Stress gastric ulceration is a clinical condition leading to morbidity/mortality and complex etiopathological
factors are involved. Pharmacotherapy of such gastric mucosal lesions is not consistent and novel
strategies are being explored. Targeting gastrointestinal factors have showed equivocal results and there is a possibility
of involvement of extra-gastrointestinal factors. Stress is a highly interactive biological response in which
the brain plays a key role. The involvement of brain substrates like the limbic system (amygdala, cortex, hippocampus)
and behavioral traits has been investigated and research data has shown that the limbic brain-gut axis
may be involved in the regulation of gastric mucosal integrity during stressful situations. The amygdaloid complex,
its connections with other limbic structures and their neural networks act in tandem to contribute to both
stress ulceration and gastroprotection. Complex neurotransmitter interactions in these areas involving biogenic
amines and neuropeptides have been shown to modulate stress ulcerogenesis in experimental models. The immune
system and brain-immune interactions also appear to play a decisive role in the genesis of such stress gastric
lesions and the possibility of a brain-gut-immune axis has been proposed during stress gastric lesions. More
recent studies have shown the involvement of oxidative stress and nitric oxide as well as their interactions during
such stress gastric pathology, indicating the possible role of antioxidants and NO modulators as gastroprotective
agents for stress ulceration. In view of the complex pathophysiology, multiple targets and lack of consistent
therapeutic modalities, newer/alternative hypotheses are constantly emerging, which could be explored for effective
treatment strategies aimed at gastric cytoprotection. Herbal agents with adaptogenic properties could be
worth exploring in this regard as some of these phytopharmaceutical agents used in traditional medicine have
been shown to exhibit gastric cytoprotection as part of their anti-stress profile. Further, their interactions with
brain neurotransmitters and immune mechanisms and their relative safety could make them prospective leads for
stress ulcer prophylaxis and treatment.