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Alterations of colonic sensitivity and gastric dysmotility after acute cisplatin and granisetron
(Wiley Online Library, 2018-11-06) Marta Martin‐Ruíz; Uranga, Jose Antonio; Paula Mosinska; Jakub Fichna; Kulmira Nurgali; Mª Isabel Martín‐Fontelles; Abalo, Raquel
Background: Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5‐HT3 antagonist, is clinically used to prevent chemotherapy‐induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known. Methods: Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg−1)/vehicle and cisplatin (6 mg kg−1)/vehicle. Thereafter, nausea‐like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle. Key Results: Cisplatin‐induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination. Conclusions and Inferences: Cisplatin‐induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5‐HT3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation.
Alterations of the small intestinal wall and motor function after repeated cisplatin in the rat.
(Wiley Online Library, 2017-06-08) Uranga, Jose Antonio; García-Martínez, Jose Manuel; García-Jiménez, Custodia; Vera, Gema; Martín-Fontelles, Isabel; Abalo, Raquel
Background. Gastrointestinal adverse effects occurring during cancer chemotherapy are well known and feared; those persisting once treatment has finished are relatively unknown. We characterized the alterations occurring in the rat small intestine, after repeated treatment with cisplatin. Methods: Male Wistar rats received saline or cisplatin (2 mg kg-1 week-1, for 5 weeks, ip). Gastric motor function was studied non-invasively throughout treatment (W1-W5) and one week after treatment finalization (W6). During W6, upper gastrointestinal motility was also invasively studied and small intestinal samples were collected for histopathological and molecular studies. Structural alterations of the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. PAS staining and immunohistochemistry for Ki-67, chromogranin A and neuronal specific enolase (NSE) were used to detect secretory, proliferating, endocrine and neural cells, respectively. The expression of different markers in the tunica muscularis was analyzed by RT/qPCR. Key results: Repeated cisplatin induced motility alterations during and after treatment. After treatment (W6), the small intestinal wall showed histopathological alterations in most parameters measured, including a reduction in the thickness of circular and longitudinal muscle layers. Expression of c-KIT (for interstitial cells of Cajal, ICC), nNOS (for inhibitory motor neurons), pChAT and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent). Conclusions and inferences: Repeated cisplatin induces relatively long-lasting gut dysmotility in the rat associated to important histopathological and molecular alterations of the small intestinal wall. In cancer survivors, the possible chemotherapy-induced histopathological, molecular and functional intestinal sequelae should be evaluated.
An Assessment of the Bioactivity of Coffee Silverskin Melanoidins.
(MDPI, 2019-02-12) Tores de la Cruz, Silvia; Iriondo-DeHond, Amaia; Herrera, T; Lopez-Tofiño, Yolanda; Galvez-Robleño, Carlos; Prodanov, Marin; Velazquez-Escobar, F; Abalo, Raquel; del Castillo, Maria Dolores
Melanoidins present in coffee silverskin, the only by-product of the roasting process, are formed via the Maillard reaction. The exact structure, biological properties, and mechanism of action of coffee silverskin melanoidins, remain unknown. This research work aimed to contribute to this novel knowledge. To achieve this goal, melanoidins were obtained from an aqueous extract of Arabica coffee silverskin (WO2013004873A1) and was isolated through ultrafiltration (>10 kDa). The isolation protocol was optimized and the chemical composition of the high molecular weight fraction (>10 kDa) was evaluated, by analyzing the content of protein, caffeine, chlorogenic acid, and the total dietary fiber. In addition, the structural analysis was performed by infrared spectroscopy. Antioxidant properties were studied in vitro and the fiber effect was studied in vivo, in healthy male Wistar rats. Melanoidins were administered to animals in the drinking water at a dose of 1 g/kg. At the fourth week of treatment, gastrointestinal motility was evaluated through non-invasive radiographic means. In conclusion, the isolation process was effective in obtaining a high molecular weight fraction, composed mainly of dietary fiber, including melanoidins, with in vitro antioxidant capacity and in vivo dietary fiber effects.
