Arachidonic acid pathway

SMP-114 (licofelone) is a drug candidate for rheumatoid arthritis, currently in Phase II clinical trials (Figure 8.57). It inhibits all three of the major enzymes involved in the arachidonic acid pathway (5-LOX, COX-1, and COX-2), thereby preventing production of both leukotrienes and prostaglandins. This mode of action could therefore lead to a better tolerability than that of conventional cyclooxygenase (COX-1 and COX-2) inhibitors because of the shunt of arachidonic acid metabolism toward the production of proinflammatory leukotrienes, via 5-lipoxygenase (LOX). 

The 6- or 7-phenyl-substituted l-ethyl-pyrazino[2,3-r-][l,2,6]thiadiazine 2,2-dioxides 187 were found to show significant platelet aggregation inhibition comparable to other antithrombotic agents. Strong evidence was found that this activity was due to interference with the platelet arachidonic acid pathway <1999JME1698>. 

Neuroinflammation emerges as a driving force in chronic neurodegenerative processes like Alzheimer s (AD) or Parkinson s disease (PD). Neuroinflammatoiy mediators such as cytokines, reactive oxygen species and molecules of the arachidonic acid pathway are generated and released by microglia, astrocytes and neurons upon stimulation and activation. In general, enhanced release of these substances has been considered to be detrimental. 

Abnormalities in Thromboxane Production and Arachidonic Acid Pathways... 

Pavoine C, Behforouz N, Gauthier C, et al. p2-Adrenergic signaling in human heart shift from the cyclic AMP to the arachidonic acid pathway. Mol Pharmacol 2003 64 1117-1125. 

Zhang L, Reith MEA. 1996. Regulation of the functional acitivity of the human dopamine tranporter by the arachidonic acid pathway. Eur. J. Pharmacol. 315 345-54... 

Inflammation is a normal and complex reaction by the body to an injury. Aloe has been used in traditional medicine for its anti-inflaimnatoiy use. The aqueous and chloroform extracts of aloe inhibit the effect on carrageen induced edema. This effect was associated with an inhibitory action on the arachidonic acid pathway via cyclooxygenase 68). Aloe gel components were able to suppress bacterial induced pro-inflarmnatoiy production of cytokines (systematically elevated after a bacterial invasion), namely TNF-a and IL-p 69). 

Phospholipases are crucial enzymes in the arachidonic acid pathway and appear to be primarily responsible for the esterolytic action that releases arachidonic acid from phospholipids (209). Once released, this acid is converted into several mediators of inflammation. The PLA2 s are small (MW 14,000) stable proteins that require Ca2 + ions for the specific hydrolysis of the 2-acyl group of 3-sn-phospholipids. 

The arachidonic acid pathway leading to the production of inflammatory mediators provides several targets for intervention on inflammation. The most widely used nonsteroidal anti-inflammatory drugs (NSAIDs) in practice... 

Meier, R.W., Niklaus, G., Dewald, B., Fey, M.F., and Tobler, A. (1995) Inhibition of Arachidonic Acid Pathway Prevents Induction of IL-8 mRNA by Phorbol Ester and Changes the Release of IL-8 from HL 60 Cells Differential Inhibition of Induced Expression of IL-8, TNF-a, IL-a and IL-ip, 7. Cell Physiol. 165,62 70. 

The defense mechanisms of G. vermiculophylla seem to involve the arachidonic acid pathway that can lead to prostaglandins and hydroxylated unsaturated fatty acid, such as members of the HETE family. Addition of H-labeled arachidonic add to wounded alga showed that labeled fatty acids were generated rapidly. Interestingly, these results suggested that the enzymatic processes necessary for the activation of the defense mechanism remained viable, despite the damage to the tissues. The metabolomic assay used validated the existence of the chanical defenses and characterized the mechanisms and biochemical pathways involved. 

Shoeb M and Ramana KV. Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radical Biol Med 52 182-190 (2012). 

The observation that several polysaccharides exert significant antiinflammatory activities also after parenteral administration, has stimulated investigations on the putative mechanism of action. From the results available so far, one can conclude that the polysaccharides interfere with the complement system and/or the cytokine release, whereas a significant influence on the arachidonic acid pathway can be excluded. 

Shoeb M, Yadav UC, Srivastava SK, Ramana KV (2011) Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages. Free Radic Biol Med 51(9) 1686-1696... 

Based on previous reports of antiinflammatory activity, a 1989 double-blind, placebo-controlled, randomized study evaluated the effect of dried leaves (70-86 mg) in the treatment of rheumatoid arthritis. Over the 6-week trial, 41 female patients with symptomatic rheumatoid arthritis received feverfew or placebo. More than 13 laboratory and/ or clinical parameters were assessed. The authors concluded that there were no important differences between the control group and those receiving feverfew. Participating patients, however, had not previously responded to conventional therapies. The results do not preclude possible benefits for the use of feverfew in osteoarthritis and soft tissue lesions. Later in vivo studies showed that both feverfew extract and parthenolide possessed antiinflammatory and antinociceptive activities in mice and rats and that such activities were dose dependent. The extract, parthenolide, and some of the constituent flavonoids were also shown to inhibit the arachidonic acid pathways in leukocytes. Another possible mechanism for the anti-inflammatory effect of feverfew is the inhibition of the expression of intercellular adhesion molecule-1 (ICAM-1). ... 

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