) and TRPA1 (mustard oil receptor) causing neuropathic pain independent of immune cell infiltration. This mechanism explains diet-induced small-fiber neuropathy in the absence of diabetes or autoimmunity.
Substrate competition with omega-3s: EPA and DHA compete with AA for COX and LOX enzymes. EPA is 50-100 times less effective substrate for COX-2 than AA, producing PGE3 (minimally inflammatory). EPA-derived Resolvins, Protectins, and Maresins actively terminate AA-initiated inflammation via ALX-FPR2 and other resolution receptors. The tissue omega-6 to omega-3 ratio determines eicosanoid production—ratios >10:1 favor inflammatory cascades.
¶ Clinical Significance
Chronic pain and neuropathy: Elevated tissue AA from high linoleic acid intake (seed oils, processed foods) directly drives neuropathic pain, peripheral neuropathy, and chronic pain syndromes. The mechanism bypasses traditional inflammatory markers—patients may have normal CRP but severe pain from neuronal oxylipin accumulation. Clinical strategy involves reducing dietary LA to % energy (eliminates seed oils, processed foods), optimizing omega-6 to omega-3 ratio to <4:1, and supplementing EPA/DHA 2-4g/day. In refractory cases, darapladib (Lp-PLA2 inhibitor) reduces oxidized AA metabolites and has shown efficacy in diabetic neuropathy.
Evolutionary mismatch: Hunter-gatherer omega-6:omega-3 ratios were 1-4:1 with tissue AA levels ~5-7% of membrane phospholipids. Modern Western diets (15-20:1 ratio) increase tissue AA to 10-15%, creating persistent pro-inflammatory eicosanoid production that drives metaflammation, insulin resistance, cardiovascular disease, and neuroinflammation. This represents a profound dietary mismatch—the human genome evolved with AA as signaling molecule, not chronic substrate excess.
Selfish immune system: The immune system's preferential sequestration of AA during infection represents selfish resource allocation—IL-1β and TNF-α increase hepatic AA synthesis and immune cell AA uptake at expense of other tissues. During sepsis, AA is redirected to leukocytes and away from brain and muscle, contributing to sickness behaviour and metabolic depression. Chronic low-grade inflammation maintains this resource diversion, explaining fatigue and cognitive dysfunction in inflammatory conditions.
Five metamodels connection:
- Location/Function: AA accumulates in neuronal membranes (not just adipose), causing localized dysfunction
- Energy: AA metabolism consumes ATP (COX reaction) and generates ROS, contributing to metabolic exhaustion
- Cognitive/Behavioral: AA-derived PGE2 crosses blood-brain barrier, induces sickness behaviour, impairs hippocampal function
- Time/Rhythm: COX-2 expression follows circadian pattern; evening AA release may contribute to nighttime pain exacerbation
- Immune/Self: AA pathway represents ancient danger signal—chronic elevation maintains unnecessary defensive posture
Biomarkers and thresholds:
- Omega-6 to omega-3 ratio >10:1 predicts inflammatory disease risk
- Red blood cell AA >10% of total fatty acids associated with increased pain sensitivity
- Plasma AA >200 μg/mL correlates with cardiovascular disease events
- Omega-3 Index (EPA+DHA in RBC) <4% insufficient to compete with AA metabolism
- Urinary PGE-M (PGE2 metabolite) reflects whole-body COX activity, useful in cancer screening
Intervention cascade:
- Remove seed oils (soybean, corn, sunflower, safflower—70-80% LA)
- Reduce animal AA (limit fatty meat, egg yolks to 2-3/week during active inflammation)
- Increase preformed EPA/DHA (fatty fish 3x/week or supplement 2-4g/day)
- Support resolution: specialized pro-resolving mediators supplementation, polyphenols (inhibit COX-2 and 5-LOX)
- Target specific pathways: COX-2 selective inhibitors, 5-LOX inhibitors (zileuton), sEH inhibitors (under development)
Patient education: Explain that pain is not just "inflammation you can feel"—it's the direct result of specific molecules made from dietary fats. Changing fat intake changes the chemical soup neurons swim in. Results typically seen in 8-12 weeks as membrane composition shifts.