Antiproliferative and palliative activity of flavonoids in colorectal cancer
(Elsevier, 2021) Fernandez, Javier; Silván Ros, Blanca; Uranga, Jose Antonio; Entrialgo, Rodrigo; Villar, Claudio; Capasso, Raffaele; Lombo, Felipe; Abalo, Raquel
Flavonoids are plant bioactive compounds of great interest in nutrition and pharmacology, due to their remarkable properties as antioxidant, anti-inflammatory, antibacterial, antifungal and antitumor drugs. More than 5000 different flavonoids exist in nature, with a huge structural diversity and a plethora of interesting pharmacological properties. In this work, five flavonoids were tested for their potential use as antitumor drugs against three CRC cell lines (HCT116, HT-29 and T84). These cell lines represent three different stages of this tumor, one of which is metastatic. Xanthohumol showed the best antitumor activity on the three cancer cell lines, even better than that of the clinical drug 5-fluorouracil (5-FU), although no synergistic effect was observed in the combination therapy with this drug. On the other hand, apigenin and luteolin displayed slightly lower antitumor activities on these cancer cell lines but showed a synergistic effect in combination with 5-FU in the case of HTC116, which is of potential clinical interest. Furthermore, a literature review highlighted that these flavonoids show very interesting palliative effects on clinical symptoms such as diarrhea, mucositis, neuropathic pain and others often associated with the chemotherapy treatment of CRC. Flavonoids could provide a double effect for the combination treatment, potentiating the antitumor effect of 5-FU, and simultaneously, preventing important side effects of 5-FU chemotherapy.
Bioaccesibility, Metabolism, and Excretion of Lipids Composing Spent Coffee Grounds
(MDPI, 2019-06-23) Iriondo, Amaia; Santillán, Fresia; Fernández-Gómez, Beatriz; Vera, Gema; Guisantes, Eduardo; Gómez, Sergio; San Andrés, Manuel Ignacio; Sanchez-Fortún, Sebastián; López Gómez, Laura; Uranga, Jose Antonio; Abalo, Raquel; del Castillo, Mª Dolores
The bioaccessibility, metabolism, and excretion of lipids composing spent coffee grounds (SCGs) were investigated. An analysis of mycotoxins and an acute toxicity study in rats were performed for safety evaluation. Total fat, fatty acids, and diterpenes (cafestol and kahweol) were determined in SCGs and their digests obtained in vitro. A pilot repeated intake study was carried out in Wistar rats using a dose of 1 g SCGs/kg b.w. for 28 days. Fat metabolism was evaluated by analysis of total fat, cholesterol, and histology in liver. The dietary fiber effect of SCGs was measured radiographically. The absence of mycotoxins and toxicity was reported in SCGs. A total of 77% of unsaturated fatty acids and low amounts of kahweol (7.09 _g/g) and cafestol (414.39 _g/g) were bioaccessible after in vitro digestion. A significantly lower (p < 0.1) accumulation of lipids in the liver and a higher excretion of these in feces was found in rats treated with SCGs for 28 days. No lipid droplets or liver damage were observed by histology. SCGs acutely accelerated intestinal motility in rats. SCGs might be considered a sustainable, safe, and healthy food ingredient with potential for preventing hepatic steatosis due to their effect as dietary fiber with a high fat-holding capacity.
Biological Treatments in Inflammatory Bowel Disease: A Complex Mix of Mechanisms and Actions
(MDPI, 2021-08-10) Ortega Moreno, Lorena; Fernández-Tomé, Samuel; Abalo, Raquel
Inflammatory bowel disease (IBD) is a chronic disease that requires lifelong medication and whose incidence is increasing over the world. There is currently no cure for IBD, and the current therapeutic objective is to control the inflammatory process. Approximately one third of treated patients do not respond to treatment and refractoriness to treatment is common. Therefore, pharmacological treatments, such as monoclonal antibodies, are urgently needed, and new treatment guidelines are regularly published. Due to the extremely important current role of biologics in the therapy of IBD, herein we have briefly reviewed the main biological treatments currently available. In addition, we have focused on the mechanisms of action of the most relevant groups of biological agents in IBD therapy, which are not completely clear but are undoubtfully important for understanding both their therapeutic efficacy and the adverse side effects they may have. Further studies are necessary to better understand the action mechanism of these drugs, which will in turn help us to understand how to improve their efficacy and safety. These studies will hopefully pave the path for a personalized medicine
Cannabinoid drugs against chemotherapy-induced adverse effects: focus on nausea/vomiting, peripheral neuropathy and chemofog in animal models.
