Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking adolescent rats. Focus on calcitonin gene-related peptide's brain levels.

Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.

Current evidence on the therapeutic use of fiber in irritable bowel syndrome.

INTRODUCTION: Patients with irritable bowel syndrome (IBS) frequently resort to natural products, or request doctors to prescribe them, to relieve their symptoms, due to the poor efficacy and tolerability of several traditional drugs. Products containing fiber are among the most used and their clinical efficacy is discussed here based on the most recent scientific evidence. AREAS COVERED: A literature search was carried out to identify the most significant publications in order to deal with the topics of the general characteristics of fibers and the scientific evidence underlying their therapeutic use, the properties of ispaghula husk and the mechanisms by which this product carries out its therapeutic actions. EXPERT OPINION: The most recent clinical guidelines on the management of IBS consider ispaghula husk, a product containing soluble fiber, as a reasonable first line therapy for IBS patients with symptoms. In contrast, products containing insoluble fibers, particularly wheat bran, do not appear to be useful in treating IBS symptoms. The clinical data on the use of prebiotics in IBS are still inconclusive. However, low daily amounts of fructo-oligosaccharides or ß-galacto-oligosaccharides (also known as trans-galacto-oligosaccharides) may be effective in improving IBS symptoms; further trials are needed to definitively establish their clinical usefulness.

Herbal medicinal products for inflammatory bowel disease: A focus on those assessed in double-blind randomised controlled trials.

Inflammatory bowel disease patients frequently use herbal products as complementary or alternative medicines to current pharmacotherapies and obtain information on them mainly from the internet, social media, or unlicensed practitioners. Clinicians should therefore take a more active role and become knowledgeable of the mechanisms of action and potential drug interactions of herbal medicines for which evidence of efficacy is available. The therapeutic efficacy and safety of several herbal medicines have been studied in double-blind randomised controlled trials (RCTs). Evidence of efficacy is available for Andrographis paniculata extract; curcumin; a combination of myrrh, extract of chamomile flower, and coffee charcoal; and the Chinese herbal medicines Fufangkushen colon-coated capsule and Xilei san in patients with ulcerative colitis; and Artemisia absinthium extract and Boswellia serrata resin extract in patients with Crohn's disease. However, most of this evidence comes from single small RCTs with short follow-up, and the long-term effects and safety of their use have not yet been established. Thus, our findings indicate that further appropriately sized RCTs are necessary prior to the recommended use of these herbal medicines in therapy. In the meantime, increasing awareness of their use, and potential drug interactions among physicians may help to reduce unwanted effects and adverse disease outcomes.

Probiotics, fibre and herbal medicinal products for functional and inflammatory bowel disorders.

Functional bowel disorders (FBD), mainly irritable bowel syndrome (IBS) and functional constipation (FC, also called chronic idiopathic constipation), are very common worldwide. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, although less common, has a strong impact on patients' quality of life, as well as being highly expensive for our healthcare. A definite cure for those disorders is still yet to come. Over the years, several therapeutic approaches complementary or alternative to traditional pharmacological treatments, including probiotics, prebiotics, synbiotics, fibre and herbal medicinal products, have been investigated for the management of both groups of diseases. However, most available studies are biased by several drawbacks, including small samples and poor methodological quality. Probiotics, in particular Saccharomyces boulardii and Lactobacilli (among which Lactobacillus rhamnosus), synbiotics, psyllium, and some herbal medicinal products, primarily peppermint oil, seem to be effective in ameliorating IBS symptoms. Synbiotics and fibre seem to be beneficial in FC patients. The probiotic combination VSL#3 may be effective in inducing remission in patients with mild-to-moderate ulcerative colitis, in whom Escherichia coli Nissle 1917 seems to be as effective as mesalamine in maintaining remission. No definite conclusions can be drawn as to the efficacy of fibre and herbal medicinal products in IBD patients due to the low number of studies and the lack of randomized controlled trials that replicate the results obtained in the individual studies conducted so far. Thus, further, well-designed studies are needed to address the real role of these therapeutic options in the management of both FBD and IBD. LINKED ARTICLES: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

Pharmacological methods for the preclinical assessment of therapeutics for OAB: an up-to-date review.

