Anti-inflammatory Potential of Alpha Linolenic Acid Mediated Through Selective COX Inhibition: Computational and Experimental Data

January 1, 2014 Human Health and Nutrition Data 0 Comments

Anti-inflammatory Potential of Alpha Linolenic Acid Mediated Through Selective COX Inhibition: Computational and Experimental Data

Year: 2014
Authors: Anand, R. Kaithwas, G.
Publication Name: Inflammation
Publication Details: Volume 37; Issue 4; pages 1297-306. doi: 10.1007/s10753-014-9857-6.


The present work investigates the anti-inflammatory activity of alpha linolenic acid (ALA) and linoleic acid (LA) using computational and experimental analysis. The binding affinity of ALA and LAwas appraised for cyclooxygenase 1, cyclooxygenase 2, and 5 lipoxygenase using AutoDock 4.2 and AutoDock Vina 1.1.2. Anti inflammatory activity of ALA and LA was further assayed using the rat paw edema test against a variety of phlogistic agents including carrageenan, arachidonic acid, prostaglandin, and leukotriene, respectively. ALA and LA were further tested for their efficacy against complete Freund’s adjuvant induced (0.05 ml) arthritis in albino rats.  Following CFA  induced arthritis, ALA and LA were tested for their inhibitory proficiency against COX 1, COX  2, and 5  LOX in vitro. The present study commends that the anti inflammatory potential of ALA could be attributed to COX inhibition, in particular, COX  2. (Authi4rs abstract)
Little literature defines the mechanism underlying the anti inflammatory potential of either ALA or LA. The authors have previously reported inflammatory and anti arthritic potential of Linum usitatissimum fixed oil, and the same was proposed to be mediated by ALA  through dual inhibition of AA metabolism. The oil was also reported to have a momentous amount of LA present in it as well. Considering the above, the present work was undertaken to evaluate the anti inflammatory potential of ALA and LA. The scope of the present work was also extended toward scrutinizing the possible mechanisms for the same, using a computational and experimental approach.
Dock energy is the sum of the intermolecular energy and the ligand’s internal energy. Binding energy is the sum of the intermolecular energy and the torsional free energy penalty. The dock energy, binding energy, and total energy of ALA for COX  1 and COX  2 were better than those of LA. COX  1 and COX  2 have better binding affinity and efficiency for ALA than those of LA.  In case of 5  LOX, there is a very slight difference of energies between ALA and LA .  AA demonstrated higher binding affinity toward COX  1 and 5  LOX in comparison with ALA and LA. The binding of AA toward COX  2 was slightly less than that of ALA and LA.  ALA and LA were further subjected to anti inflammatory screening against a variety of phlogistic agents including carrageenan, AA , PGE2, and LTB4.  Following carrageenan, ALA was appraised against AA  induced inflammation in rats. ALA manifested cogent inhibition of paw edema against AA  induced test, suggesting the inhibition of either COX or LOX or both pathways of AA cascade. It is evident that LA did not manifest any inflammatory potential either against carrageenan or AA. ALA exhibited significant inhibition of PGE2   and LTB4 induced paw edema that is analogous to LA.  Inflammation is characterized by redness, swelling, and pain. These occur due to local vasodilatation, increased capillary permeability, and infiltration of leukocytes. The results suggest that ALA has the capacity to inhibit inflammation evoked by AA, prostaglandin, and leukotriene, which possibly could be mediated through inhibition of either the COX or LOX pathway or both. The results suggest slightly less efficacy of ALA toward LOX inhibition in comparison to COX, as depicted in the docking studies.  ALA was further subjected for test against immunological chronic inflammation, which is more analogous to clinical situations, CFA induced arthritis. ALA considerably decreased humoral immune response, apparently due to its ability to inhibit acute inflammation by reducing vascular permeability and inhibiting other mediators such as PGE2. The secondary inflammatory response observed from the 11th day was also inhibited by ALA as effectively as aspirin. The secondary lesions have been shown to be presumably due to a delayed hypersensitivity reaction, and ALA produced an evident effect on this as well, indicating that ALA might be effective in RA treatment.
In the present study, the anti inflammatory action of ALA  was incomparably reduced in the IL 1 and TNFalpha levels in the sera of AA rats. ALA shifts the balance of the pro inflammatory cytokine toward normal and thereby confirms its utility in chronic inflammatory conditions such as RA. ALA was further evaluated for COX and LOX inhibition assay in vitro.  Results suggest the inhibitory activity of ALA  toward COX; however, no significant inhibition of LOX was observed in vitro.  The results indicate that ALA acts as inhibitors of the COX enzyme with slightly higher selectivity toward COX  2. The anti inflammatory potential of the ALA observed in the present report could be the consequence of the inhibition of the COX pathway of the AA cascade. The results from the computational approach are also in support of the experimental data.  Thus, it can be concluded that ALA exhibits a significant anti inflammatory effect mediated through the inhibition of the AA pathway. Selective inhibition of the COX pathway with discernible inhibition of COX  2 could be the underlying mechanism for the anti inflammatory effect observed. (Editors comments)

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