(Wolters Kluwer Health, 2022-04) Bagues, Ana; López-Tofiño, Yolanda; Llorente-Berzal, Álvaro; Abalo, Raquel
Although new drugs are being developed for cancer treatment, classical chemotherapeutic agents are still front-line therapies, despite their frequent association with severe side effects that can hamper their use. Cannabinoids may prevent or palliate some of these side effects. The aim of the present study is to review the basic research which has been conducted evaluating the effects of cannabinoid drugs in the treatment of three important side effects induced by classical chemotherapeutic agents: nausea and vomiting, neuropathic pain and cognitive impairment. Several published studies have demonstrated that cannabinoids are useful in preventing and reducing the nausea, vomits and neuropathy induced by different chemotherapy regimens, though other side effects can occur, such as a reduction of gastrointestinal motility, along with psychotropic effects when using centrally-acting cannabinoids. Thus, peripherally-acting cannabinoids and new pharmacological options are being investigated, such as allosteric or biased agonists. Additionally, due to the increase in the survival of cancer patients, there are emerging data that demonstrate an important cognitive deterioration due to chemotherapy, and because the cannabinoid drugs have a neuroprotective effect, they could be useful in preventing chemotherapy-induced cognitive impairment (as demonstrated through studies in other neurological disorders), but this has not yet been tested. Thus, although cannabinoids seem a promising therapeutic approach in the treatment of different side effects induced by chemotherapeutic agents, future research will be necessary to find pharmacological options with a safer profile. Moreover, a new line of research awaits to be opened to elucidate their possible usefulness in preventing cognitive impairment.
Cannabinoid pharmacology and therapy in gut disorders
(2018) Uranga, Jose Antonio; Vera, Gema; Abalo, Raquel
Cannabis sp. and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases. After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system. This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies. To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche. This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).
Cannabinoid pharmacology and therapy in gut disorders
(Elsevier, 2018-08-02) Uranga Ocio, Jose Antonio; Vera, Gema; Abalo, Raquel
Cannabis sp. and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases. After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system. This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies. To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche. This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).
Cannabinoids to Fight Chemotherapy-Induced Adverse Effects
(Springer, 2023) Bagues, Ana; Benítez, David; Abalo, Raquel
One of the main causes of death around the world is cancer. Although the development of antitumor drugs has increased life expectancy in these patients during the past decades, chemotherapy is associated to acute and long-lasting impactful side effects. The endocannabinoid system is formed by the cannabinoid receptors CB1 and CB2, the endogenous agonists of these receptors, and all the enzymes necessary for the metabolism of the endocannabinoids. The wide distribution of the endocannabinoid system and its involvement in the modulation of a wide range of biological processes highlight the great therapeutic potential of cannabis and cannabinoids in many diseases, including gastrointestinal alterations, pain, cachexia, or cancer. To date, only a few cannabinoid agonists have been approved for different pathologies, although in relation to cancer, only oral capsules and solutions based on synthetic analogues of Δ9-tetrahydrocannabinol have been approved for the treatment of chemotherapy-induced nausea and vomiting. Despite the vast positive results obtained from animal studies regarding the usefulness of cannabinoids to reduce other symptoms related to cancer and its treatment, such as neuropathic pain or cachexia, conflicting evidence exists in the clinical setting, due, mainly, to the lack of more high-quality clinical studies. Moreover, the psychotropic effects and immune suppression mediated by CB1 and CB2 agonists, respectively, arise safety concerns that need to be considered. In conclusion, although strategies aimed at modulating the endocannabinoid system can play a pivotal role in the treatment of different side effects associated to cancer chemotherapy, future studies will be needed to confirm their effectiveness and safety in the clinical setting.