INTRODUCTION: Licenced oral pharmacotherapies for overactive bladder (OAB) act on muscarinic receptors or ß3-adrenoceptors. The search for new drugs to treat OAB that have novel mechanisms of action is very active, with the aim of discovering more effective and/or better tolerated agents. METHODS: A literature review of the most frequently used pharmacological methods for the preclinical assessment of new agents aimed at treating OAB, such as isolated organ technique, electrophysiological techniques, radioligand binding assay, and animal models, was carried out. Novel potential developments based on recent knowledge of urothelial and neural mechanisms are also discussed. RESULTS: The isolated organ technique, electrophysiological techniques, and the radioligand binding assay are very effective methods for the demonstration that a novel pharmacological target with a specific and high affinity binding site for a new drug is present in the bladder and its modulation regulates functions critical for the pathophysiology of OAB. Afterward, the new drug should be shown to be effective in animal models of OAB, although the translational value of these models is limited by a poor pathophysiological relationship with human OAB. Exciting novel perspectives focusing in particular on the theory of the mucosal-bladder network have recently opened new paths in the discovery and assessment of new therapeutics in this field. CONCLUSIONS: Available experimental models still play a central role in the appraisal of OAB therapeutics; however, their shortcomings and the paucity of very effective drugs indicate the need for new models that better reproduce the pathophysiological features of OAB. Some emerging lines of research show promise. A change of perspective in the future evaluation of putative drugs is required, especially in the light of the latest knowledge on the key role of the mucosal-bladder network and the brain-bladder neural pathways.

The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy.

Over the past recent years, a great number of studies have been directed toward the evaluation of the human host-gut microbiota interaction, with the goal to progress the understanding of the etiology of several complex diseases. Alterations in the intestinal microbiota associated with inflammatory bowel disease are well supported by literature data and have been widely accepted by the research community. The concomitant implementation of high-throughput sequencing techniques to analyze and characterize the composition of the intestinal microbiota has reinforced the view that inflammatory bowel disease results from altered interactions between gut microbes and the mucosal immune system and has raised the possibility that some form of modulation of the intestinal microbiota may constitute a potential therapeutic basis for the disease. The aim of this review is to describe the changes of gut microbiota in inflammatory bowel disease, focusing the attention on its involvement in the pathogenesis of the disease, and to review and discuss the therapeutic potential to modify the intestinal microbial population with antibiotics, probiotics, prebiotics, synbiotics and fecal microbiota transplantation.

Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders.

Protein conformational diseases, such as Alzheimer's, Parkinson's and Huntington's, affect a large portion of aging population. The pathogenic dysfunctional aggregation of proteins in non-native conformations is associated with metabolic derangements and excessive production of reactive oxygen species. Reduction of cellular expression and activity of antioxidant proteins result in increased oxidative stress. Free-radicals derived from mitochondrial dysfunction and from the cyclooxygenase enzyme activity play a role in oxidative damage of brain. Cyclooxygenase also mediates in neuro-inflammation by the production of pro-inflammatory prostaglandins which contribute to brain injury. The pathogenic role of cyclooxygenase has been demonstrated in Alzheimer and Parkinson diseases. The brain responses to detect and control diverse forms of stress are accomplished by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat shock proteins are a highly conserved system responsible for the preservation and repair of correct protein conformation. Heme oxygenase-1, a inducible and redox-regulated enzyme, is currently considered as having an important role in cellular antioxidant defense. A neuroprotective effect, due to its heme degrading activity, and tissue-specific pro-oxidant effects, due to its products CO and free iron, are under debate. There is a current interest in dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiology of Alzheimer disease, with a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, two powerful antioxidants, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, have emerged as strong inducers of the heat shock response. Food supplementation with curcumin and ferulic acid is considered a nutritional approach to reduce oxidative damage and amyloid pathology in Alzheimer disease.