Botanical Drugs as an Emerging Strategy in Inflammatory Bowel Disease: A Review.

Crohn's disease and ulcerative colitis are the two most common categories of inflammatory bowel disease (IBD), which are characterized by chronic inflammation of the intestine that comprises the patients' life quality and requires sustained pharmacological and surgical treatments. Since their aetiology is not completely understood, nonfully efficient drugs have been developed and those that show effectiveness are not devoid of quite important adverse effects that impair their long-term use. Therefore, many patients try with some botanical drugs, which are safe and efficient after many years of use. However, it is necessary to properly evaluate these therapies to consider a new strategy for human IBD. In this report we have reviewed the main botanical drugs that have been assessed in clinical trials in human IBD and the mechanisms and the active compounds proposed for their beneficial effects.

Orexin A in the ventral tegmental area enhances saccharin-induced conditioned flavor preference: The role of D1 receptors in central nucleus of amygdala.

In industrialized societies, food intake is largely determined by its hedonic characteristics, which can be modified by our experience via taste learning. In this learning, the hedonic value of a neutral flavor changes after its association with a motivationally significant stimulus. Experiment 1 analyzes the effect of orexin administration (53 and 107 ng) in the ventral tegmental area (VTA) on hedonic intake through acquisition of a flavor-taste preference and a flavor-taste aversion. Accordingly, animals underwent four one-bottle acquisition sessions with unilateral application of orexin-A or saline in the VTA at 10 min before a 15-min flavor intake period. Preference and aversion were tested by a two-bottle test containing the flavors used for CS+ and CS-. Results indicate that intra-VTA orexin strengthens flavor-taste conditioned flavor preference (CFP) by saccharin but does not facilitate flavor-taste aversion induced by association of a neutral flavor with the unpalatable taste of quinine. Experiment 2 examines the acquisition of a flavor-taste preference after co-administration of an effective dose of orexin-A in the VTA and of D1-like dopamine receptor antagonist SCH23390 (6 and 12 nmol) in the central nucleus of the amygdala (CeA). SCH23390 impedes the CFP strengthening observed after intra-VTA orexin administration, indicating that this effect may be mediated by dopaminergic receptors in the CeA. These data suggest that the simultaneous presentation of a flavor and a hedonically positive taste may be detected by orexinergic neurons that activate dopamine-releasing neurons of the VTA, thereby reinforcing the positive signals required to develop a taste preference.

Role of anterior piriform cortex in the acquisition of conditioned flavour preference.

Flavour aversion learning (FAL) and conditioned flavour preference (CFP) facilitate animal survival and play a major role in food selection, but the neurobiological mechanisms involved are not completely understood. Neuroanatomical bases of CFP were examined by using Fos immunohistochemistry to record neuronal activity. Rats were trained over eight alternating one-bottle sessions to acquire a CFP induced by pairing a flavour with saccharin (grape was CS+ in Group 1; cherry in Group 2; in Group 3, grape/cherry in half of animals; Group 4, grape/cherry in water). Animals were offered the grape flavour on the day immediately after the training and their brains were processed for c-Fos. Neurons evidencing Fos-like immunoreactivity were counted in the infralimbic cortex, nucleus accumbens core, and anterior piriform cortex (aPC). Analysis showed a significantly larger number of activated cells after learning in the aPC alone, suggesting that the learning process might have produced a change in this cortical region. Ibotenic lesions in the aPC blocked flavour-taste preference but did not interrupt flavour-toxin FAL by LiCl. These data suggest that aPC cells may be involved in the formation of flavour preferences and that the integrity of this region may be specifically necessary for the acquisition of a CFP.

Anti-inflammatory effect of diosmectite in hapten-induced colitis in the rat.

