Ludmila P. Filaretova

Previously, we demonstrated that administration of dexamethasone (Dex) at a dose of 1 mg/kg, 24 h before an ulcerogenic stimulus exerts a pro-ulcerogenic effect, accompanied by disturbances in carbohydrate metabolism. In the present study, we examined the influence of housing conditions - standard conditions (SC), social isolation (SI), and environmental enrichment (EE) conditions - on the Dex-induced changes in carbohydrate metabolism, as well as on hematological parameters. Experiments were conducted with male rats during the winter period. Starting from the age of 30 days, the animals were housed for 6 weeks under SC, SI, or EE conditions. Dex (1 mg/kg, intraperitoneal) or its vehicle (control) was administered 24 h prior to the glucose tolerance test (GTT), after which food was removed. Following the GTT, indomethacin (IM) was administered at an ulcerogenic dose; 4 h later, the rats were decapitated, and blood samples were collected to assess corticosterone levels and hematological parameters, including calculation of the neutrophil-to-lymphocyte ratio (NLR). Alongside the IM administration experiment, a control experiment including vehicle administration was performed according to the same protocol, in which the vehicle of IM was administered instead of IM itself. Administration of glucose during the GTT led to the increase in the blood glucose levels, reaching maximum (peak) at 30 min in all control, previously fasted animals (SC, SI, EE groups). Beginning at 60 min, the glucose levels gradually declined in all control groups, returning to the baseline only in the control rats from the EE group. In the rats maintained under SC conditions, pretreatment with Dex resulted in the reduction in the peak of the glycemic curve, accompanied by the corresponding decrease in the area under the curve (AUC) and reduced rate of decline in the blood glucose levels compared with the respective control group. In the rats housed under EE condition, resistance to the effects of Dex was observed, as evidenced by the absence of changes in the glycemic curve peak, AUC, or rate of decline in the blood glucose levels relative to the corresponding control group. The control rats from the SI group exhibited lower values of the glycemic curve peak, AUC, and rate of decline in the blood glucose levels than the rats from the SC and EE groups. Administration of Dex did not produce any further changes in these parameters. Dex administration induced a marked increase in the NLR in all groups (SC, SI, and EE), both in the rats treated with IM and in the animals receiving its vehicle. Taken together, these findings indicate that a single administration of Dex (1 mg/kg; 24 h after injection) to the rats from the SC group could alter glycemic response and increase NLR. Housing under EE conditions prevents the Dex-induced changes in the glycemic curve.

—According to the results of our research glucocorticoids produced in response to ulcerogenic stress stimuli are gastroprotective factors. The aim of this review article is to demonstrate, through the analysis of data obtained in our studies, that the inhibition of glucocorticoid synthesis by metyrapone can be an adequate and valuable approach for studying the contribution of glucocorticoids, produced during acute activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, to gastroprotection in rats. When studying the contribution of glucocorticoids produced in response to moderate, normally non-ulcerogenic stressors or to the administration of the corticotropin-releasing factor (CRF) to gastroprotection, it was shown that the suppression of synthesis of these hormones by metyrapone leads to (1) the transformation of normally non-ulcerogenic stimuli into ulcerogenic ones; (2) the elimination of the gastroprotective effect of stress preconditioning; (3) the elimination of the gastroprotective effect of CRF. The effects of metyrapone were reproduced under conditions of suppressed glucocorticoid production using the selective CRF-1 receptor antagonist NBI 27914 and the blockage of glucocorticoid receptors with their antagonist RU38486. The data presented suggest that (a) glucocorticoids produced in response to moderate stress stimuli contribute to the protection of the gastric mucosa under these conditions and increase its resistance to subsequent ulcerogenic stimuli (i.e., they contribute to the gastroprotective effect of stress preconditioning); (b) glucocorticoids produced in response to CRF administration participate in the realization of its gastroprotective action. The data obtained confirm that the activation of the HPA axis is a gastroprotective component of stress response, and stress-produced glucocorticoids are important gastroprotective factors.