Changes in Fatty Acid Dietary Profile Affect the Brain-Gut Axis Functions of Healthy Young Adult Rats in a Sex-Dependent Manner.
(Nutrients, 2021) Jacenik, Damian; Bagüés, Ana; López - Gómez, Laura; López - Tofiño, Yolanda; Iriondo-DeHond, Amaia; Serra, C; Banovcanová, L; Gálvez-Robleño, Carlos; Fichna, Jakub; Del Castillo, Maria Dolores; Uranga, Jose Antonio; Abalo, Raquel
Dietary modifications, including those affecting dietary fat and its fatty acid (FA) composition, may be involved in the development of brain-gut axis disorders, with different manifestations in males and females. Our aim was to evaluate the impact of three purified diets with different FA composition on the brain-gut axis in rats of both sexes. Male and female Wistar rats fed a cereal-based standard diet from weaning were used. At young adult age (2-3 months old), animals were divided into three groups and treated each with a different refined diet for 6 weeks: a control group fed on AIN-93G diet containing 7% soy oil (SOY), and two groups fed on AIN-93G modified diets with 3.5% soy oil replaced by 3.5% coconut oil (COCO) or 3.5% evening primrose oil (EP). Different brain-gut axis parameters were evaluated during 4-6 weeks of dietary intervention. Compared with SOY diet (14% saturated FAs, and 58% polyunsaturated FAs), COCO diet (52.2% saturated FAs and 30% polyunsaturated FAs) produced no changes in brain functions and minor gastrointestinal modifications, whereas EP diet (11.1% saturated FAs and 70.56% polyunsaturated FAs) tended to decrease self-care behavior and colonic propulsion in males, and significantly increased exploratory behavior, accelerated gastrointestinal transit, and decreased cecum and fecal pellet density in females. Changes in FA composition, particularly an increase in ω-6 polyunsaturated FAs, seem to facilitate the development of brain-gut axis alterations in a sex-dependent manner, with a relatively higher risk in females.
Changes in the diet composition of fatty acids and fiber affect the lower gastrointestinal motility but have no impact on cardiovascular parameters: In vivo and in vitro studies
(Wiley Online Library, 2019-05-30) Paula Mosińska; Marta Martin‐Ruiz; Antonio González; López Miranda, Visitación; Herradón, Esperanza; Uranga, Jose Antonio; Vera, Gema; Adrián Sanchez‐Yáñez; Mª Isabel Martin‐Fontelles; Jakub Fichna; Abalo, Raquel
Background: Food and diet are central issues for proper functioning of the cardiovascular (CV) system and gastrointestinal (GI) tract. We hypothesize that different types of dietary FAs affect CV parameters as well as GI motor function and visceral sensitivity. Methods: Male Wistar rats were fed with control diet (CTRL), diet supplemented with 7% soybean oil (SOY), SOY + 3.5% virgin coconut oil (COCO), and SOY + 3.5% evening primrose oil (EP) for 4 weeks. The content of insoluble fiber in CTRL was higher than in SOY, COCO, or EP. Body weight gain and food/water intake were measured. At day 28, biometric, biochemical, CV parameters, GI motor function (X‐ray and colon bead expulsion test), and visceral sensitivity were evaluated. Changes in propulsive colonic activity were determined in vitro. The colon and adipose tissue were histologically studied; the number of mast cells (MCs) in the colon was calculated. Results: SOY, COCO, and EP had increased body weight gain but decreased food intake vs CTRL. Water consumption, biometric, biochemical, and CV parameters were comparable between groups. SOY increased the sensitivity to colonic distention. All groups maintained regular propulsive neurogenic contractions; EP delayed colonic motility (P < 0.01). SOY, COCO, and EP displayed decreased size of the cecum, lower number and size of fecal pellets, and higher infiltration of MCs to the colon (P < 0.001). Conclusions and Inferences: Dietary FAs supplementation and lower intake of insoluble fiber can induce changes in the motility of the lower GI tract, in vivo and in vitro, but CV function and visceral sensitivity are not generally affected.
Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy
(Elsevier, 2012) Vera, Gema; Cabezos, Pablo Antonio; Martín, María Isabel; Abalo, Raquel
Clinical use of antineoplastic drugs is associated with the development of numerous adverse effects that many patients find intolerable, including peripheral neuropathy. Cannabinoids have relieved neuropathic pain in different animal models. But their therapeutic activities could be affected by their psychoactive properties. The aim of this work was to determine the effect of cannabinoids in cisplatin-evoked neuropathy. For this purpose, the non-selective agonist WIN55,212-2 (WIN), the CB1-selective agonist ACEA or the CB2-selective agonist JWH133 (or their vehicle)was either systemically administered at a non-psychoactive dose or locally injected in cisplatin-treated rats. Selective CB1 and CB2 cannabinoid antagonists (AM251 and SR144528, respectively)were used to characterize cannabinoid effects. Cisplatin-treated rats showed mechanical allodynia but not thermal hyperalgesia. Cannabinoid agonists alleviated mechanical allodynia. This effect was mediated by both CB1 and CB2 cannabinoid receptors when the cannabinoid was systemically applied. At the dose used, cannabinoid agonists had no psychoactive effect. The local effect of the drug involved the activation of peripheral CB1 receptors whereas involvement of CB2 receptors was less clear. In a rat model of cisplatin-induced neuropathy, cannabinoids have an antinociceptive effect, but the cannabinoid receptors involved could be different depending on the route of administration. Non-psychoactive doses of cannabinoid agonists are capable of alleviating the signs of peripheral neuropathy when systemically applied. Interestingly, local administration of selective CB1 agonists or systemic administration of CB2 agonists, which are non-psychoactive, may serve as new therapeutic alternatives for symptom management in painful neuropathy associated with cisplatin treatment.
Characterization of cannabinoid-induced relief of neuropathic pain in rat models of type 1 and type 2 diabetes
(Elsevier, 2012) Vera, Gema; López-Miranda, Visitación; Herradón, Esperanza; Martín, María Isabel; Abalo, Raquel
Diabetic neuropathy is a frequent complication of diabetes mellituswith a tremendous impact on patients' quality of life, and it remains poorly treated. Cannabinoids relieve the signs of diabetic neuropathy in different experimental models, including streptozotocin- (STZ-) induced type 1 diabetic rodents, and they may also relieve neuropathic signs in type 2 diabetic animals. This study compares the effect of the non-selective cannabinoid agonist WIN 55,212-2 (WIN) in Zucker Diabetic Fatty (ZDF) rats (type 2 diabetes) and in STZ-injected Wistar rats (type 1 diabetes). WIN (or its vehicle) was either systemically administered at a non-psychoactive dose or locally injected. Selective CB1 and CB2 cannabinoid antagonists were used to characterize WIN antineuropathic effects. Both type 1 and type 2 diabetic rats showed mechanical allodynia but not thermal hyperalgesia. WIN alleviated mechanical allodynia in both models of diabetes. In STZ-treated rats, both cannabinoid receptors were involved, whereas in ZDF rats, WIN effects seemed to mainly involve the activation of CB1 receptors. Higher doses of WIN were needed to significantly relieve mechanical allodynia upon intraplantar administration in ZDF vs. STZ-injected rats. Cannabinoids, acting on systemic and/or peripheral receptors, may serve as a new therapeutic alternative for symptom management in painful neuropathy associated with both type 1 and type 2 diabetes. Additionally, our results highlight the need for appropriate selection of diabetic experimental models because the results from studies in STZ-induced diabetic rodents might not be applicable in all diabetic situations.