1. Diosmectite is a natural silicate effectively used in the treatment of infectious diarrhoea. Its antidiarrhoeal properties involve adsorption of toxins and bacteria and modifications of the rheological characteristics of gastrointestinal mucus. Hence, the aim of this study was to test the intestinal anti-inflammatory activity of diosmectite. 2. Diosmectite (500 mg x kg(-1) day(-1), p.o.) was administered as a post-treatment to rats with chronic trinitrobenzene sulphonic acid colitis. Colonic status was checked 1 and 2 weeks after colitis induction by macroscopic, histological and biochemical examination. 3. Diosmectite post-treatment resulted in amelioration of the morphological signs (intestinal weight, macroscopic damage, necrosed area, histology) and biochemical markers (myeloperoxidase activity, glutathione levels, MUC2 expression, inducible nitric oxide synthase and interleukin-1beta (IL-1beta) and leukotriene B(4) synthesis), as well as in the reduction of the severity of diarrhoea. The effect of the clay was comparable to that of sulphasalazine (50 mg x kg(-1) day(-1)). 4. 5. Diosmectite exhibited a dose-dependent capacity to adsorb proteins in vitro as well as a dose-dependent inhibitory effect on the basolateral secretion of IL-8 by lipopolysaccharide (LPS)-stimulated HT29 cells. Diosmectite had a dose-dependent inhibitory effect on IL-1beta production by LPS-stimulated THP-1 cells. 6. The effect of diosmectite on MUC2 was post-transcriptional, since mRNA levels were unaffected. However, diosmectite is able to upregulate MUC2 mRNA levels in HT29-MTX cells. 7. Diosmectite has anti-inflammatory activity administered as a post-treatment. Possible mechanisms include adsorption of luminal antigens, increase of colonic mucin levels and possibly a direct modulatory action of cytokine production by mucosal cells.

Orexin-1 receptor antagonist in central nucleus of the amygdala attenuates the acquisition of flavor-taste preference in rats.

Previous studies demonstrated that the intracerebroventricular administration of SB-334867-A, a selective antagonist of orexin OX1R receptors, blocks the acquisition of saccharin-induced conditioned flavor preference (CFP) but not LiCl-induced taste aversion learning (TAL). Orexinergic fibers from the lateral hypothalamus end in the central nucleus of the amygdala (CeA), which expresses orexin OX1R receptors. Taste and sensory inputs also are present in CeA, which may contribute to the development of taste learning. This study analyzed the effect of two doses (1.5 and 6µg/0.5µl) of SB-334867-A administered into the CeA on flavor-taste preference induced by saccharin and on TAL induced by a single administration of LiCl (0.15M, 20ml/kg, i.p.). Outcomes indicate that inactivation of orexinergic receptors in the CeA attenuates flavor-taste preference in a two-bottle test (saccharin vs. water). Intra-amygdalar SB-334867-A does not affect gustatory processing or the preference for the sweet taste of saccharin given that SB-334867-A- and DMSO-treated groups (control animals) increased the intake of the saccharin-associated flavor across training acquisition sessions. Furthermore, SB-334867-A in the CeA does not block TAL acquisition ruling out the possibility that functional inactivation of OX1R receptors interferes with taste processing. Orexin receptors in the CeA appear to intervene in the association of a flavor with orosensory stimuli, e.g., a sweet and pleasant taste, but could be unnecessary when the association is established with visceral stimuli, e.g., lithium chloride. These data suggest that orexinergic projections to the CeA may contribute to the reinforcing signals facilitating the acquisition of taste learning and the change in hedonic evaluation of the taste, which would have important implications for the OX1R-targeted pharmacological treatment of eating disorders.

[Orexin: clinical and therapeutic implications]. / Orexina: implicaciones clínicas y terapéuticas.

INTRODUCTION. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. DEVELOPMENT. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. CONCLUSIONS. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction.

