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, 13 (6), 1086-95

Adelmidrol, a Palmitoylethanolamide Analogue, Reduces Chronic Inflammation in a Carrageenin-Granuloma Model in Rats

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Adelmidrol, a Palmitoylethanolamide Analogue, Reduces Chronic Inflammation in a Carrageenin-Granuloma Model in Rats

Daniele De Filippis et al. J Cell Mol Med.

Abstract

Palmitoylethanolamide (PEA) and some of its analogues have shown great efficacy in the treatment of pain and inflammation. Adelmidrol - the International Nonproprietary Name (INN) of the di-amide derivative of azelaic acid - is one of these analogues. The anti-inflammatory and analgesic effects of PEA and adelmidrol are hypothesized to be mediated, at least in part, by mast cell down-modulation. Mast cell mediators released at early stage of the inflammatory process drive the inflammatory reaction to chronicity as it happens in X-carrageenin-induced granulomatous tissue formation. In the present study, the choice of testing adelmidrol depends upon the physicochemical properties of the compound, i.e. the amphipatic feature, that make it more easily soluble than PEA. In this study, we investigated the effect of adelmidrol on granuloma formation induced by lambda-carrageenin-soaked sponge implant in rats. Our results show that the local administration of the compound under study significantly decreases weight and neo-angiogenesis in granulomatous tissue. The anti-inflammatory effect was due to the modulation of mast cells degranulation, as shown by histological analysis and by the inhibition of the release of several pro-inflammatory and pro-angiogenic enzymes (e.g. iNOS, chymase and metalloproteinase MMP-9), and mediators (e.g. nitric oxide and TNF-alpha). The results indicate that adelmidrol, given locally, may represent a potential therapeutic tool in controlling chronic inflammation.

Figures

Figure 1
Figure 1
(A) Effect of adelmidrol on λ-carrageenin-induced granulomatous tissue formation. Adelmidrol was administrated at the time of implantation (t 0). The administration of GW6471, a PPAR-alpha antagonist, did not reverse the effect of adelmidrol. Granulomatous tissue formation was evaluated 96 hrs after implantation as wet weight of tissue around the sponge. (B) Effect of adelmidrol on λ-carrageenin-induced leucocytes infiltration evaluated as myeloperoxidase activity. Data are expressed as mean ± S.E.M. of n= 3 separate experiments; *P < 0.05, **P < 0.01, ***P < 0.001 versus saline; °°P < 0.01; °°°P < 0.001 versusλ-carrageenin alone.
Figure 2
Figure 2
Effect of adelmidrol on A-carrageenin-induced TNF-α, iNOS expression in granulomatous tissue at 96 hrs. Representative Western blot analysis and relative densitometric analysis of (A) TNF-α and (B) iNOS. Tubulin expression is shown as control. Data are representative of 3 separate experiments. Results are expressed as mean ± S.E.M. of 3 experiments; *P < 0.05, **P < 0.01, ***P < 0.001 versus saline; °P < 0.05, °°P< 0.01, °°°P < 0.001 versusλ-carrageenin alone.
Figure 3
Figure 3
Effect of adelmidrol on λ-carrageenin-induced nitric oxide production. Nitric oxide production was determined by measuring the accumulation of (A) nitrite and nitrate in granulomatous tissues and (B) in supernatant of 24-hrs-cultured granulomatous tissues. Data are expressed as mean ± S.E.M. of 3 experiments; *P < 0.05, **P < 0.01, ***P < 0.001 versus saline; °P < 0.05, °°P < 0.01, °°°P < 0.001 versusλ-carrageenin alone.
Figure 4
Figure 4
Effect of adelmidrol on λ-carrageenin-induced mast cell activation. (A) Mast cell degranulation was evaluated on microscopically visible connective mast cells stained with 0.05% (w/v) toluidine blue and counterstained with 0.1% (w/v) nuclear fast red (magnification 100×). A differentiation between not degranulated (deep blue) and degranulated (light blue) mast cell was valuable. In (B) is shown the counting of mast cell number. Representative Western blot analysis and relative densitometric analysis of (C) Chymase and (D) MMP-9. Tubulin expression is shown as control. Data are representative of 3 separate experiments. Results are expressed as mean ± S.E.M. of 3 experiments; *P < 0.05, **P < 0.01, ***P < 0.001 versus saline; °P < 0.05, °°P < 0.01, °°°P < 0.001 versusλ-carrageenin alone.
Figure 5
Figure 5
Effect of adelmidrol on λ-carrageenin-induced angiogenesis. New vessel formation was evaluated as (A) haemoglobin content (Hb); (B) CD31 protein expression, a marker of endothelial cells. Results are expressed as mean ± S.E.M. of 3 experiments. *P < 0.05, **P < 0.01, ***P < 0.001 versus saline; °P < 0.05, °°P < 0.01, °°°P < 0.001 versusλ-carrageenin alone. (C) Representative histological analysis of granulomatous tissue stained with haematoxylin and eosin. Fields are representative of 3 separate experiments. Original magnification, 100×.

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