Content Validity of the Spanish Adaptation of the Premature Infant Pain Profile Revised
(Elsevier, 2023) Núñez-López, Irene; Cid-Expósito, María-Gema; Abalo, Raquel; Serrano-Gutiérrez, Ana; Jiménez-Fernández, Lucía; Collados-Gómez, Laura
Background: To the best of our knowledge, there are no validated neonatal pain assessment scales in Spanish. Given the need for such a scale, a study was undertaken to adapt and validate the Premature Infant Pain Profile-Revised (PIPP-R) scale. After translation and back-translation, content validity was addressed, a crucial phase in validation studies, in which researchers examine whether the items that make up the scale represent the content that the scale is intended to assess. Aims: The aim was to provide evidence for the content validity of the Spanish adaptation of the PIPP-R scale. Method: The study used the Delphi technique with 10 experts. Data collection was anonymous and was conducted through an online platform. It was an ad hoc survey consisting of four questions, with a fivepoint Likert scale for each item on the scale and for the instruction table. An item-content validity index (I-CVI) and a scale-content validity index (S-CVI) were calculated for the analysis. Results: After two rounds of the survey, all items exceeded an I-CVI of 0.9. The S-CVI value was 0.98 (±0.03) for the scale, and 1 for its instruction table. The kappa index yielded values indicating an excellent degree of agreement. Conclusions: The Spanish version of the PIPP-R obtained a high degree of content validity according to the expert group and the Delphi technique
Contractility of isolated colonic smooth muscle strips from rats treated with cancer chemotherapy: differential effects of cisplatin and vincristine.
(Frontiers Media, 2023-12-18) López-Tofiño, Yolanda; Barragán Del Caz, Luis Felipe; Benítez-Álvarez, David; Molero-Mateo, Paula; Nurgali, Kulmira; Vera, Gema; Bagües, Ana; Abalo, Raquel
Background: Certain antineoplastic drugs cause gastrointestinal disorders even after the end of treatment. Enteric neuropathy has been associated with some of these alterations. Our goal was to assess the impact of repeated treatment with cisplatin and vincristine on the contractility of circular and longitudinal muscle strips isolated from the rat colon. Methods: Two cohorts of male rats were used: in cohort 1, rats received one intraperitoneal (ip) injection of saline or cisplatin (2 mg kg-1 week-1) on the first day of weeks 1-5; in cohort 2, rats received two cycles of five daily ip injections (Monday to Friday, weeks 1-2) of saline or vincristine (0.1 mg kg-1 day-1). Body weight and food and water intake were monitored throughout the study. One week after treatment, responses of colonic smooth muscle strips to acetylcholine (10-9-10-5 M) and electrical field stimulation (EFS, 0.1-20 Hz), before and after atropine (10-6 M), were evaluated in an organ bath. Results: Both drugs decreased body weight gain. Compared to saline, cisplatin significantly decreased responses of both longitudinal and circular smooth muscle strips to EFS, whereas vincristine tended to increase them, although in a non-significant manner. No differences were observed in the muscle response to acetylcholine. Atropine abolished the contractile responses induced by acetylcholine, although those induced by EFS were only partially reduced in the presence of atropine. Conclusion: The findings suggest that although both drugs cause the development of enteric neuropathy, this seems to have a functional impact only in cisplatin-treated animals. Understanding the effects of chemotherapy on gastrointestinal motor function is vital for enhancing the quality of life of cancer patients.
Cultural Adaptation and Validation of the Premature Infant Pain Profile-Revised (PIPP-R) Pain Measurement Scale: Research Protocol
(MDPI, 2022-09-28) Núñez-López, Irene; Collados-Gómez, Laura; Abalo, Raquel; Martínez-Pérez, Patricia; Moreno-Vicente, Álvaro; Cid-Expósito, María-Gema
Introduction: The main objective of this study is to validate the PIPP-R scale (Premature Infant Pain Profile-Revised) for measuring neonatal pain in the Spanish hospital setting. Materials and Methods: The original scale will be translated from English into Spanish and a consensus translation will be prepared by the research team, which will be back-translated from Spanish into English. The content validity of the Spanish version of the scale will be measured using the Delphi method. Subsequently, a multicenter observational study will be conducted to assess construct validity, internal consistency, and intra-observer and inter-observer agreement. Pain will be assessed by comparing scores for a specific non-painful procedure with those for a specific painful procedure. The sample will include 300 subjects in intensive care and intermediate care units, who will be equally distributed among the participating hospitals. The subjects will be stratified into three groups by gestational age. Discussion: The original version of the PIPP-R scale is useful for objectively assessing neonatal acute and procedural pain from a gestational age of 25 weeks and over. It is important to culturally adapt the original validated scale and to test its validity and reliability in the Spanish healthcare context. The results of this study may represent significant progress in pain management.
Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats
(Wiley Online Library, 2015-08-24) López Miranda, Visitación; Soto Montenegro, M Luisa; Uranga, Jose Antonio; Vera, Gema; Herradón, Esperanza; González, Cristina; Blas, C; MARTINEZ-VILLALUENGA, M; LOPEZ-PEREZ, Ana Esther; Desco, Manuel; Abalo, Raquel
Background Monosodium glutamate (MSG) is a flavor- enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. Methods Two groups of adult male Wistar rats were used: control and treated with MSG (4 g/L in drinking water) for 6 weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. Key Results Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. Conclusions & Inferences Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research.
Effects of Commercial Probiotics on Colonic Sensitivity after Acute Mucosal Irritation
(MDPI, 2022-05-26) López-Gómez, Laura; Antón, Jaime; López-Tofiño, Yolanda; Pomana, Bianca; Uranga, Jose Antonio; Abalo, Raquel
Gastrointestinal pathologies associated with abdominal pain, such as irritable bowel syndrome or inflammatory bowel disease, lack sufficiently effective treatments. In our study we have used a rat model of visceral pain (72 animals; n = 8-13 per experimental group) to analyze the consequences of intracolonic administration of the irritant acetic acid on visceral sensitivity, histology of the colonic wall, and inflammatory response. Moreover, we have studied the possible beneficial effects of a pretreatment with a commercial probiotic (Actimel®). Contrary to expectations, acetic acid application (7 cm proximal to the anus) decreased the nociceptive response to intracolonic mechanical stimulation, with a slight increase in the histological damage of colonic mucosa. The intensity of these changes depended on the concentration (4% or 0.6%) and the time of application (30 or 60 min). Pretreatment with probiotics (by daily gavage, for 1 week) normalized the values obtained in the visceral sensitivity test but revealed an increase in the number of macrophages. These results suggest a possible activation of inhibitory mechanisms early after colonic irritation, not previously described (which need further experimental confirmation), and the ability of probiotics to normalize the effects of acetic acid. In addition, pretreatment with probiotics has a direct effect on immune functions, stimulating macrophagic activity.
Effects of the food additive monosodium glutamate on cisplatin-induced gastrointestinal dysmotility and peripheral neuropathy in the rat
(Wiley Online Library, 2020-10-28) Yolanda López-Tofiño; Vera, Gema; López Gómez, Laura; Girón, Rocío; Nurgali, Kulmira; Uranga, Jose Antonio; Abalo, Raquel
Background: Cisplatin is an antineoplastic drug known to produce intense vomiting, gastric dysmotility, and peripheral neuropathy. Monosodium glutamate (MSG) is a flavor enhancer with prokinetic properties potentially useful for cancer patients under chemotherapy. Our aim was to test whether MSG may improve gastrointestinal motor dysfunction and other adverse effects induced by repeated cisplatin in rats. Methods: Male Wistar rats were exposed or not to MSG (4 g L−1) in drinking water from week 0 to 1 week after treatment. On the first day of weeks 1–5, rats were treated with saline or cisplatin (2 mg kg−1 week−1, ip). Gastrointestinal motility was measured by radiological methods after first and fifth administrations, as well as 1 week after treatment finalization. One week after treatment, the threshold for mechanical somatic sensitivity was recorded. Finally, samples of stomach, terminal ileum and kidneys were evaluated in sections using conventional histology. The myenteric plexus was immunohistochemically evaluated on distal colon whole-mount preparations. Key Results: Monosodium glutamate prevented the development of cisplatin-induced neuropathy and partially improved intestinal transit after the fifth cisplatin administration with little impact on gastric dysmotility. MSG did not improve the histological damage of gut wall, but prevented the changes induced by cisplatin in the colonic myenteric plexus. Conclusion and Inferences: Our results suggest that MSG can improve some dysfunctions caused by anticancer chemotherapy in the gut and other systems, associated, at least partially, with neuroprotectant effects. The potentially useful adjuvant role of this food additive to reduce chemotherapy-induced sequelae warrants further evaluation.

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