TITLE: Orexina: implicaciones clinicas y terapeuticas.Introduccion. Se ha descrito recientemente una nueva clase de neuropeptidos, las orexinas, tambien llamadas hipocretinas, producidos por un reducido grupo de neuronas hipotalamicas y cuyas acciones son mediadas por dos tipos de receptores, OX1R y OX2R. En concreto, las neuronas orexinergicas se han localizado en exclusiva en celulas de areas del hipotalamo lateral, dorsomedial y perifornical. A pesar de este origen anatomico tan localizado, las neuronas orexinergicas se proyectan ampliamente a numerosas regiones troncoencefalicas, corticales y limbicas. Desarrollo. Este patron difuso de distribucion de las fibras orexinergicas estaria indicando la intervencion de este sistema peptidico en una amplia variedad de funciones y, de hecho, se ha relacionado con los mecanismos que permiten la regulacion del ciclo sueño-vigilia, la ingesta de comida y de bebida y determinados aprendizajes como el aprendizaje de preferencias gustativas. Se ha sugerido tambien que la alteracion en el funcionamiento del sistema orexinergico explicaria la aparicion de determinados trastornos clinicos como la narcolepsia, la obesidad o la adiccion a drogas de abuso. Conclusiones. Nuevas investigaciones ayudaran a conocer el funcionamiento de las neuronas orexinergicas y la interaccion entre los sistemas que regulan la emocion, la homeostasis energetica y los mecanismos de recompensa con los sistemas que regulan el ciclo de sueño-vigilia. Se confia en que ese conocimiento permita desarrollar nuevos farmacos que, actuando sobre el sistema orexinergico, sean eficaces en el tratamiento de las alteraciones del sueño como el insomnio o la narcolepsia, de los trastornos de la alimentacion o de la drogadiccion.

SB-334867-A, a selective orexin-1 receptor antagonist, enhances taste aversion learning and blocks taste preference learning in rats.

Lateral hypothalamus (LH) has been proposed as a possible center for the anatomical convergence of gustatory and postingestive information relevant to taste aversion learning (TAL) and conditioned flavor preference (CFP). Orexin, a neuropeptide that mainly originates in neurons in lateral hypothalamic areas, was recently related to learning and memory processes. The present study was designed to analyze a possible relationship between the orexinergic system and taste learning. We studied the effect of intracerebroventricular administration of three doses (3, 6, and 12 µg/1 µl) of the selective orexin-1 receptor antagonist SB-334867-A on the acquisition of TAL induced by a single administration of LiCl. Infusion of SB-334867-A did not block this learning and appeared to enhance TAL in a two-bottle test. However, SB-334867-A (6 µg/1 µl) blocked taste preference learning when a flavor associated with saccharin (CS+) was offered on alternate days against a different flavor without saccharin (CS-), during three acquisition sessions. These results offer evidence of a relationship between the orexinergic system and taste learning; they tentatively suggest the possibility that endogenous orexin and gustatory and postingestive (visceral and oral) signals converge in brain areas relevant to the acquisition of taste learning.

Orexina: implicaciones clínicas y terapéuticas / Orexin: clinical and therapeutic implications

Introducción. Se ha descrito recientemente una nueva clase de neuropéptidos, las orexinas, también llamadas hipocretinas, producidos por un reducido grupo de neuronas hipotalámicas y cuyas acciones son mediadas por dos tipos de receptores, OX1R y OX2R. En concreto, las neuronas orexinérgicas se han localizado en exclusiva en células de áreas del hipotálamo lateral, dorsomedial y perifornical. A pesar de este origen anatómico tan localizado, las neuronas orexinérgicas se proyectan ampliamente a numerosas regiones troncoencefálicas, corticales y límbicas. Desarrollo. Este patrón difuso de distribución de las fibras orexinérgicas estaría indicando la intervención de este sistema peptídico en una amplia variedad de funciones y, de hecho, se ha relacionado con los mecanismos que permiten la regulación del ciclo sueño-vigilia, la ingesta de comida y de bebida y determinados aprendizajes como el aprendizaje de preferencias gustativas. Se ha sugerido también que la alteración en el funcionamiento del sistema orexinérgico explicaría la aparición de determinados trastornos clínicos como la narcolepsia, la obesidad o la adicción a drogas de abuso. Conclusiones. Nuevas investigaciones ayudarán a conocer el funcionamiento de las neuronas orexinérgicas y la interacción entre los sistemas que regulan la emoción, la homeostasis energética y los mecanismos de recompensa con los sistemas que regulan el ciclo de sueño-vigilia. Se confía en que ese conocimiento permita desarrollar nuevos fármacos que, actuando sobre el sistema orexinérgico, sean eficaces en el tratamiento de las alteraciones del sueño como el insomnio o la narcolepsia, de los trastornos de la alimentación o de la drogadicción (AU)

Introduction. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. Development. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. Conclusions. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction (AU)