The aim of the study was to investigate the effects of rat housing conditions—standard conditions, social isolation, environmental enrichment—and the subsequent reversal of these conditions on the vulnerability of the gastric mucosa to ulcerogenic stimuli, somatic pain sensitivity, and treadmill work capacity. Rats, aged 30 days, were placed in standard conditions (SC), social isolation (Is), and environmental enrichment (EE) for 4 weeks. Then half of each group underwent a reversal of housing conditions: SC rats were moved to Is, Is rats were placed in EE, EE rats were moved to Is, for 2 weeks. The other half served as a control with no change in their initial housing. Two weeks after the reversal, vulnerability of the gastric mucosa to ulcerogenic action of indomethacin (IM, 35 mg/kg, sc), somatic pain sensitivity (hot plate test), and work capacity (measured by the running distance on a treadmill) were assessed in control and reversed groups. Social isolation induced a proulcerogenic effect, increasing IM-induced gastric erosions, which was effectively reversed when rats were transferred to an environmental enrichment. Conversely, transferring rats from an environmental enrichment to social isolation exacerbated ulcerogenic action of IM. Somatic pain sensitivity and treadmill work capacity were also influenced by housing conditions, with environmental enrichment showing positive effects. The present findings show that social isolation of rats induces a proulcerogenic effect. Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and increases resilience to pain stimuli and treadmill work capacity.

—Corticotropin-releasing factor (CRF) and capsaicin-sensitive afferent neurons with efferent-like function (CSN) make an important contribution to the regulation of the functions of the gastrointestinal tract (GIT) and gastroprotection. The aim of the review was to analyze the data of literature, including the results of our own studies on the interaction of CRF and CSN in the gastroprotection and regulation of the functions of the gastrointestinal tract, with a focus on their most studied interaction in the regulation of the motor function of the gastrointestinal tract. Based on the results obtained by the authors of the review, the contribution of CSN to the implementation of the gastroprotective effect of CRF and, conversely, the participation of CRF in the gastroprotective effect of capsacin, which activates CSN, is discussed. The contribution of glucocorticoid hormones to the implementation of the gastroprotective action of CRF and the compensatory gastroprotective role of these hormones under conditions of shutdown of CSN functioning are considered.

The paraventricular nucleus (PVN) of the hypothalamus is recognized as the main source of corticotropin-releasing factor (CRF) in the pituitary portal system. CRF plays a key role in the stress response by activating the hypothalamic–pituitary–adrenocortical (HPA) axis through a cascade of events culminating in the release of glucocorticoid hormones into the blood. Several mechanisms are involved in the control of HPA axis activation, including its feedback inhibition regarded as an important regulatory mechanism of glucocorticoid hormone production. In addition to adaptive physiological responses, varied somatic and mental disorders can develop in response to stress, including acute gastric mucosal lesions, erosions and ulcers. Stress activates both ulcerogenic and protective mechanisms of the gastric mucosa. The review was conceived to demonstrate how an endocrinological approach to gastroenterological problems contributed to elucidating the role of the HPA axis in regulating the maintenance of gastric mucosal integrity and thus led to new insights. Our findings on the role of the hypothalamic PVN in HPA axis activation and feedback inhibition paved the way for experimental studies, which showed that HPA axis activation is a gastroprotective component of the stress response, while glucocorticoid hormones produced in response to stress act as gastroprotective, not ulcerogenic, factors, as has been commonly believed. These data allowed suggesting that glucocorticoid hormones may also be involved in the gastroprotective effect of CRF, and our further studies confirmed that exogenous CRF is able to protect the gastric mucosa from both stress- and indomethacin-induced damage due to the involvement of glucocorticoid hormones. Taken together, these data provide a convincing argument in favor of the gastroprotective role of HPA axis activation.

Remote ischemic preconditioning (RIPC) is one of the most effective approaches to attenuate tissue injury caused by severe ischemia-reperfusion (I/R). Experimental studies have demonstrated that RIPC is capable of producing a protective effect not only on heart, but also on brain, lungs, kidneys, liver, intestine, and stomach. We previously demonstrated that glucocorticoids participate in protective effect of local gastric ischemic preconditioning against I/R-induced gastric injury. In the present study we investigated whether RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids. Anesthetized fasted Sprague Dawley male rats were exposed to prolonged gastric I/R (30 min occlusion of celiac artery followed by 3 h of reperfusion) alone or with preliminary brief RIPC (10 min non-invasive occlusion of right hind limb blood flow followed by reperfusion for 30 min). First, we investigated the effect of RIPC on I/R-induced injury by itself. Then to study the role of glucocorticoids similar experiments were carried out: 1) in rats pretreated with the inhibitor of glucocorticoid synthesis, metyrapone (30 mg/kg, i.p), and in control animals; 2) in adrenalectomized rats without or with corticosterone replacement (4 mg/kg, s.c.) and in sham-operated animals; 3) in rats pretreated with glucocorticoid receptor antagonist RU-38486 (20 mg/kg, s.c.) and in control animals. I/R induced corticosterone rise and resulted in the gastric erosion formation. RIPC significantly reduced the erosion area in control animals. Metyrapone injected shortly before RIPC caused a decrease in plasma corticosterone levels and prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. Adrenalectomy performed 1 week before experiment created long-lasting corticosterone deficiency and had no effect on the gastroprotective effect of RIPC. Nevertheless, corticosterone replacement which mimics the corticosterone rise, similar to RIPS, significantly reduced erosion areas of gastric mucosa in adrenalectomized rats supporting the role of glucocorticoids in gastroprotection. RU-38486, which occupied glucocorticoid receptors, similar to metyrapone prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. The results of the present study demonstrate for the first time that RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids.

