The fruit extract of Xylopia aethiopica (dunal) a. rich. (annonaceae) and its principal constituent, Xylopic acid, modulate inflammation
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Date
AUGUST 2015
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Abstract
Xylopia aethiopica extract is traditionally employed, among other uses, in the treatment
of inflammatory conditions. This study aimed at investigating the anti-inflammatory
properties of the aqueous ethanol (70%
v
/v) extract of the dried fruit of Xylopia
aethiopica and its principal constituent, xylopic acid. The anti-inflammatory effect of
the extract and xylopic acid were preliminarily established by in vitro assay employing
the albumen denaturation method. The extract and xylopic acid showed a
concentration-dependent inhibition of protein denaturation at the concentration ranges
6.25 - 200 µg ml
-1
with IC50 of 10.12 µg ml
-1
and 15.55 µg ml
-1
respectively. The in
vivo acute anti-inflammatory effect of the extract (30, 100, 300 mg kg
-1
) and xylopic
acid (10, 30, 100 mg kg
-1
) were established using the carrageenan-induced acute
inflammation model in mice. The inhibition of inflammation obtained were significant,
with the highest dose suppressing oedema to 48.13 ± 10.90% and 60.81 ± 3.25% by the
extract in both prophylactic and therapeutic models; and 56.58 ± 3.91% and 68.11 ±
3.59% by xylopic acid in the prophylactic and therapeutic models respectively of the
inflamed control response. In the allergy studies, passive cutaneous anaphylactic and
systemic anaphylactic studies were conducted. Pinnal inflammation reaction model and
compound 48/80-induced passive cutaneous anaphylaxis model were employed in the
passive cutaneous anaphylaxis studies. The antigen-induced inflammation was
significantly suppressed by both the extract and xylopic acid with maximum
suppression of 62.83 ± 0.83% and 77.62 ± 2.26% respectively. The extract and xylopic
acid inhibited mast cell degranulation and caused a reduction in the extent of mast cell
degranulation and skin tissue damage. Compound 48/80-induced systemic anaphylaxis
and Lipopolysaccharide (LPS)-induced septic shock models were employed in the
systemic anaphylaxis studies. The extract (30, 100, 300, 1000 mg kg
-1
) and xylopic acid
(10, 30, 100, 300 mg kg
-1
) offered 40 - 100% and 40 – 90% survival proportion in the
compound 48/80-induced systemic anaphylaxis respectively. In the LPS-induced septic
shock, the intraperitoneal administration of LPS caused significant mortality in vehicle-treated animals. In the extract-treated animals, there was dose-dependent protection
against endotoxic shock with maximum protection of 70%, xylopic acid also gave a
maximum of 70% protection from endotoxic shock. In the chronic inflammatory study,
the role of reactive oxygen species inhibition in the chronic inflammatory process was
investigated using the acetic acid-induced colitis model in rats. The extract and xylopic
iv
acid showed anti-oxidant activity in acetic acid-induced colitis by decreasing the
activity of myeloperoxidase and lowering lipid peroxidation as well as increasing the
activities of catalase, superoxide dismutase and ascorbate peroxidase in vivo hence
affecting the generation of reactive oxygen species which are involved in the
inflammatory process and affects cellular activity and proliferation during the
inflammatory process. The anti-arthritic property of the extract and xylopic acid were
investigated using adjuvant-induced arthritis model in rats. The extract, at the highest
dose, reduced the total limb swelling over 28 days in the ipsilateral limb to 41.07 ±
4.71% prophylactically and 42.90 ± 5.60% therapeutically of the arthritic control rats;
with xylopic acid showing a maximal reduction in total limb swelling in the ipsilateral
limb to 51.29 ± 8.34% prophylactically and 62.21 ± 11.85% therapeutically of the
arthritic control rats with its highest dose administered. The extract and xylopic acid
also showed inflammation alleviation in the other indices monitored. With the
mechanism elucidation studies carried out, the extract and xylopic acid showed anti-histaminic activity with inhibitory effect on histamine-induced inflammation, indirect
anti-histaminic activity in the clonidine-induced catalepsy model and possible
competitive H1 receptor blockade. The extract and xylopic acid also showed effect on
serotonergic, bradykinin and phospholipid/arachidonate pathways of inflammation
with inhibitory effect on expression of intercellular adhesion molecule 1 and cellular
component recruitment in the inflammatory process. Xylopic acid was identified to
inhibit the serum expression of pro-inflammatory cytokines, IL-6 and TNF-alpha, in
chronic inflammation. These novel findings show the anti-inflammatory property of the
aqueous ethanol extract of the dried fruit of Xylopia aethiopica and its principal
constituent, xylopic acid, obtained from the bio-fractionation of the petroleum ether
extract of the dried fruit of Xylopia aethiopica.
Description
A thesis submitted to the Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences in fulfilment of the requirements for the degree of Doctor Of Philosophy.