Tatiana Bagaeva

Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats

Our previous investigations suggest that the reduction of stress-induced corticosterone release, or inhibition of corticosterone actions, promotes stress-induced gastric erosions in rats. In this study the effect of glucocorticoid deficiency on susceptibility to gastric mucosal injury by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated in rats. Gastric erosions induced in male rats by indomethacin (25 mg/kg sc) or acidified aspirin (40 mM po) were studied one week after adrenalectomy with or without corticosterone replacement or after occupation of glucocorticoid receptors by the antagonist RU-38486 during the period of erosion formation. Corticosterone for replacement (4 mg/kg sc) was injected 15 min before the administration of indomethacin or acidified aspirin to adrenalectomized rats. The antagonist RU-38486 (10 mg/kg po) was administered twice, 20 min before and 60 min after NSAID administration. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Indomethacin or acidified aspirin induced both plasma corticosterone rise and gastric erosions. Adrenalectomy decreased both basal and NSAID-induced corticosterone levels and markedly promoted gastric erosion formation caused by the NSAID. An acute corticosterone replacement mimicking indomethacin-and aspirin-induced corticosterone rise prevented the effect of adrenalectomy on the gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of gastric erosions induced by indomethacin as well as aspirin. These observations suggest a gastroprotective action of glucocorticoids released in response to NSAID treatment against NSAID-induced injury.

Gastroprotective action of glucocorticoids during the formation and the healing of indomethacin-induced gastric erosions in rats

The aim of the present study consisted of the investigation of glucocorticoid role in the formation and the healing of indomethacin-induced (25 mg/kg, s.c.) gastric erosions in rats. The effect of deficiency of glucocorticoid production followed by corticosterone replacement on the formation and the healing of the gastric erosions was evaluated. Glucocorticoid production was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg i.p.) injected 1 week before the onset of ulcerogenic stimulus. Indomethacin induced corticosterone rise and caused gastric erosions. The loss of indomethacin-induced plasma corticosterone rise potentiated the formation of indomethacin-induced erosions in both models. The area of gastric erosions in rats with glucocorticoid deficiency was considerably larger than that in control animals 4 h after indomethacin administration as well as during 48 h after the drug administration (period of erosion healing). Injecting corticosterone in rats with glucocorticoid deficiency significantly decreased the formation of indomethacin-induced gastric erosions and promoted their healing. Thus, the present data support the gastroprotective action of glucocorticoids in the formation and in the healing of indomethacin-induced mucosal injury.

Various ulcerogenic stimuli are potentiated by glucocorticoid deficiency in rats

The effects of glucocorticoid deficiency with or without corticosterone replacement on susceptibility to gastric mucosal injury by various ulcerogenic stimuli have been evaluated in rats. Gastric erosions were induced in male rats by stimuli of different modalities and intensities: 20% ethanol (po), aspirin (300 mg/kg, ip), acidified aspirin (40 mM, po) and 100% acetic acid (applied to gastric serosa). Glucocorticoid supply was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg, ip) injected one week before the onset of ulcerogenic stimulus. Corticosterone for replacement (4 mg/kg, sc) was injected in rats with glucocorticoid deficiency 15 min before the onset of ulcerogenic stimulus. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Ulcerogenic stimuli induced both plasma corticosterone rise and gastric mucosal injury. The area of mucosal damages induced various stimuli ranged from small to extensive. Glucocorticoid deficiency significantly potentiated an ulcerogenic action of every ulcerogenic stimulus. Replacing corticosterone prevented or significantly decreased erosion-potentiating effect of glucocorticoid deficiency. These results show that endogenous glucocorticoids released during ulcerogenic influences help gastric mucosa to resist a harmful action of both weak and strong ulcerogenic stimuli.

From Gastroprotective to Ulcerogenic Effects of Glucocorticoids: Role of Long-Term Glucocorticoid Action

Glucocorticoids may have dual action on the gastric mucosa: gastroprotective and ulcerogenic. In this article, we review the data which suggested that an initial action of endogenous glucocorticoids, including stress-produced ones as well as exogenous glucocorticoids is gastroprotective and consider possible mechanisms of the conversion of physiological gastroprotective action of glucocorticoid hormones to their pathological ulcerogenic effect.

Gastroprotective action of glucocorticoid hormones in rats with desensitization of capsaicin-sensitive sensory neurons

The ability of glucocorticoid hormones to protect gastric mucosa during desensitization of capsaicin-sensitive afferent neurons has been investigated in rats. Functional ablation of the afferent neurons was performed by pre-treatment with neurotoxic doses of capsaicin (100 mg/kg s.c.). After 1 week of recovery, capsaicin-desensitized, as well as control rats were adrenalectomized or shamoperated. Seven days later, indomethacin at an ulcerogenic dose (35 mg/kg s.c.) was given to each group of rats. One half of adrenalectomized capsaicin-pre-treated rats were injected by corticosterone for replacement (4 mg/kg s.c., 15 min before indomethacin). Gastric lesions, plasma corticosterone and blood glucose levels were estimated 4 h after indomethacin administration. Indomethacin caused gastric erosions that were aggravated by adrenalectomy or desensitization of capsaicinsensitive afferent neurons approximately with the same extension. Combination of adrenalectomy with the sensory desensitization profoundly potentiated the effect of sensory desensitization alone on indomethacin-induced gastric erosions: the mean gastric erosion area was increased approximately 10-fold. Corticosterone replacement completely prevented this profound effect of adrenalectomy. The results suggest a pivotal role of glucocorticoid hormones in the maintenance of gastric mucosal integrity in the case of impaired gastroprotective mechanisms provided by PGs and capsaicin-sensitive sensory neurons.