The hypothalamic-pituitary-adrenocortical (HPA) system is a key hormonal branch of the brain-gut axis in stress and corticotropin-releasing hormone (CRH) is a principal stimulator of the HPA system. According to our finding activation of the HPA system has gastroprotective role in stress and CRH may protect the gastric mucosa against stress-induced injury through involvement of glucocorticoids. To extend this idea to indomethacin-induced gastric injury in the present work we studied whether CRH may protect the gastric mucosa against ulcerogenic action of indomethacin (IM) through involvement of glucocorticoids. CRH administration (1.25 mu g/kg and 2.5 mu g/kg, i.p.) markedly, dose-dependently, increased plasma corticosterone level and significantly, dose-dependently, suppressed the occurrence of gastric erosion induced by IM (35 mg/kg, s.c.) in conscious rats. To estimate the role of glucocorticoids in CRH-induced gastroprotection, the effect of CRH (1.25 mu g/kg) on the IM-induced gastric erosion was studied after acute reduction of corticosterone release by metyrapone (30 mg/kg, i.p., 30 min before CRH administration) or by CRH receptor type 1 antagonist NBI 27914 (10 mg/kg, i.p., 15 min before CRH administration) and also after occupation of glucocorticoid receptors by their antagonist RU-38486 (20 mg/kg, i.p., 2 h before CRH administration). The effects were compared with those in control rats without acute reduction of corticosterone release or occupation of glucocorticoid receptors. Both metyrapone and NBI 27914 injected shortly before CRH administration caused an inhibition of CRH-induced corticosterone response and prevented protective effect of CRH on the gastric mucosa against the IM-induced erosion. The gastroprotective effect of CRH was also eliminated by the pretreatment with glucocorticoid receptor antagonist RU-38486. The results obtained suggest that exogenous CRH may protect the gastric mucosa against IM-induced gastric injury through involvement of glucocorticoids.

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are widely used to reduce pain and inflammation. However, additional to analgesic and anti‐inflammatory effects, NSAIDs have adverse effects on the gastrointestinal tract due to inhibiting synthesis of prostaglandins that play a key role in the gastrointestinal protection. Previously we have shown that glucocorticoids exert compensatory gastroprotective action under circumstances of prostaglandin deficiency. We have also demonstrated that forced treadmill running is a natural stressor activating the hypothalamic‐pituitary‐adrenocortical (HPA) axis and moreover stressor that has a gastroprotective effect against ulcerogenic action of indomethacin (IM). Here we verify the hypothesis that glucocorticoids released during forced treadmill running are involved in its gastroprotective influence against ulcerogenic action of IM. The contribution of glucocorticoids to the gastroprotective effect of forced treadmill running was studied by using the inhibitor of glucocorticoid synthesis metyrapone. On a day of experiment preliminary fasted (24 h) rats were subjected forced running in treadmill (15 m/min at a 0 incline) for 30 min, then, they were given back in their cages and kept at room temperature for 1 h before the IM administration. Control animals were kept in their cages, but they were also given IM as ulcerogenic stimulus. Metyrapone (30 mg/kg, ip) or its vehicle was administered 30 min before the onset of treadmill session in running as well as control rats. IM‐induced gastric erosions were examined 4 h after IM administration. Plasma corticosterone levels as well as somatic pain sensitivity (tail flick test) were also measured before and after IM administration. A single treadmill running session by itself caused an elevation of plasma corticosterone levels suggesting the HPA axis activation and development of stress‐induced analgesia. Pretreatment with metyrapone eliminated corticosterone rise induced by treadmill running. A single treadmill running session 1 h before IM injection attenuated IM‐induced gastric erosions. Pretreatment with metyrapone not only prevented the gastroprotective effect of treadmill running but also aggravated the ulcerogenic action of IM. The data suggest that glucocorticoids released under forced treadmill running are involved in its gastroprotective effect against the ulcerogenic action of IM. Thus, forced treadmill running can increase the resilience of gastric mucosa to ulcerogenic action of IM through the mechanisms associated with glucocorticoids.