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Gastroprotective Triterpenoids: Pharmacological Mechanism
Figure 3. Phospholipase A 2 (PLA 2) synthesizes arachidonic acid (AA) from membrane phospholipids.
Cyclooxygenases metabolizes AA to different prostaglandins in gastric mucosa PGE 2 and PGI 2 are
bioconverted to increase mucosal gastric blood flow, increase mucus and bicarbonate secretion by
COX-1. While prostaglandins synthesized from COX-2 participates decreasing leukocyte adherence
and in re-epithelization of gastric cells. When an NSAID is administered, prostaglandins synthesis is
inhibited by NSAID-inhibit COX and then gastroprotection is disrupted.
Besides, the increment on leukocyte adherence induce by NSAIDs is another important
step in the pathogenicity caused in gastric mucosa. Treatment with monoclonal antibodies
that blocked neutrophil adherence to the vascular endothelium markedly attenuated the
severity of NSAID gastropathy in rats and rabbits [112, 113]. The augmented leukocyte
adherence in mesentery is induced in an early step by leukotrienes due to inhibitors of
leukotriene synthesis or antagonist of leukotriene receptors have been shown protective
effects in experimental NSAID-induced gastric damage [112, 113]. Also, it has been studied
the leukotriene B4 levels after NSAID administration to rats [15] and humans [114].
Furthermore, inhibitors of leukotriene B4 exert a decrement on leukocyte adherence to
venules induce by NSAID [91].
Neutrophil adherence is regulated by endothelial expression of intracellular adhesion
molecule 1 (ICAM-1) and selectin expression in neutrophil, those molecules allows the
attachment of neutrophil to endothelial tissue [92, 115]. Another signal molecule that mediate
NSAID-induced leukocyte adherence is the increment observed in TNF-α; TNF-α levels are
increased in plasma after indomethacin administration to rats, and this correlates with the
accumulation of neutrophils in the gastric microcirculation and the appearance of gastric
injury [93].
Traditional NSAIDs inhibit COX-1 and COX-2, and then their gastric toxicity is induced
by inhibition of prostaglandins derived from both enzymes. In the nineteen decade
researchers thought that just COX-1 played the role of gastroprotective enzyme and COX-2
synthesized pro-inflammatory prostaglandins. With this premise coxibs (selective COX-2
inhibitors) were synthesized to reduce gastric injury induced by NSAID treatment [116].
113