Compensatory gastroprotective role of glucocorticoid hormones during inhibition of prostaglandin and nitric oxide production and desensitization of capsaicin-sensitive sensory neurons

Abstract.Glucocorticoid hormones produced in response to various ulcerogenic stimuli contribute to the maintenance of the gastric mucosal integrity. The role of glucocorticoids in gastroprotection becomes especially important where there is deficiency of prostaglandins (PGs) or nitric oxide (NO) or desensitization of capsaicin-sensitive sensory neurons (CSN). It has been found that neither inhibition of PG or NO production nor desensitization of CSN by itself provokes damage in the gastric mucosa of rats with normal corticosterone levels. However, each of these treatments results in mucosal damage in adrenalectomized rats; this effect being prevented by corticosterone replacement. Indomethacin-induced gastric erosions are potentiated to similar degrees by adrenalectomy, inhibition of NO production or desensitization of CSN. The potentiation caused by inhibition of NO production or CSN desensitization is further enhanced by concomitant glucocorticoid deficiency. These results suggest a pivotal compensatory role of glucocorticoids in the maintenance of the gastric mucosal integrity under the adverse conditions where the gastroprotective mechanisms provided by PGs, NO and capsaicin-sensitive sensory neurons are impaired.

The Realization of the Brain-Gut Interactions with Corticotropin-Releasing Factor and Glucocorticoids

Background The brain and the gut interact bi-directionally through the brain-gut axis. The interaction is mediated by the autonomic nervous system and the hypothalamic-pituitary-adrenocortical (HPA) system. The first brilliant demonstration of the brain-gut interactions was the cephalic phase of gastric and pancreatic secretion discovered by Ivan Pavlov, the first physiologist who was awarded the Nobel Prize for Physiology or Medicine in 1904. This review aims to identify the HPA system as a key hormonal branch of the brain-gut axis in stress. Methods We first outlined main components of the brain-gut axis and then focused on the HPA system as a key hormonal branch of the brain-gut axis in stress. We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. Results Seventy-one articles were included in the review, the eleventh of them were articles of Filaretova L. and co-authors. We will discuss in our articles how an endocrinological approach to gastroenterological field can advance our understanding of the HPA axis role in regulation of gastric mucosal integrity and uncover new findings. According to these findings activation of the HPA system is gastroprotective component of the brain-gut axis in stress but not ulcerogenic one as it was generally accepted. Corticotropin-releasing factor (CRF) and glucocorticoids are important natural players provided gastroprotection. The results suggest that an initial action of endogenous glucocorticoids, including stress- and CRF-produced ones, as well as exogenous glucocorticoids, even used at pharmacological doses, is physiological gastroprotective. Prolongation of the hormonal action may lead to the transformation of gastroprotective hormonal effect to proulcerogenic one. Conclusion The findings of this review demonstrate that corticotropin-releasing factor and glucocorticoids contribute to the realization of the brain-gut interactions and that activation of the HPA system is gastroprotective component of this interaction in stress.

A stressz indukálta kortikoszteronszint-emelkedés fenntartja a gyomornyálkahártya integritását patkányok esetén, Stress-induced corticosterone rise maintain gastric mucosal integrity in rats

Background and purpose To investigate contribution of glucocorticoids to the maintenance of gastric mucosal integrity during stress we predominantly used ulcerogenic stress models. Using these models we demonstrated that glucocorticoids released in response to the ulcerogenic stimuli attenuated their harmful action on the gastric mucosa. In the present study we hypothesized that mild stressors does not damage the gastric mucosa due to gastroprotective action of glucocorticoids released in response to these stressors. Methods To verify the hypothesis the effects of normally non-ulcerogenic mild stimuli (15-30 min cold-restraint) on the gastric mucosal integrity have been studied under the circumstances of inhibition of the hypothalamic-pituitaryadrenocortical axis in rats. The hypothalamic-pituitary-adrenocortical axis was inhibited by: 1) fast inhibitory action of metyrapone, inhibitor glucocorticoid synthesis; 2) fast inhibitory action of NBI 27914, the selective antagonist of cortricotropin- releasing factor receptor type 1; 3) delayed inhibitory action of a single pharmacological dose of cortisol injected one week before the onset of stress stimulus. Results Each of these pretreatments significantly decreased 15-30 min cold-restraint-produced corticosterone levels: 37.2±1 vs 22.5±1.2 (p<0.05) after metyrapone; 52.1±0.9 vs 41.4±1 (p<0.05) after NBI, and 64.2±4.2 vs 16.7±1.5 (p<0.05) after cortisol pretreatment. The inhibition of stress-induced corticosterone rise resulted in an ap - pearance of gastric lesions after the onset of these mild stressors in rats. Conclusion The results suggest that in rats with inhibited stress-induced corticosterone rise normally non-ulcerogenic stimuli are transformed into ulcerogenic ones and confirm the hypothesis. The findings further support for the point of view that glucocorticoids released during acute stress are gastroprotective factors.

Optical properties of polaritons in excitonic layers in symmetric and asymmetric dielectric environment

Polaritonic excitations in a layer with strong excitonic response are theoretically studied. The dielectric function of the layer is assumed in the Lorentzian form with only one excitonic pole taken into account. The dispersion as well as optical absorption spectra of polaritonic excitations in such a layer are calculated. Both cases of symmetric and asymmetric dielectric environment of the excitonic layer are considered. Special attention is paid to so-called slow radiative polaritons excited in the total reflection regime. The problem of the impact of the higher polariton modes on optical spectra of the excitonic layer is addressed for the first time.