¶ Key Facts
- AA comprises 5-10% of membrane phospholipids in most tissues, 15-20% in immune cells and neurons
- Western diets provide omega-6:omega-3 ratios of 15-20:1 vs. evolutionary 1-4:1
- Dietary linoleic acid intake directly correlates with tissue AA levels (r=0.6-0.8) over 12-16 weeks
- PLA2G7 (Lp-PLA2) preferentially cleaves oxidized phospholipids, releasing pronociceptive oxylipins
- AA-derived 9-HODE and 13-HODE directly activate TRPV1 (EC50 ~10 μM) and TRPA1 nociceptors
- COX-2 produces 10-20x more PGE2 than COX-1 during inflammation; NF-κB induction increases COX-2 mRNA 50-fold
- One molecule of aspirin irreversibly inactivates one COX enzyme for the lifetime of that platelet (7-10 days)
- 5-LOX requires FLAP (5-lipoxygenase activating protein) and calcium for membrane localization
- LTB4 is 100x more potent neutrophil chemoattractant than C5a complement fragment
- EPA competitively inhibits AA metabolism with 50-100x lower inflammatory potency—but only when tissue EPA:AA >1:4
- Reducing dietary LA from 7% to 2.5% of energy decreases tissue AA by 30-40% within 12 weeks
- CYP450-derived EETs have half-lives of 30-60 seconds due to rapid sEH hydrolysis
- Neuronal membrane AA content >12% of total fatty acids associated with small fiber neuropathy regardless of diabetes status
- Darapladib (Lp-PLA2 inhibitor) reduced composite neuropathy scores by 40% in diabetic neuropathy trial
- The ALA (omega-3 plant precursor) to EPA conversion rate is <5% in humans—insufficient to compete with AA without preformed EPA/DHA intake
¶ Connections
- linoleic acid — dietary precursor converted to AA via delta-6-desaturase and elongase; tissue AA levels directly proportional to LA intake over 12-16 weeks
- PLA2G7 — calcium-dependent cytosolic phospholipase A2 that cleaves AA from sn-2 position of membrane phospholipids in response to inflammatory signals
- omega-6 to omega-3 ratio — determines competitive enzyme substrate availability; ratios >10:1 favor pro-inflammatory AA metabolism over resolution
- oxylipins — bioactive lipid mediators derived from AA including Prostaglandins, leukotrienes, thromboxanes, and hydroxy-eicosatetraenoic acids
- peripheral neuropathy — AA-derived oxylipins accumulate in neuronal membranes causing direct nociceptor activation independent of diabetes
- inflammation — AA is the primary endogenous substrate for inflammatory eicosanoid cascades; tissue AA content determines inflammatory capacity
- prostaglandin E2 — major AA metabolite via COX-2 that causes fever, pain sensitization, immune activation, and vasodilation
- COX-2 — inducible cyclooxygenase enzyme (NF-κB regulated) that converts AA to PGH2, precursor of inflammatory prostaglandins
- leukotrienes — AA metabolites via 5-LOX pathway causing bronchoconstriction, vascular permeability, and neutrophil chemotaxis
- TRPV1 — capsaicin receptor directly activated by AA-derived 9-HODE and 13-HODE causing burning pain sensation
- neuropathic pain — chronic pain from neuronal AA metabolite accumulation activating TRPV1/TRPA1; distinct from inflammatory or nociceptive pain
- diet — high linoleic acid from seed oils and animal AA from fatty meat/eggs increase tissue AA; fatty fish provides competitive EPA/DHA
- EPA — omega-3 fatty acid that competitively inhibits AA metabolism with 50-100x lower inflammatory potency; requires tissue EPA:AA >1:4
- DHA — omega-3 fatty acid that reduces tissue AA via competitive incorporation and inhibition of delta-5-desaturase
- chronic pain — elevated membrane AA and oxylipin production maintain peripheral sensitization and central sensitization
- cardiovascular disease — AA-derived TXA2 promotes platelet aggregation and vasoconstriction; elevated plasma AA (>200 μg/mL) predicts CVD events
- specialized pro-resolving mediators — EPA/DHA-derived Resolvins, Protectins, Maresins that actively terminate AA-initiated inflammation
- neuroinflammation — microglial activation increases COX-2 and AA release, generating inflammatory mediators that impair hippocampal neurogenesis
- darapladib — selective Lp-PLA2 inhibitor that reduces oxidized AA-phospholipid cleavage; showed efficacy in diabetic neuropathy
- membrane phospholipids — AA stored esterified in sn-2 position of phosphatidylcholine and phosphatidylinositol awaiting PLA2 liberation
- Cytochrome P450 — CYP2C/CYP2J enzymes metabolize AA to anti-inflammatory epoxyeicosatrienoic acids (EETs) with analgesic and vasodilatory effects
- 5-LOX — lipoxygenase enzyme requiring FLAP cofactor that converts AA to LTB4 (neutrophil chemotaxis) and cysteinyl leukotrienes
- metaflammation — chronic low-grade inflammation driven by sustained AA excess from Western diet mismatch
- insulin resistance — AA-derived inflammatory mediators activate JNK and IKK pathways, serine-phosphorylating insulin receptor substrate-1
- NF-κB — transcription factor activated by AA-derived PGE2 that induces COX-2, creating positive feedback amplification loop
- dorsal root ganglia — sensory neuron cell bodies where AA accumulates in membrane phospholipids causing oxylipin-mediated nociceptor sensitization
- small fiber neuropathy — length-independent neuropathy from AA-oxylipin accumulation in C-fibers and A-delta fibers
- Delta-6 Desaturase — rate-limiting enzyme for AA synthesis from linoleic acid; inhibited by trans fats, alcohol, aging, and cortisol
- Aspirin-triggered resolvins — specialized pro-resolving mediators formed when acetylated COX-2 converts EPA to 18R-HEPE precursor
- TNF-α — inflammatory cytokine that activates PLA2G7 and induces COX-2 expression, increasing AA liberation and metabolism
¶ Module References
- Module 1