e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability, and SH scavenge toxic free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced

secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection, as direct (in vitro) cytoprotection is also of limited value. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated (see below). This short review is written with three goals: (i) to selleck compound argue that the mechanism of gastroprotection is still poorly defined, although I will propose a new, multifactorial, and contemporary mechanistic explanation for the surprisingly potent gastroprotective action of wide variety of drugs. (ii) Although the original “gastric cytoprotection” experiments of Robert[1, 2] and the deluge of subsequent similar studies worldwide referred to prevention of acute gastric mucosal lesions or erosions, without reducing PDE inhibitor gastric acidity, I suggest that almost 35 years after

Robert’s seminal work, there is a new possibility to accelerate the healing of chronic gastroduodenal ulcers without inhibiting gastric acid secretion. (iii) There is a growing clinical need to find novel gastroprotective

drugs which prevent and/or accelerate the healing of nonsteroidal anti-inflammatory drugs (NSAID)-induced and both H. pylori-positive and negative gastroduodenal ulcers.[8, 9] Since the initial studies of Robert used pretreatment with very small doses of PG in rats to prevent acute hemorrhagic erosions caused by concentrated ethanol, HCl, NaOH, hot water, or hypertonic NaCl2,[1, 2] “gastric cytoprotection” selleck kinase inhibitor became a magnet to search for mechanistic explanation(s) for this unexpected effect of tiny doses of Prostaglandin E2 (PG-E2) (i.e. about 10–100 times smaller than the dose required to inhibit gastric acid secretion). Furthermore, even PG from the F series that have no effect on gastric acidity exert gastroprotection, as revealed by our initial studies.[6, 7] The biggest surprise in this field, however, has come from first studies of Paul Guth who demonstrated that “gastric cytoprotection” is not unique to PG molecules since non-antisecretory doses of cimetidine and probanthine also exert similar acute gastric mucosal protective effects.